Muscle biopsy for the diagnosis of ANCA-associated vasculitis: A case series and literature review

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In general, skin, kidney, upper airway and lower airway tissues are selected as biopsy targets. However, some patients present with few abnormalities in these major organs. Herein, we report three patients with AAV who presented with myalgia as a main symptom, with high C-reactive protein levels and a positive myeloperoxidase-ANCA test without elevated serum creatine kinase levels. All the patients underwent muscle magnetic resonance imaging and muscle biopsy (MB) to diagnose AAV. We also investigated peer-reviewed cases of AAV that were diagnosed by MB to confirm the efficacy of MB for AAV. Several retrospective studies have reported MB sensitivity to AAV and its predictors. We argue that an MB from the area where myalgia, muscle weakness, and abnormal MRI signals are present is useful for the diagnosis of AAV. ANCA-associated vasculitis muscle biopsy myopathy muscle vasculitis MRI Figures Figure 1 Introduction ANCA-associated vasculitis (AAV) is characterized by necrotizing vasculitis of small arteries and capillaries and ANCA positivity. In patients with AAV, inflammation causes systemic symptoms and organ damage through the affected vessels. The diagnosis is confirmed by a combination of clinical symptoms, imaging findings, and histological findings [ 1 , 2 , 3 ]. Biopsies of organs such as the kidneys, skin, upper respiratory tract, lungs, and nerves are considered; however, they cannot be performed in the absence of abnormal findings or because of poor general conditions of patients. In addition, these biopsies may be technically difficult or can cause sequelae. Compared with these methods, muscle biopsy (MB) is considered relatively safe. Herein, we report three patients with AAV who underwent MB for diagnosis. We also investigated the impacts of MBs on the diagnosis of AAV by conducting a literature review. Methods The peer-reviewed literature cases were included by searching for the terms “anca-associated vasculitis” or “antineutrophil cytoplasmic antibody-associated vasculitis” and “muscle biopsy” in the PubMed database between January 2008 and June 2025. Patients whose diagnosis could not be limited to AAV in the literature were excluded. Case Presentation We analyzed the clinical characteristics of the three patients with AAV. The baseline laboratory data before treatment are shown in Table 1. The patients’ major organ lesions, abnormal muscle areas on MRI and muscle biopsy findings are shown in Table 2 . Patient 1 A 73-year-old woman with limited cutaneous systemic sclerosis without interstitial pneumonia and pulmonary hypertension was referred to our hospital for anorexia, muscle weakness and fever. Six months before referral, she had been diagnosed with systemic sclerosis based on Raynaud’s phenomenon, digital sclerosis, dysphagia, and positive anti-centromere antibodies. Six weeks prior to admission, she had lost seven kilograms of body weight, and one week prior to admission, myalgia with muscle weakness had appeared. Her past medical history was significant for hypertension and hypothyroidism, both of which were well controlled with amlodipine and levothyroxine sodium hydrate. She was not on statins. Physical examination revealed no rash and no muscle-grasping pain. Manual muscle testing revealed 3/3 in the iliopsoas muscles and 5/5 in the other upper and lower limb muscles. The laboratory data revealed leukocytosis and an elevated serum CRP level, while the creatine kinase (CK) level was normal. Urinalysis revealed no abnormalities. Both rheumatoid factor and MPO-ANCA results were positive (Table 1). Antinuclear antibodies and anti-centromere antibodies were positive, but other immunological tests, such as anti-ARS antibodies, anti-Mi-2 antibodies, anti-TIF1-gamma antibodies, and anti-dsDNA antibodies, were negative. Chest computed tomography (CT) revealed slight reticular shadows in both lower lungs. MRI revealed hyperintensity in the bilateral iliopsoas and gluteus medius muscles on T2-weighted images (Fig. 1 a). MB of the gluteus medius revealed inflammation around small blood vessels, with lymphocytic infiltration, fibrinoid necrosis of the vessels, and a small intermuscular lymphocytic infiltrate but no intramuscular lymphocytic infiltrate (Fig. 1 b). On the basis of muscle symptoms and positive MPO-ANCA and MB results, a diagnosis of microscopic polyangiitis (MPA) was made according to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria. In other words, she was diagnosed with overlapping systemic sclerosis and AAV. After biopsy, a high dose of prednisolone (1 mg/kg/day) was administered, and myalgia and muscle weakness resolved within a few days, and the serum CRP levels and MPO-ANCA titers decreased. She was discharged on 30 mg of prednisolone and 50 mg of azathioprine, ande then received intravenous cyclophosphamide as remission induction therapy. Patient 2 An 81-year-old man with a six-week history of fever, general malaise, and pain and weakness in the lower extremities was admitted to another hospital. He had a history of paroxysmal atrial fibrillation and hypertension. He did not take statins. Laboratory tests revealed an elevated CRP level and positive rheumatoid factor and MPO-ANCA results, and the patient was subsequently transferred to our hospital. Tenderness in the trapezius and left rectus femoris muscles was observed. Manual muscle testing revealed 4/4 for the forearm flexors and extensor muscles, 3/3 for the iliopsoas muscles, and 5/5 for the other upper and lower limb muscles. Leukocytosis was observed, while the CK level and urinalysis results were within normal limits. Antinuclear antibodies were positive (speckled pattern), but specific antibodyies, such as anti-SS-A antibodies, anti-SS-B antibodies, anti-Sm antibodies, anti-RNP antibodies, anti-ARS antibodies, were negative. A chest CT revealed slight reticular shadows in both lower lungs. MRI revealed high intensity in the bilateral iliopsoas, psoas, quadriceps femoris, medial and lateral vastus on T2-weighted images (Fig. 1 c). Biopsy of the left lateral vastus muscle revealed perivascular lymphocytic infiltration and fibrinoid necrosis but no myonecrosis or intramuscular lymphocytic infiltration (Fig. 1 d). A diagnosis of MPA was made on the basis of muscle symptoms and positive MPO-ANCA and MB results. After the biopsy followed by the initiation of prednisolone (1 mg/kg/day), he recovered from muscle pain and weakness within a few days, and his CRP and MPO-ANCA levels decreased. Rituximab was administered once a week for four weeks for the induction of remission, and he has maintained in remission for the past two years. Patient 3 A 62-year-old man visited another hospital because of a two-month history of calf pain, numbness in the lower limbs, and weight loss of 18 kg. He had been treated for dyslipidemia with statin drugs, but his leg pain did not improve even after discontinuing statins. He was transferred to our hospital because of an elevated CRP level, mononeuritis multiplex, and a positive MPO-ANCA result. Manual muscle testing revealed no weakness in the proximal limb muscles. Leukocytosis was observed, but the CK level and urinalysis results were within normal limits. Antinuclear antibodies and other immunological testing were all negative. Nerve conduction tests showed decreased amplitude in the motor branch of the left ulnar nerve, the motor branch of the left tibial nerve, and the sensory branch of the right sural nerve. A chest CT revealed slight pulmonary emphysema. MRI revealed bilateral hyperintensity in the biceps femoris, semitendinosus, and semimembranosus muscles on T2-weighted images (Fig. 1 e). Biopsies of the gastrocnemius muscle and sural nerve were performed. The MB showed only a small group of atrophic muscle fibers and no evidence of vasculitis (Fig. 1 f), whereas the nerve biopsy revealed perivascular inflammation (Fig. 1 g). On the basis of mononeuritis multiplex and positive MPO-ANCA and nerve biopsy results, the patient was diagnosed with MPA. Subsequently, treatment with a combination of prednisolone (1 mg/kg/day) and intravenous cyclophosphamide was started, and calf pain and numbness in the lower extremities improved. Tabel 1. Characteristics and laboratory data of our three patients. Reference range Patient 1 Patient 2 Patient 3 Patient Features Age, sex 72, Female 81, Male 62, Male Laboratory data Complete blood cell count White blood cells (/µL) 3,500-9,800 15,100 20,800 14,500 Hemoglobin (g/dL) 13.5–17.6 12.3 11.6 11.3 Platelets (/µL) 131×10 3 -362×10 3 530×10 3 665×10 3 594×10 3 Biochemistry AST (U/L) 10–33 80 104 33 ALT (U/L) 6–35 58 68 49 ALP (U/L) 38–113 276 140 164 T-Bil (mg/dL) 0.2–1.2 0.4 0.3 0.3 LDH (IU/L) 124–222 198 212 117 BUN (mg/dL) 8.4–20.4 10.9 16.5 14.8 Cr (mg/dL) 0.62–1.04 0.59 1.13 0.61 eGFR (mL/min/1.73 m 2 ) 74.5 48.1 101.9 CK 50–200 51 7 21 Immunochemistry CRP (mg/dL) ≦ 0.35 11.33 22.52 7.94 IgG (mg/dL) 870–1700 1756 1512 2331 Rheumatoid factor (IU/mL) ≦ 15.0 128.6 134.3 190.0 ANA (times) < 40× 1280× 320× < 40× MPO-ANCA (U/mL) < 3.5 82.1 108.8 4.6 PR3-ANCA (U/mL) < 3.5 0.1 3,3 0.2 Coagulation test APTT (seconds) 23.0–39.0 N/A 42.0 41.4 PT-INR N/A 1.49 1.17 Fibrinogen (mg/dL) 170–410 N/A N/A 876 D-dimer (µg/mL) ≦ 1.00 N/A 3.07 1.64 Urinalysis Urinary red blood cells (/HPF) 1–4 1–4 1–4 1–4 Urine protein (g/g Cr) < 0.15 0.14 0.28 0.17 Granular cast (/WF) - - - AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; LDH: lactate dehydrogenase; CK: creatine kinase; CRP: C-reactive protein; Ig: immunoglobulin; ANA: antinuclear antibody; PR3-ANCA: proteinase 3-antineutrophil cytoplasmic antibody; MPO-ANCA: myeloperoxidase-antineutrophil cytoplasmic antibody; APTT: activated partial thromboplastin time; PT-INR: prothrombin time-international normalized ratio. Table 2 Patients’ major organ lesions, abnormal muscle areas on MRI and findings of muscle biopsy. Patient 1 Patient 2 Patient 3 Clinical features Myalgia femur brachium, femur - Muscle weakness iliopsoas iliopsoas - Lung ILD ILD - Kidney - - - Skin - - - PNS - - mononeuritis multiplex T2WI hyperintense muscle lesion on MRI iliopsoas, gluteus medius iliopsoas, psoas, quadriceps femoris, medial vastus, lateral vastus biceps femoris, semitendinosus, semimembranosus Lesion for muscle biopsy gluteus medius lateral vastus gastrocnemius Findings of muscle biopsy fibrinoid necrosis, perivascular lymphocytic infiltration fibrinoid necrosis, perivascular lymphocytic infiltration No findings of vasculitis PNS: peripheral nerve system, ILD: interstitial lung disease. (a) T2-weighted MR image of the lower limb in Patient 1 . Bilateral high-intensity signals in the bilateral iliopsoas and gluteus medius muscles were observed (arrows). (b) Hematoxylin and eosin staining of the gluteus medius muscle in Patient 1 (×400). No intramuscular lymphocytic infiltration was noted. The infiltration of neutrophils, lymphocytes, and macrophages in the intermuscular space and in the blood vessels within the surrounding fatty tissue was observed. Fibrinoid necrosis was observed in some vessel walls. (c) Fat-suppressed T2-weighted MR image of the lower limb in Patient 2 . High-intensity signals were seen in bilateral iliopsoas, psoas, quadriceps femoris, medial and lateral vastus (arrows). (d) Elastin van Gieson staining of the left lateral vastus in Patient 2 (×40). A few myonecrotic fibers were observed. Inflammatory cell infiltration was observed around blood vessels, and in some vessels, inflammatory cell infiltration was also observed within the vessel wall. (e) Fat-suppressed T2-weighted MR image of the lower limb in Patient 3 . Bilateral high-intensity signals in the biceps femoris, semitendinosus, and semimembranosus muscles were observed (arrows). (f) Elastin van Gieson staining of the gastrocnemius muscle in Patient 3 (×400). Muscle atrophy and slight keratinized fibrosis were observed, but no evidence of myonecrosis or perivascular necrotic regeneration was observed. (g) Hematoxylin and eosin staining of the sural nerve in Patient 3 (×400). The neuroepithelium was edematous, with perivascular inflammatory cell infiltration, including that of plasma cells. Tearing of the internal elastic plate and destruction of the wall structure were observed. Results Muscle biopsies were performed on the three patients with suspected AAV. In two of the three patients, intramuscular microvasculitis findings were observed, whereas one patient did not show any findings of vasculitis in the muscle. All the patients were successfully treated with prednisolone with immunosuppressive agents. Only Patient 3 underwent nerve biopsy. We investigated a total of 10 peer-reviewed case reports and retrospective studies retrieved from the PubMed database in which muscle biopsies were performed and AAV was diagnosed in 197 patients. Among the 10 articles comprising 197 patients with a diagnosis of AAV as a result of MB, six articles were case reports, and four articles (191 patients) were single-center retrospective studies. Discussion This study summarizes the clinical and laboratory findings of three ANCA-positive patients with myalgia who underwent MBs. We found 200 patients in the literature, including our three patients who underwent MBs and were diagnosed with AAV. Muscular inflammation usually occurs within the spectrum of idiopathic inflammatory myopathies (IIMs) and connective tissue diseases. Myalgia in systemic vasculitis has received little attention and is considered a type of systemic symptom similar to fever and weight loss. However, since the 1970s, vasculitis involving muscles has been reported. The first case involved a patient with polyarteritis nodosa who experienced recurrent episodes of calf pain and whose calf MB revealed moderate vessel vasculitis and disruption of surrounding muscle fibers [ 4 ]. In the first case of MPA reported in 2007, the patient had interstitial lung disease prior to the onset of myopathy, and an MB of the quadriceps muscle revealed perivasculitis [ 5 ]. In 2011, three cases of primary small vessel vasculitis of the muscle were reported [ 6 ]. Muscle involvement has been reported in other types of systemic vasculitis [ 7 ]. Thus, muscle vasculitis, although rare, is not an exceptional manifestation of systemic vasculitis [ 8 ]. In a retrospective study of 93 patients diagnosed with AAV or polyarteritis nodosa, myalgia was observed in 21 (22.6%) patients. The prevalence of MPA in all patients presenting with myalgia was more than 50% at the initial diagnosis. Myalgia was present in the lower extremities of all the patients, and more than 80% of the patients had pain in the calf muscle [ 9 ]. The muscle symptoms of MPA and IIM are similar, but the blood test, MRI, and pathology findings are different. The serum levels of CK are rarely elevated in patients with MPA [ 8 , 10 ]; on T2-weighted MRI images, high intensity in the intramuscular and fascia hyperintensities is common in patients with AAV, whereas that in the subcutaneous fat is common in patients with IIM [ 11 ]; MBs in patients with IIM show perimuscular inflammation, whereas those in patients with AAV show perivascular inflammation. These findings suggest that myalgia and muscle weakness in patients with AAV are caused by vasculitis. Several studies have reported the sensitivity of MBs to systemic vasculitis. Hervier et al. reported a retrospective study of patients who underwent muscle biopsies in their hospital [ 12 ]. Thirty-one patients presented with active systemic vasculitis due to the presence of necrotizing vasculitis or inflammatory cells infiltrating small vessel walls with no necrosis. The sensitivity of MB was 67%, and the specificity was > 99%. Importantly, 13 patients started steroids prior to MB. Myalgia was not associated with muscle vasculitis, and an increased CK level was not correlated with a positive MB, which could be due to the lack of an ischemic effect on muscle fibers. Nunokawa et al. conducted a prospective study of 49 patients with suspected systemic vasculitis without nephritis or rash [ 13 ]. All the patients underwent MB of their femurs, and AAV was diagnosed if fibrinoid necrosis was noted. Thirty-five patients were ultimately diagnosed with AAV, 20 of whom were MB positive, indicating that the sensitivity of MB for AAV was 57%. The sensitivity increased to 75% if neurological symptoms were present. The specificity was not reported in this study. Patients with myalgia tended to have more positive muscle biopsies, but the difference was not statistically significant. A total of 11 case reports and retrospective studies were retrieved from PubMed [ 10 , 14 – 23 ]. Lacou et al. conducted a retrospective study of 78 patients with vasculitis who underwent MB at diagnosis [ 14 ]. Patients with neurological symptoms underwent MB of the lower extremities, while those without neurological symptoms underwent MB of the thighs, and a diagnosis of AAV was made if fibrinoid necrosis or inflammatory cell infiltration of the blood vessels was observed. MB was positive in 45 patients, and the sensitivity of MB for AAV was reported to be 58%. Multivariate analysis revealed that female sex, MPO-ANCA positivity, and neutrophil count were associated with MB positivity. Two retrospective studies were recently published from Japan. Ueda et al. reported AAV patients who underwent biopsy of the bilateral vastus lateralis of the quadriceps femoris [ 15 ]. Their study included 71 patients with a final diagnosis of AAV who received an MB of the bilateral vastus lateralis at disease onset, and 41 patients (57.7%) had positive MB findings. The authors also assert that unilateral biopsies may have a lower diagnostic sensitivity for AAV than bilateral biopsies do. Hanai et al. assessed the clinical characteristics of Japanese AAV patients who underwent MB and examined the relationship between MB and positive results for muscular vasculitis and kidney involvement [ 16 ]. Among the 38 patients, 17 patients (44.7%) had positive MBs, and kidney involvement was significantly more common in MB-positive patients (70.6%) than in MB-negative patients (28.6%). The study also reported that myalgia and edema of the lower extremities were significantly more common in MB-positive patients than in MB-negative patients. Based on the literature investigated in this review, the factors that predict the diagnosis of myositis and positive MB results in AAV remain unclear. Considering our three cases, two out of the three patients were diagnosed with AAV by MB. All three patients presented with myalgia and systemic symptoms such as fever and body wight loss, but organ-specific lesions were not observed in the skin, ear, nose, throat, lungs, or kidneys. Therefore, we performed MRI of the muscles to obtain clues for diagnosis. Based on the results of the neuromuscular biopsy and immunosuppressive therapy, myalgia and muscle weakness in patient 1 and 2 were thought to be caused by myositis associated with AAV, while calf pain in patient 3 was presumed to be caused by neuropathy in AAV. All three patients presented with neutrophilia and MPO-ANCA positivity, and these two were consistent with the items reported by Lacou et al. to be correlated with positive MB results. The two patients who were diagnosed with AAV by MB ( Patient 1 and 2 ) had muscle pain and weakness, and MRI revealed abnormalities in the corresponding areas. MB was performed from the same area, while the sites of muscle pain, abnormal MRI areas, and MB sites were all different in the MB-negative patient ( Patient 3 ). Therefore, we argue that MBs performed in the areas where myalgia, muscle weakness, and abnormal MRI signals are present are useful in the diagnosis of AAV. In conclusion, MB is worth considering in the diagnosis of AAV. MB could be useful when a patient with suspected AAV presents with myalgia, weakness, and imaging abnormalities in the same muscle. Declarations Funding: There was no funding. Ethical Approval and accordance: This research waived the need for approval by Osaka Police Hospital Ethics Committee in accordance with the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects. Consent to participate: We obtained written informed consent from the patients to participate in the study. Consent to publication: We obtained written informed consent from the patients for the publication of data, images, and case details in this report. Authors' contributions: Writing – original draft: Yui Chokyu and Takayuki Shibahara; Writing – review & editing: Takayuki Shibahara; Supervision: Suzuka Otaki, Ikumi Matsuo, Tomomi Tada, Nachi Ishikawa, Jun Fujimoto and Shinji Higa. Competing interests: The authors declare that they have no conflicts of interest. Authorship: All the authors have read the journal policies and is submitting their manuscript in accordance with those policies. Data Availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Acknowledgements Not applicable. 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Shibahara","email":"data:image/png;base64,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","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":true,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Shibahara","suffix":""},{"id":535247804,"identity":"1a30bfa7-809a-4c76-92c3-041dd00cd59a","order_by":2,"name":"Suzuka Otaki","email":"","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":false,"prefix":"","firstName":"Suzuka","middleName":"","lastName":"Otaki","suffix":""},{"id":535247805,"identity":"7b0d9857-be43-41d9-b881-7929c4f91654","order_by":3,"name":"Ikumi Matsuo","email":"","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":false,"prefix":"","firstName":"Ikumi","middleName":"","lastName":"Matsuo","suffix":""},{"id":535247806,"identity":"d5c3f2fd-3bbd-4059-bac6-88b22ab94b0f","order_by":4,"name":"Tomomi Tada","email":"","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":false,"prefix":"","firstName":"Tomomi","middleName":"","lastName":"Tada","suffix":""},{"id":535247807,"identity":"c812d132-12f7-48e7-b415-8719bad28a3f","order_by":5,"name":"Nachi Ishikawa","email":"","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":false,"prefix":"","firstName":"Nachi","middleName":"","lastName":"Ishikawa","suffix":""},{"id":535247809,"identity":"4c22c2c9-cefb-44f7-9ec0-653babb1bfa7","order_by":6,"name":"Jun Fujimoto","email":"","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Fujimoto","suffix":""},{"id":535247811,"identity":"faf02e67-34c3-47ec-83ee-b9877a727bb3","order_by":7,"name":"Shinji Higa","email":"","orcid":"","institution":"Osaka Keisatsu Hospital, Osaka International Medical \u0026 Science Center","correspondingAuthor":false,"prefix":"","firstName":"Shinji","middleName":"","lastName":"Higa","suffix":""}],"badges":[],"createdAt":"2025-08-22 00:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7429625/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7429625/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94824475,"identity":"a36eebbe-c052-4af2-b75f-f4c31a74d884","added_by":"auto","created_at":"2025-10-31 06:49:02","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6206244,"visible":true,"origin":"","legend":"","description":"","filename":"20250930MusclebiopsyforAAV.docx","url":"https://assets-eu.researchsquare.com/files/rs-7429625/v1/50e770f55d5041ac0832cda2.docx"},{"id":94760082,"identity":"cb308b23-6ae6-4877-93ff-fcdbcb70ae8c","added_by":"auto","created_at":"2025-10-30 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11:54:06","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97867,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7429625/v1/ed2105ea5d3b860cfd16c3de.html"},{"id":94760079,"identity":"3f0b7a96-3313-4767-9207-74501b947556","added_by":"auto","created_at":"2025-10-30 11:54:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1798454,"visible":true,"origin":"","legend":"\u003cp\u003eMR and pathological images of each patient\u003c/p\u003e\n\u003cp\u003e(a) T2-weighted MRimage of the lower limb in \u003cem\u003ePatient 1\u003c/em\u003e. Bilateral high-intensity signals in the bilateral iliopsoas and gluteus medius muscles were observed (arrows). (b) Hematoxylin and eosin staining of the gluteus medius muscle in \u003cem\u003ePatient 1\u003c/em\u003e (×400). No intramuscular lymphocytic infiltrationwas noted. The infiltration of neutrophils, lymphocytes, and macrophages in the intermuscular space and in the blood vessels within the surrounding fatty tissue was observed. Fibrinoid necrosis was observed in some vessel walls. (c) Fat-suppressed T2-weighted MR image of the lower limb in \u003cem\u003ePatient 2\u003c/em\u003e. High-intensity signals were seen in bilateral iliopsoas, psoas, quadriceps femoris, medial and lateral vastus (arrows). (d) Elastin van Gieson staining of the left lateral vastus in \u003cem\u003ePatient2\u003c/em\u003e (×40). A few myonecrotic fibers were observed. Inflammatory cell infiltration was observedaround blood vessels, and in some vessels, inflammatory cell infiltration was also observed within the vessel wall. (e) Fat-suppressed T2-weighted MR image of the lower limb in \u003cem\u003ePatient 3\u003c/em\u003e. Bilateral high-intensity signals in the biceps femoris, semitendinosus, and semimembranosus muscles were observed (arrows). (f) Elastin van Gieson staining of the gastrocnemius muscle in \u003cem\u003ePatient 3\u003c/em\u003e (×400). Muscle atrophy and slightkeratinized fibrosis were observed, but no evidence of myonecrosis orperivascular necrotic regeneration was observed. (g) Hematoxylin and eosin staining of the sural nerve in \u003cem\u003ePatient 3\u003c/em\u003e (×400). The neuroepithelium was edematous, with perivascular inflammatory cell infiltration, including that of plasma cells. Tearing of the internal elastic plate and destruction of the wall structure were observed.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7429625/v1/36321e0ad6b9b546dfab0aff.png"},{"id":96363671,"identity":"e6eaa0a1-0278-4720-9a15-098880fb5955","added_by":"auto","created_at":"2025-11-20 10:07:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2711244,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7429625/v1/9b96bc3a-f027-4302-a94b-fd343f350ee7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Muscle biopsy for the diagnosis of ANCA-associated vasculitis: A case series and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eANCA-associated vasculitis (AAV) is characterized by necrotizing vasculitis of small arteries and capillaries and ANCA positivity. In patients with AAV, inflammation causes systemic symptoms and organ damage through the affected vessels. The diagnosis is confirmed by a combination of clinical symptoms, imaging findings, and histological findings [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Biopsies of organs such as the kidneys, skin, upper respiratory tract, lungs, and nerves are considered; however, they cannot be performed in the absence of abnormal findings or because of poor general conditions of patients. In addition, these biopsies may be technically difficult or can cause sequelae. Compared with these methods, muscle biopsy (MB) is considered relatively safe.\u003c/p\u003e\u003cp\u003eHerein, we report three patients with AAV who underwent MB for diagnosis. We also investigated the impacts of MBs on the diagnosis of AAV by conducting a literature review.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe peer-reviewed literature cases were included by searching for the terms \u0026ldquo;anca-associated vasculitis\u0026rdquo; or \u0026ldquo;antineutrophil cytoplasmic antibody-associated vasculitis\u0026rdquo; and \u0026ldquo;muscle biopsy\u0026rdquo; in the PubMed database between January 2008 and June 2025. Patients whose diagnosis could not be limited to AAV in the literature were excluded.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eWe analyzed the clinical characteristics of the three patients with AAV. The baseline laboratory data before treatment are shown in Table\u0026nbsp;1. The patients\u0026rsquo; major organ lesions, abnormal muscle areas on MRI and muscle biopsy findings are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePatient 1\u003c/h3\u003e\n\u003cp\u003eA 73-year-old woman with limited cutaneous systemic sclerosis without interstitial pneumonia and pulmonary hypertension was referred to our hospital for anorexia, muscle weakness and fever. Six months before referral, she had been diagnosed with systemic sclerosis based on Raynaud\u0026rsquo;s phenomenon, digital sclerosis, dysphagia, and positive anti-centromere antibodies. Six weeks prior to admission, she had lost seven kilograms of body weight, and one week prior to admission, myalgia with muscle weakness had appeared. Her past medical history was significant for hypertension and hypothyroidism, both of which were well controlled with amlodipine and levothyroxine sodium hydrate. She was not on statins. Physical examination revealed no rash and no muscle-grasping pain. Manual muscle testing revealed 3/3 in the iliopsoas muscles and 5/5 in the other upper and lower limb muscles. The laboratory data revealed leukocytosis and an elevated serum CRP level, while the creatine kinase (CK) level was normal. Urinalysis revealed no abnormalities. Both rheumatoid factor and MPO-ANCA results were positive (Table\u0026nbsp;1). Antinuclear antibodies and anti-centromere antibodies were positive, but other immunological tests, such as anti-ARS antibodies, anti-Mi-2 antibodies, anti-TIF1-gamma antibodies, and anti-dsDNA antibodies, were negative. Chest computed tomography (CT) revealed slight reticular shadows in both lower lungs. MRI revealed hyperintensity in the bilateral iliopsoas and gluteus medius muscles on T2-weighted images (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). MB of the gluteus medius revealed inflammation around small blood vessels, with lymphocytic infiltration, fibrinoid necrosis of the vessels, and a small intermuscular lymphocytic infiltrate but no intramuscular lymphocytic infiltrate (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). On the basis of muscle symptoms and positive MPO-ANCA and MB results, a diagnosis of microscopic polyangiitis (MPA) was made according to the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria. In other words, she was diagnosed with overlapping systemic sclerosis and AAV. After biopsy, a high dose of prednisolone (1 mg/kg/day) was administered, and myalgia and muscle weakness resolved within a few days, and the serum CRP levels and MPO-ANCA titers decreased. She was discharged on 30 mg of prednisolone and 50 mg of azathioprine, ande then received intravenous cyclophosphamide as remission induction therapy.\u003c/p\u003e\n\u003ch3\u003ePatient 2\u003c/h3\u003e\n\u003cp\u003eAn 81-year-old man with a six-week history of fever, general malaise, and pain and weakness in the lower extremities was admitted to another hospital. He had a history of paroxysmal atrial fibrillation and hypertension. He did not take statins. Laboratory tests revealed an elevated CRP level and positive rheumatoid factor and MPO-ANCA results, and the patient was subsequently transferred to our hospital. Tenderness in the trapezius and left rectus femoris muscles was observed. Manual muscle testing revealed 4/4 for the forearm flexors and extensor muscles, 3/3 for the iliopsoas muscles, and 5/5 for the other upper and lower limb muscles. Leukocytosis was observed, while the CK level and urinalysis results were within normal limits.\u003c/p\u003e\u003cp\u003eAntinuclear antibodies were positive (speckled pattern), but specific antibodyies, such as anti-SS-A antibodies, anti-SS-B antibodies, anti-Sm antibodies, anti-RNP antibodies, anti-ARS antibodies, were negative. A chest CT revealed slight reticular shadows in both lower lungs. MRI revealed high intensity in the bilateral iliopsoas, psoas, quadriceps femoris, medial and lateral vastus on T2-weighted images (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Biopsy of the left lateral vastus muscle revealed perivascular lymphocytic infiltration and fibrinoid necrosis but no myonecrosis or intramuscular lymphocytic infiltration (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). A diagnosis of MPA was made on the basis of muscle symptoms and positive MPO-ANCA and MB results. After the biopsy followed by the initiation of prednisolone (1 mg/kg/day), he recovered from muscle pain and weakness within a few days, and his CRP and MPO-ANCA levels decreased. Rituximab was administered once a week for four weeks for the induction of remission, and he has maintained in remission for the past two years.\u003c/p\u003e\n\u003ch3\u003ePatient 3\u003c/h3\u003e\n\u003cp\u003eA 62-year-old man visited another hospital because of a two-month history of calf pain, numbness in the lower limbs, and weight loss of 18 kg. He had been treated for dyslipidemia with statin drugs, but his leg pain did not improve even after discontinuing statins. He was transferred to our hospital because of an elevated CRP level, mononeuritis multiplex, and a positive MPO-ANCA result. Manual muscle testing revealed no weakness in the proximal limb muscles. Leukocytosis was observed, but the CK level and urinalysis results were within normal limits. Antinuclear antibodies and other immunological testing were all negative. Nerve conduction tests showed decreased amplitude in the motor branch of the left ulnar nerve, the motor branch of the left tibial nerve, and the sensory branch of the right sural nerve. A chest CT revealed slight pulmonary emphysema. MRI revealed bilateral hyperintensity in the biceps femoris, semitendinosus, and semimembranosus muscles on T2-weighted images (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee). Biopsies of the gastrocnemius muscle and sural nerve were performed. The MB showed only a small group of atrophic muscle fibers and no evidence of vasculitis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef), whereas the nerve biopsy revealed perivascular inflammation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eg). On the basis of mononeuritis multiplex and positive MPO-ANCA and nerve biopsy results, the patient was diagnosed with MPA. Subsequently, treatment with a combination of prednisolone (1 mg/kg/day) and intravenous cyclophosphamide was started, and calf pain and numbness in the lower extremities improved.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTabel 1. Characteristics and laboratory data of our three patients.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eReference range\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatient 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePatient 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePatient 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient Features\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, sex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72, Female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e81, Male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e62, Male\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLaboratory data\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComplete blood cell count\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite blood cells (/\u0026micro;L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,500-9,800\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15,100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20,800\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14,500\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.5\u0026ndash;17.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelets (/\u0026micro;L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e131\u0026times;10\u003csup\u003e3\u003c/sup\u003e-362\u0026times;10\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e530\u0026times;10\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e665\u0026times;10\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e594\u0026times;10\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBiochemistry\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAST (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u0026ndash;33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u0026ndash;35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALP (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38\u0026ndash;113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e276\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e164\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT-Bil (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.2\u0026ndash;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDH (IU/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e124\u0026ndash;222\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e198\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e212\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e117\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBUN (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.4\u0026ndash;20.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCr (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.62\u0026ndash;1.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e74.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e48.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e101.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50\u0026ndash;200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eImmunochemistry\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e≦\u0026thinsp;0.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.94\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgG (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e870\u0026ndash;1700\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1756\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1512\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2331\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRheumatoid factor (IU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e≦\u0026thinsp;15.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e128.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e134.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e190.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eANA (times)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;40\u0026times;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1280\u0026times;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e320\u0026times;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;40\u0026times;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMPO-ANCA (U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;3.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e108.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePR3-ANCA (U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;3.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3,3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCoagulation test\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPTT (seconds)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.0\u0026ndash;39.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePT-INR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFibrinogen (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e170\u0026ndash;410\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e876\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD-dimer (\u0026micro;g/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e≦\u0026thinsp;1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eUrinalysis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary red blood cells (/HPF)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u0026ndash;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u0026ndash;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u0026ndash;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u0026ndash;4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine protein (g/g Cr)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGranular cast (/WF)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; LDH: lactate dehydrogenase; CK: creatine kinase; CRP: C-reactive protein; Ig: immunoglobulin; ANA: antinuclear antibody; PR3-ANCA: proteinase 3-antineutrophil cytoplasmic antibody; MPO-ANCA: myeloperoxidase-antineutrophil cytoplasmic antibody; APTT: activated partial thromboplastin time; PT-INR: prothrombin time-international normalized ratio.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatients\u0026rsquo; major organ lesions, abnormal muscle areas on MRI and findings of muscle biopsy.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatient 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatient 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePatient 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical features\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyalgia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003efemur\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ebrachium, femur\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMuscle weakness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eiliopsoas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eiliopsoas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eILD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eILD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKidney\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003emononeuritis multiplex\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT2WI hyperintense muscle lesion on MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eiliopsoas,\u003c/p\u003e\u003cp\u003egluteus medius\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eiliopsoas, psoas,\u003c/p\u003e\u003cp\u003equadriceps femoris,\u003c/p\u003e\u003cp\u003emedial vastus,\u003c/p\u003e\u003cp\u003elateral vastus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ebiceps femoris, semitendinosus, semimembranosus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLesion for\u003c/p\u003e\u003cp\u003emuscle biopsy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003egluteus medius\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003elateral vastus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003egastrocnemius\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFindings of\u003c/p\u003e\u003cp\u003emuscle biopsy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003efibrinoid necrosis,\u003c/p\u003e\u003cp\u003eperivascular lymphocytic infiltration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003efibrinoid necrosis,\u003c/p\u003e\u003cp\u003eperivascular lymphocytic infiltration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo findings of vasculitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ePNS: peripheral nerve system, ILD: interstitial lung disease.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e(a) T2-weighted MR image of the lower limb in \u003cem\u003ePatient 1\u003c/em\u003e. Bilateral high-intensity signals in the bilateral iliopsoas and gluteus medius muscles were observed (arrows). (b) Hematoxylin and eosin staining of the gluteus medius muscle in \u003cem\u003ePatient 1\u003c/em\u003e (\u0026times;400). No intramuscular lymphocytic infiltration was noted. The infiltration of neutrophils, lymphocytes, and macrophages in the intermuscular space and in the blood vessels within the surrounding fatty tissue was observed. Fibrinoid necrosis was observed in some vessel walls. (c) Fat-suppressed T2-weighted MR image of the lower limb in \u003cem\u003ePatient 2\u003c/em\u003e. High-intensity signals were seen in bilateral iliopsoas, psoas, quadriceps femoris, medial and lateral vastus (arrows). (d) Elastin van Gieson staining of the left lateral vastus in \u003cem\u003ePatient 2\u003c/em\u003e (\u0026times;40). A few myonecrotic fibers were observed. Inflammatory cell infiltration was observed around blood vessels, and in some vessels, inflammatory cell infiltration was also observed within the vessel wall. (e) Fat-suppressed T2-weighted MR image of the lower limb in \u003cem\u003ePatient 3\u003c/em\u003e. Bilateral high-intensity signals in the biceps femoris, semitendinosus, and semimembranosus muscles were observed (arrows). (f) Elastin van Gieson staining of the gastrocnemius muscle in \u003cem\u003ePatient 3\u003c/em\u003e (\u0026times;400). Muscle atrophy and slight keratinized fibrosis were observed, but no evidence of myonecrosis or perivascular necrotic regeneration was observed. (g) Hematoxylin and eosin staining of the sural nerve in \u003cem\u003ePatient 3\u003c/em\u003e (\u0026times;400). The neuroepithelium was edematous, with perivascular inflammatory cell infiltration, including that of plasma cells. Tearing of the internal elastic plate and destruction of the wall structure were observed.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eMuscle biopsies were performed on the three patients with suspected AAV. In two of the three patients, intramuscular microvasculitis findings were observed, whereas one patient did not show any findings of vasculitis in the muscle. All the patients were successfully treated with prednisolone with immunosuppressive agents. Only Patient 3 underwent nerve biopsy.\u003c/p\u003e\u003cp\u003eWe investigated a total of 10 peer-reviewed case reports and retrospective studies retrieved from the PubMed database in which muscle biopsies were performed and AAV was diagnosed in 197 patients. Among the 10 articles comprising 197 patients with a diagnosis of AAV as a result of MB, six articles were case reports, and four articles (191 patients) were single-center retrospective studies.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study summarizes the clinical and laboratory findings of three ANCA-positive patients with myalgia who underwent MBs. We found 200 patients in the literature, including our three patients who underwent MBs and were diagnosed with AAV.\u003c/p\u003e\u003cp\u003eMuscular inflammation usually occurs within the spectrum of idiopathic inflammatory myopathies (IIMs) and connective tissue diseases. Myalgia in systemic vasculitis has received little attention and is considered a type of systemic symptom similar to fever and weight loss. However, since the 1970s, vasculitis involving muscles has been reported. The first case involved a patient with polyarteritis nodosa who experienced recurrent episodes of calf pain and whose calf MB revealed moderate vessel vasculitis and disruption of surrounding muscle fibers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the first case of MPA reported in 2007, the patient had interstitial lung disease prior to the onset of myopathy, and an MB of the quadriceps muscle revealed perivasculitis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In 2011, three cases of primary small vessel vasculitis of the muscle were reported [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Muscle involvement has been reported in other types of systemic vasculitis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, muscle vasculitis, although rare, is not an exceptional manifestation of systemic vasculitis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn a retrospective study of 93 patients diagnosed with AAV or polyarteritis nodosa, myalgia was observed in 21 (22.6%) patients. The prevalence of MPA in all patients presenting with myalgia was more than 50% at the initial diagnosis. Myalgia was present in the lower extremities of all the patients, and more than 80% of the patients had pain in the calf muscle [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe muscle symptoms of MPA and IIM are similar, but the blood test, MRI, and pathology findings are different. The serum levels of CK are rarely elevated in patients with MPA [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; on T2-weighted MRI images, high intensity in the intramuscular and fascia hyperintensities is common in patients with AAV, whereas that in the subcutaneous fat is common in patients with IIM [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; MBs in patients with IIM show perimuscular inflammation, whereas those in patients with AAV show perivascular inflammation. These findings suggest that myalgia and muscle weakness in patients with AAV are caused by vasculitis.\u003c/p\u003e\u003cp\u003eSeveral studies have reported the sensitivity of MBs to systemic vasculitis. Hervier et al. reported a retrospective study of patients who underwent muscle biopsies in their hospital [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Thirty-one patients presented with active systemic vasculitis due to the presence of necrotizing vasculitis or inflammatory cells infiltrating small vessel walls with no necrosis. The sensitivity of MB was 67%, and the specificity was \u0026gt;\u0026thinsp;99%. Importantly, 13 patients started steroids prior to MB. Myalgia was not associated with muscle vasculitis, and an increased CK level was not correlated with a positive MB, which could be due to the lack of an ischemic effect on muscle fibers.\u003c/p\u003e\u003cp\u003eNunokawa et al. conducted a prospective study of 49 patients with suspected systemic vasculitis without nephritis or rash [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. All the patients underwent MB of their femurs, and AAV was diagnosed if fibrinoid necrosis was noted. Thirty-five patients were ultimately diagnosed with AAV, 20 of whom were MB positive, indicating that the sensitivity of MB for AAV was 57%. The sensitivity increased to 75% if neurological symptoms were present. The specificity was not reported in this study. Patients with myalgia tended to have more positive muscle biopsies, but the difference was not statistically significant.\u003c/p\u003e\u003cp\u003eA total of 11 case reports and retrospective studies were retrieved from PubMed [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Lacou et al. conducted a retrospective study of 78 patients with vasculitis who underwent MB at diagnosis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patients with neurological symptoms underwent MB of the lower extremities, while those without neurological symptoms underwent MB of the thighs, and a diagnosis of AAV was made if fibrinoid necrosis or inflammatory cell infiltration of the blood vessels was observed. MB was positive in 45 patients, and the sensitivity of MB for AAV was reported to be 58%. Multivariate analysis revealed that female sex, MPO-ANCA positivity, and neutrophil count were associated with MB positivity.\u003c/p\u003e\u003cp\u003eTwo retrospective studies were recently published from Japan. Ueda et al. reported AAV patients who underwent biopsy of the bilateral vastus lateralis of the quadriceps femoris [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Their study included 71 patients with a final diagnosis of AAV who received an MB of the bilateral vastus lateralis at disease onset, and 41 patients (57.7%) had positive MB findings. The authors also assert that unilateral biopsies may have a lower diagnostic sensitivity for AAV than bilateral biopsies do.\u003c/p\u003e\u003cp\u003eHanai et al. assessed the clinical characteristics of Japanese AAV patients who underwent MB and examined the relationship between MB and positive results for muscular vasculitis and kidney involvement [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Among the 38 patients, 17 patients (44.7%) had positive MBs, and kidney involvement was significantly more common in MB-positive patients (70.6%) than in MB-negative patients (28.6%). The study also reported that myalgia and edema of the lower extremities were significantly more common in MB-positive patients than in MB-negative patients.\u003c/p\u003e\u003cp\u003eBased on the literature investigated in this review, the factors that predict the diagnosis of myositis and positive MB results in AAV remain unclear. Considering our three cases, two out of the three patients were diagnosed with AAV by MB. All three patients presented with myalgia and systemic symptoms such as fever and body wight loss, but organ-specific lesions were not observed in the skin, ear, nose, throat, lungs, or kidneys. Therefore, we performed MRI of the muscles to obtain clues for diagnosis. Based on the results of the neuromuscular biopsy and immunosuppressive therapy, myalgia and muscle weakness in \u003cem\u003epatient 1\u003c/em\u003e and \u003cem\u003e2\u003c/em\u003e were thought to be caused by myositis associated with AAV, while calf pain in \u003cem\u003epatient 3\u003c/em\u003e was presumed to be caused by neuropathy in AAV. All three patients presented with neutrophilia and MPO-ANCA positivity, and these two were consistent with the items reported by Lacou et al. to be correlated with positive MB results. The two patients who were diagnosed with AAV by MB (\u003cem\u003ePatient 1\u003c/em\u003e and \u003cem\u003e2\u003c/em\u003e) had muscle pain and weakness, and MRI revealed abnormalities in the corresponding areas. MB was performed from the same area, while the sites of muscle pain, abnormal MRI areas, and MB sites were all different in the MB-negative patient (\u003cem\u003ePatient 3\u003c/em\u003e). Therefore, we argue that MBs performed in the areas where myalgia, muscle weakness, and abnormal MRI signals are present are useful in the diagnosis of AAV.\u003c/p\u003e\u003cp\u003eIn conclusion, MB is worth considering in the diagnosis of AAV. MB could be useful when a patient with suspected AAV presents with myalgia, weakness, and imaging abnormalities in the same muscle.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding:\u003c/p\u003e\n\u003cp\u003eThere was no funding.\u003c/p\u003e\n\u003cp\u003eEthical Approval and accordance:\u003c/p\u003e\n\u003cp\u003eThis research waived the need for approval by Osaka Police Hospital Ethics Committee in accordance with the Ethical Guidelines for Life Science and Medical Research Involving Human Subjects.\u003c/p\u003e\n\u003cp\u003eConsent to participate:\u003c/p\u003e\n\u003cp\u003eWe obtained written informed consent from the patients to participate in the study.\u003c/p\u003e\n\u003cp\u003eConsent to publication:\u003c/p\u003e\n\u003cp\u003eWe obtained written informed consent from the patients for the publication of data, images, and case details in this report.\u003c/p\u003e\n\u003cp\u003eAuthors' contributions:\u003c/p\u003e\n\u003cp\u003eWriting – original draft: Yui Chokyu and Takayuki Shibahara; Writing – review \u0026amp; editing: Takayuki Shibahara; Supervision: Suzuka Otaki, Ikumi Matsuo, Tomomi Tada, Nachi Ishikawa, Jun Fujimoto and Shinji Higa.\u003c/p\u003e\n\u003cp\u003eCompeting interests:\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003eAuthorship:\u003c/p\u003e\n\u003cp\u003eAll the authors have read the journal policies and is submitting their manuscript in accordance with those policies.\u003c/p\u003e\n\u003cp\u003eData Availability:\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSuppiah R, Robson JC, Grayson PC, Ponte C, Craven A, Khalid S, Judge A, Hutchings A, Merkel PA, Luqmani RA, Watts RA, DCVAS INVESTIGATORS. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis. 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PMID: 36549887.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"ANCA-associated vasculitis, muscle biopsy, myopathy, muscle vasculitis, MRI","lastPublishedDoi":"10.21203/rs.3.rs-7429625/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7429625/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is diagnosed on the basis of a combination of clinical symptoms, imaging findings, and histological findings. In general, skin, kidney, upper airway and lower airway tissues are selected as biopsy targets. However, some patients present with few abnormalities in these major organs. Herein, we report three patients with AAV who presented with myalgia as a main symptom, with high C-reactive protein levels and a positive myeloperoxidase-ANCA test without elevated serum creatine kinase levels. All the patients underwent muscle magnetic resonance imaging and muscle biopsy (MB) to diagnose AAV. We also investigated peer-reviewed cases of AAV that were diagnosed by MB to confirm the efficacy of MB for AAV. Several retrospective studies have reported MB sensitivity to AAV and its predictors. We argue that an MB from the area where myalgia, muscle weakness, and abnormal MRI signals are present is useful for the diagnosis of AAV.\u003c/p\u003e","manuscriptTitle":"Muscle biopsy for the diagnosis of ANCA-associated vasculitis: A case series and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-30 11:53:56","doi":"10.21203/rs.3.rs-7429625/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":"9b077aec-b3d2-4080-84b1-53dc7e6fc4db","owner":[],"postedDate":"October 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-19T08:39:01+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-30 11:53:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7429625","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7429625","identity":"rs-7429625","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}