Published online Oct 16, 2023.
https://doi.org/10.3346/jkms.2023.38.e327
Case 15: A 53-Year-Old Woman With Bilateral Leg Pain and Weakness
PRESENTATION OF CASE 15
Dr. Youngwook Ryu: A 53-year-old woman presented to our hospital with a complaint of persistent pain and weakness in both legs for the past month.
The pain, primarily centered in the calf areas, had worsened over time, accompanied by intermittent fever. The patient had previously sought medical attention at another hospital, where deep vein computed tomography and lumbar spine magnetic resonance imaging (MRI) were conducted, but no specific findings were identified. Neuromuscular electromyography was recommended, leading the patient to seek consultation at our hospital's neurology department, ultimately resulting in admission.
The patient had a history of hypertension and dyslipidemia, and she was currently on statin medication. On examination, her body temperature was measured at 37.6°C, with no observable pitting edema or skin lesions on either leg. Sensory function in both legs was intact, but motor strength was notably reduced, particularly in the proximal areas. While mild hyporeflexia was noted in both knees and the Homan's sign was positive, no pathological reflexes were observed.
The complete blood count revealed elevated white blood cell count (11,570 × 106/L) and platelet count (486 × 109/L), along with decreased hemoglobin levels (11.7 g/dL). Blood chemistry analysis indicated slightly elevated levels of aspartate transaminase (60 U/L), alanine transaminase (52 U/L), and creatine phosphokinase (CPK) (254 U/L). Among the inflammatory markers, the erythrocyte sedimentation rate (ESR) was elevated at 44 mm/hr, along with an elevated C-reactive protein (CRP) level of 9.70 mg/dL, and ferritin levels of 448 ng/mL. D-dimer levels were also elevated at 4.88 mg/L. Urinalysis and viral marker assessments yielded nonspecific results. The cerebrospinal fluid study did not reveal any abnormal findings, including pleocytosis or cytoalbuminologic dissociation. Laboratory test results are shown in Table 1.
Table 1
Laboratory results on initial presentation
Although nerve conduction studies demonstrated normal motor and sensory nerve conduction in both legs, motor unit action potential (MUAP) amplitude was reduced in the left tensor fasciae latae and left iliopsoas muscles. These muscles are located in the thigh region, rather than in the calf area where the patient primarily experienced pain. Calf muscles such as the tibialis anterior and medial gastrocnemius muscles exhibited normal MUAP values.
Further evaluation through lower extremity vein ultrasonography at our hospital ruled out the presence of deep vein thrombosis.
CLINICAL IMPRESSION
Dr. Youngjae Park: The patient was consulted by our department for the probability of autoimmune disease and the need for further rheumatologic evaluation. What potential rheumatologic clinical impressions could be drawn for this patient?
Dr. Youngwook Ryu: It could be a myopathy due to inflammatory myositis.
Dr. Youngjae Park: What additional studies could aid in confirming our clinical impression?
IMAGE PRESENTATION
Dr. Youngwook Ryu: The enhanced lower leg MRI was performed and exhibited diffuse streaky and branching hyperintensities, accompanied by enhanced signals, along the muscles of both calves (Fig. 1). Additionally, fluid collections were observed along the subcutaneous layers and deep fascia in the medial lower leg and ankle regions.
Fig. 1
Enhanced Lower Leg magnetic resonance imaging. Coronal (A) and axial (B) images of a contrast-enhanced magnetic resonance imaging of the lower leg showing diffuse streaky or branching hyperintensity and enhancement across both calves.
AUTOIMMUNE STUDY
Dr. Youngwook Ryu: In the autoimmune study, the serum level of rheumatoid factor (RF) was elevated (70.5 IU/mL), and the anti-nuclear antibody was positive with a titer of 1:320, displaying homogeneous and speckled pattern. Among autoantibodies to extractable nuclear antigens, only anti-SS-A and anti-SS-B antibodies showed positive results, while other antibodies, including anti-Jo-1 antibodies, were negative. Interestingly, the antineutrophil cytoplasmic antibody (ANCA) test using indirect immunofluorescence revealed positivity of perinuclear ANCA at a titer of 1:320, and the anti-myeloperoxidase (MPO) antibody was also positive (7040.0 CU). Autoimmune study results are shown in Table 2.
Table 2
Results of autoimmune studies
PATHOLOGICAL FINDINGS
Dr. Youngwook Ryu: For pathologic confirmation, we performed a biopsy in the right medial gastrocnemius muscle, and appropriate tissue was obtained. Pathological examination of biopsy specimens revealed the presence of neutrophil infiltrations in the perivascular area, indicative of vasculitis (Fig. 2A). Additionally, fibrinoid necrosis was observed (Fig. 2B). There was no pathologic evidence of granuloma. Immunohistochemistry staining for CD3, CD4, CD8, CD20, and CD45RB all displayed positive results.
Fig. 2
The right medial gastrocnemius muscle biopsy specimen stained with hematoxylin and eosin. (A) Vasculitis accompanied by degenerated muscle fibers and lymphocytic infiltration. (B) Areas of fibrinoid necrosis (black arrow).
DIAGNOSIS
Dr. Youngjae Park: Based on the positivity of anti-MPO antibodies and necrotizing vasculitis in the muscle biopsy, ANCA-associated vasculitis (AAV) was diagnosed.
Dr. Howook Jeon: There are typically three subtypes of AAV. To which subtype of AAV could this patient be classified?
Dr. Jiwon Yang: The most widely used classification algorithm for AAV is the 2007 European Medicine Agency algorithm, modified with 2012 Chapel Hill Consensus Conference definitions.1, 2 This algorithm can be employed when a clinical diagnosis of primary systemic vasculitis is established. Applying this algorithm to our patient, the patient does not meet the American College of Rheumatology (ACR) or Lanham criteria for eosinophilic granulomatosis with polyangiitis, also does not fulfil the ACR criteria for granulomatosis with polyangiits (GPA), and the histological findings are compatible with small-vessel vasculitis. In addition, there are no surrogate markers for GPA.
Given these considerations, the patient could be classified under the category of microscopic polyangiitis (MPA) according to the applied algorithm. Notably, this patient also satisfies the 2022 ACR/EULAR (European Alliance of Associations for Rheumatology) classification criteria for MPA.3
GENERAL INTRODUCTION OF THE DISEASE MANAGEMENT
Dr. Eui-Jong Kwon: What is the preferred treatment for AAV or MPA, and what has been this patient's disease progression?
Dr. Jiwon Yang: At the time of the patient’s diagnosis with AAV, there was no evidence of major organ involvement. Consequently, we initiated intravenous (IV) methylprednisolone at a dose of 1 mg/kg. While continuing IV methylprednisolone, the patient's fever subsided and both ESR and CRP levels decreased. However, on the 15th day of hospitalization, the patient developed a left foot drop (Fig. 3).
Fig. 3
Clinical progress until hospital day 17. Peak BT, serum levels of CRP, and the ESR from admission to hospital day 17. Following the confirmation of vasculitis through muscle biopsy, systemic glucocorticoid therapy was commenced on hospital day 13.
BT = body temperature, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein.
According to the 2021 ACR/Vasculitis Foundation guidelines for managing AAV, remission induction therapies for active severe GPA or MPA include rituximab (RTX) or cyclophosphamide (CYC).4 Severe disease manifestations encompass diffuse alveolar hemorrhage, glomerulonephritis, mononeuritis multiplex, gangrenous skin disease, scleritis, and sensory neuronal deafness. Another report has suggested that RTX demonstrates superiority over CYC in cases of anti-proteinase 3 antibody vasculitis, whereas RTX and CYC exhibit comparable efficacies in anti-MPO antibody vasculitis.5
In this instance, the patient presented with mononeuritis multiplex, leading us to administer IV RTX. After initiation of RTX induction, the foot drop improved, allowing us to gradually taper methylprednisolone and transition to oral (PO) prednisolone. Subsequent to two more IV RTX infusions and the addition of methotrexate (MTX) in the outpatient setting, the patient's pain and weakness in both legs notably improved. The patient presently reports no limitations in activities of daily living, and follow-up assessments have revealed reduced ANCA titer and anti-MPO antibody levels (Fig. 4).
Fig. 4
Clinical progress after left foot drop occurred. The serum levels of CRP and the ESR subsequent to the occurrence of left foot drop are presented. Following the third administration of rituximab, glucocorticoid was gradually tapered, and MTX was added. Follow-up ANCA titer and anti-MPO antibody levels decreased.
ANCA = antineutrophil cytoplasmic antibody, MPO = myeloperoxidase, ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, HD = hospital day, IV = intravenous, MTX = methotrexate.
In accordance with the 2021 ACR/Vasculitis Foundation guidelines, post-remission induction with RTX or CYC, maintenance therapies using RTX, MTX, azathioprine (AZA), mycophenolate mofetil, or leflunomide are recommended. If remission is not achieved, switching to an alternative remission induction agent (RTX or CYC) may be considered. In cases of relapse during maintenance therapy, CYC is recommended for severe flares on RTX, and RTX is recommended for severe flares not on RTX.4
DISCUSSION
Dr. Eui-Jong Kwon: This case is very interesting because there were no typical clinical features of MPA such as renal or pulmonary involvements in initial presentation. Have there been any reported cases similar to this patient?
Dr. Jiwon Yang: In 2002, a systematic review study on inflammatory muscle involvement in systemic vasculitis was published.6 This study reviewed 108 papers and analyzed 395 patients affected by muscle vasculitis. The majority of patients had medium or small vessel vasculitis, primarily polyarteritis nodosa and AAV, or vasculitis secondary to rheumatoid arthritis (RA). The most common histological findings were necrotizing vasculitis of perimysium vessels. CPK levels were mostly within the normal range, and MRI findings were indistinguishable from idiopathic inflammatory myopathies. Overall, patients demonstrated positive responses to conventional immunosuppressants and glucocorticoids.
Furthermore, several case reports have highlighted muscle weakness as an initial feature of AAV.
In the first case, a 76-year-old woman presented with myalgia and elevated CRP levels, while muscle MRI indicated muscle edema, despite CPK levels being within the normal range. Positive anti-MPO antibodies and muscle biopsy consistent with small-vessel vasculitis were observed. High-dose prednisolone was initiated, tapered over six months, and when symptoms relapsed, AZA was added. The addition of AZA led to the maintenance of remission.7
In another case, an 82-year-old man experienced worsening fatigue, myalgia, and weakness in both legs. Similarly, CRP was elevated while CPK remained normal. Positive anti-MPO antibodies were detected, and muscle biopsy showed fibrinoid necrosis of the medium-sized vessels. High-dose steroids were administered and tapered, with remission sustained through the combination of RTX.8
Lastly, our recent experience involved a similar case at our hospital. A 54-year-old man presented with pain in both legs. Although fever, elevated ESR and CRP levels were noted, CPK and myoglobin levels remained within the normal range. Thigh MRI revealed intramuscular high signal intensity mainly around intramuscular vascular branches with vessel engorgement. Anti-MPO antibodies were positive in his serum. Histologic assessment of a thigh muscle biopsy indicated necrotizing fibrinoid vasculitis.
Dr. Kyung-Su Park: How should we interpret the positive results for anti-SS-A antibody, anti-SS-B antibody, and RF? Have any additional evaluations been conducted in relation to these findings?
Dr. Jiwon Yang: The patient reported experiencing dryness in the eyes and mouth, prompting evaluations for Sjögren’s syndrome. The Schirmer’s test yielded a positive result, and the unstimulated whole salivary flow rate measured 0 mL/5 min. The total score based on the 2016 ACR/EULAR classification criteria for Sjögren’s syndrome was 5, suggesting the possibility of secondary Sjögren's syndrome.
Regarding the positivity of RF, it’s important to note that the patient did not exhibit clinical synovitis in at least one joint. However, even when applying the 2010 ACR/EULAR classification criteria for RA to this particular case, the total score is 4, less than 6, thus not compatible with the criteria for RA.
Related questions
Available at https://doi.org/10.3346/jkms.2023.38.e351
Disclosure:The authors have no potential conflicts of interest to disclose.
Author Contributions:
Conceptualization: Park Y.
Data curation: Yang J, Ryu Y, Jeon H, Kwon E, Park Y.
Supervision: Park KS.
Writing - original draft: Yang J.
Writing - review & editing: Park Y.
ACKNOWLEDGMENTS
The Case Conference section is prepared from the monthly case conference of the Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
References
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