27 January 2023: Articles
Case Report of 59-Year-Old Woman with Bilateral Upper Limb Musculoskeletal Amyloid, Initially Diagnosed as Rheumatoid Arthritis
Mistake in diagnosis, Diagnostic / therapeutic accidentsHai Binh Bui1ABDEF, Thi Sinh Phan2BCDE, Quoc Thanh Truong3CDE, Tien Luu Doan4BCDE, Thi Hai Van Hoang5DEF*
Am J Case Rep 2023; 24:e938582
BACKGROUND: Amyloid light-chain (AL) amyloidosis is usually due to deposition of immunoglobulin lambda light chains from plasma cells in patients with multiple myeloma. AL amyloid may involve the salivary glands, gastrointestinal tract, peripheral nerves, and skin. However, musculoskeletal amyloid and amyloid arthropathy are rare. This report is of a woman with bilateral upper limb musculoskeletal amyloid and amyloid arthropathy associated with multiple myeloma, initially diagnosed and managed as a case of rheumatoid arthritis.
CASE REPORT: A 59-year-old woman who was initially diagnosed with rheumatoid arthritis presented with bilateral polyarthritis in the upper limbs. Despite treatment with corticosteroids, methotrexate, and hydroxychloroquine, her symptoms did not improve. After 4 months, she revisited our hospital with the appearance of swollen soft tissue in the upper right arm and numbness of the right hand. She had an arthroscopic synovectomy of the right shoulder joint, and the mass in the right elbow area was removed. These specimens were positive by Congo red stain and confirmed the deposition of light chain protein as amyloid. She was diagnosed with multiple myeloma according to International Myeloma Working Group criteria, including bone marrow plasma cells more the 10%, lytic lesions in bone, and anemia.
CONCLUSIONS: This report highlights the importance of imaging, biopsy, and laboratory investigations in patients with arthropathy and musculoskeletal disease. In this case, the patient was seronegative for rheumatoid arthritis, and the presentation with very thick and nodular synovium supported an alternative diagnosis. The identification of musculoskeletal amyloid and amyloid arthropathy confirmed underlying multiple myeloma.
Keywords: Amyloidosis, Arthritis, Arthritis, Rheumatoid, Multiple Myeloma, Female, Humans, Middle Aged, Diagnosis, Differential, Upper Extremity
Amyloid light-chain (AL) amyloidosis is a systemic disease characterized by the deposition of kappa or lambda-type monoclonal light chains from bone marrow plasma cells . The fragments are deposited and accumulate in different tissues, which ultimately leads to the destruction of tissue and progressive disease . The first study of AL amyloidosis was done in Olmsted Country and published in 1992 . It is an uncommon systemic disease, with an estimated annual incidence of 9.7 to 14.0 cases per million .
Amyloidosis is classified into several types that depend on the precursor of amyloid fibril. The 4 most common types of systemic amyloidosis are primary (AL) amyloidosis, familial amyloidosis, wild-type transthyretin systemic amyloidosis, and secondary amyloidosis . In a cohort study of rheumatoid arthritis (RA), secondary amyloidosis was the most common in RA (16.3%) .
The effects of amyloid deposition on almost all organs and systems means it can present with a variety of symptoms or signs, such as nephrotic syndrome, liver involvement, and restrictive cardiomyopathy; it can also present in the salivary glands, gastrointestinal tract, peripheral nerves, and skin [6,7]. According to a cohort study, the frequency of amyloid arthropathy is 3% of patients with multiple myeloma . The joints most frequently diagnosed with AL amyloidosis are the shoulders and wrists, but can be in other joints in the upper limbs . Other involvement such as peripheral joints is possible, which can mimic a systemic rheumatic disease. This report is of a 59-year-old woman with bilateral upper limb musculoskeletal amyloid and amyloid arthropathy associated with multiple myeloma, initially diagnosed and managed as a case of RA.
A 59-year-old woman with ostensible polyarthritis was admitted to the Outpatient Department at Bach Mai Hospital. She had bilateral shoulder pain and pain in several small joints in her hands for 1 year. The symptoms were subacute and low-grade. She reported that it disturbed her daily activities because she had swelling, tenderness, and decreased movement of several joints in her hands, including metacarpophalangeal. It always happened in the morning. Her history showed she had moderate anemia, with a hemoglobin level of 9.5 g/dL (reference range: 12.0 to 16.0 g/dL), her peripheral blood leukocyte count was 7980/mL (neutrophils 4680/mL, lymphocytes 2660/mL), and her platelet count was 284×106/mL. The erythrocyte sedimentation rate was elevated at 55 mm/h, and serum C-reactive protein level was 5.1 mg/L. Both the rheumatoid factor and the anti-cyclic citrullinated peptide antibody were negative, at 6.2 U/mL (reference range: < 14 U/mL) and 1.9 U/mL (<5: negative), respectively. RA with negative rheumatoid factor was diagnosed by the outpatient doctor, who prescribed the patient prednisolone, methotrexate, and hydroxychloroquine. At the beginning, during the acute phase, she was receiving therapy with 32 mg methylprednisolone per day. Then, the doctor tapered the doses by 10% each week for 3 months. After 3 months, her status was initially controlled on 4 mg per day, while combined with methotrexate and hydroxychloroquine. However, her symptoms relapsed, resulting in her admission to the local hospital in October 2020.
After 1 month, she had bilateral femoral neck fractures with a slight trauma and was referred to the Surgery Department at the local hospital. Fracture of both femoral necks was diagnosed, without any imaging recorded. The patient had total bilateral hip replacement, rehabilitation, and medication to manage pain. She had very low bone mass density (T scores at hip and spine were −4.7 and −3.4, respectively), so she was given an intravenous bisphosphonate therapy and oral calcium and vitamin D3 supplements. No other tests were recorded. She had little symptom improvement after 4 months. Her shoulder joints were still painful and she had emerging swollen soft tissue on the right elbow joint. She was examined in the Outpatient Department of Bach Mai Hospital several times within 4 months and only felt better when using high-dose corticosteroid of 40 mg per day. Moreover, the symptoms relapsed after the lowering of the corticosteroid dose.
Seven months ago, she came back to us with symptoms of numbness and paresthesia in both hands and was admitted to our Rheumatology Department. On general physical examination, she was moderately built and poorly nourished, conscious and oriented, and her pulse and skin temperature were normal. Her blood pressure was 120/70 mmHg. There was mild pallor but no cyanosis or lymphadenopathy. Examination of skin revealed no purpura, petechiae, or ecchymoses on the body. Clinical examination of the cardiovascular, nervous, respiratory, and digestive systems was unremarkable. Rheumatology examination revealed swelling, tenderness, and decreased movement of several joints in the upper limbs, including small joints in both hands, and especially in the right shoulder and elbow. Morning stiffness lasted more than 1 h. Her hips were difficult to move because of the hip replacements. Laboratory examination revealed hemoglobin of 10.8 g/dL (reference range: 12.0 to 16.0 g/dL), normal total leucocyte count (6800/mL, with 52% of neutrophils) and platelet count (342×106/mL). The erythrocyte sedimentation rate was 60 mm in the first hour. Peripheral blood smear showed normocytic, normochromic red blood cells. The random blood glucose level was within the reference range. The following test results were also within the reference range: serum creatinine 71 µmol/L (64 to 104 µmol/L), serum total calcium 2.43 mmol/L (2.15 to 2.55 mmol/l), ionized calcium 1.2 mmol/L (1.17 to 1.29 mmol/L), serum alkaline
phosphatase 53 IU/L (40 to 129 IU/L), and serum parathyroid hormone 2.93 pmol/L (1.6 to 6.9 pmol/L). Liver function tests revealed serum total bilirubin, serum albumin 3.67 g/dL (3.4 to 4.8 g/dL), SGOT, and SGPT were within the reference range. Serum total protein was 5.82 g/dL (6.4 to 8.3 g/dL). The prothrombin time, activated partial thromboplastin time, and international normalized ratio were normal. Alpha-fetoprotein was negative. The HBsAg ELISA and anti-hepatitis C were negative. The HIV ELISA was nonreactive. The 24-h urine protein was 1560 mg/day. The Bence Jones protein in the urine was negative. Ultrasonography of the abdomen and chest X-ray were normal. The patient underwent esophagogastroduodenoscopy and colonoscopy for evaluation of gastrointestinal bleeding and tumor or other symptoms, and the results were normal. Radiographs of the skull, lumbar spine, and pelvis did not show lytic lesions but showed diffuse osteoporosis and total hip arthroplasty. Plain radiograph of the right shoulder showed lytic bone lesions and multiple juxta-articular and subchondral cystic lesions. Ultrasound of shoulders, elbows, and wrists showed minimal hypoechoic synovial hypertrophy, with or without effusion, especially focal mixed echoic nodule, like a mass in the right shoulder and elbow joint. Magnetic resonance imaging (MRI) of the right shoulder joint (Figure 1) showed thick synovitis and multiple nodular deposition in the synovial membrane of abnormal soft tissue, which had low signal intensity on T1-weighted imaging, intermediate signal intensity on T2-weighted fat-suppressed imaging, and peripheral T1-weighted contrast enhancement imaging. These substances also filled the subchondral defects and extended to the periarticular soft tissue. Furthermore, an elbow MRI, as seen in Figure 2, also showed a nodule in the anterior elbow.
She underwent an arthroscopic synovectomy and removal of the suspicious tumor of the shoulder and elbow joint. The arthroscopic view of the affected joint synovium showed synovial hyperplasia and congestion in all joints; therefore, the surgeons conducted synovial biopsies and hemostasis procedures. The open release surgical technique for carpal tunnel syndrome in her hands helped her feel better, with less numbness of the upper extremities.
Figure 3 illustrates the histological findings from the right shoulder specimen. The pathology of 2 specimens from the right shoulder synovium and right elbow mass showed the same result, namely the deposition of amyloid and inflammatory invasion in around the tissue and no detected malignant cells. These specimens were positive by Congo red stain (Figure 3C, 3D: typical apple-green birefringence under a polarized microscope).
With this histochemical method, the deposition of light chain protein was confirmed. As seen in Figure 4, immunofixation electrophoresis analysis showed imaging of the peak of the kappa chain. The measurement of free light chain in the blood showed the increased kappa (22 800 mg/L; reference range, 3.3–19.4 mg/L), and the amount of plasma cell infiltrate in the bone marrow specimen was 48% (Figure 5). The International Myeloma Working Group criteria was used for the diagnosis of multiple myeloma, including clonal bone marrow plasma cells of 48% (>10%), the deposition of light chain protein in shoulder synovium and right elbow mass, anemia without any identified causes, and lytic lesions in the right humeral head bone. This was a case of a symptomatic kappa light chain multiple myeloma complicated by AL amyloidosis. Up to now, she has been treated with chemotherapy in the Hematology Department. Her symptoms are relieved and her status is better.
This case report illustrates one of important clinical features of myeloma diagnosis, which is that we need to consider the kappa immunoglobulin light chain, not only the lambda light chains. Musculoskeletal diseases are associated with a variety of amyloid types, including AL, wild-type transthyretin systemic, and beta-2 microglobulin amyloidosis. Light chain protein can affect most tissues, but the musculoskeletal manifestations of amyloid deposition can be subtle and insidious. The onset of rheumatoid symptoms coincides with multiple myeloma; thus, it is diagnosed late . This case did not have any typical presence of light chain immunoglobulin deposition disease, including nephrotic syndrome, restrictive cardiomyopathy, or involvement of the liver, salivary glands, gastrointestinal tract, peripheral nerves, or skin [7,10]. The patient had bilateral shoulder synovitis, and metacarpophalangeal and proximal interphalangeal arthritis, which increased the difficulty in distinguishing between AL amyloidosis and typical RA. According to 2 case reports from Katoh et al, 2 case reports from Alpay et al, 1 case report from Majumder et al, AL amyloidosis occasionally causes inflammatory polyarthritis and morning stiffness, which are indistinguishable from polyarthritis [11–13]. Multiple myeloma requires conducting intensive examinations according to the International Myeloma Working Group diagnosis criteria, and our patient had fully met the criteria for the diagnosis of multiple myeloma . In many studies, the presence of the lambda light chains is more frequent than that of kappa light chains, but in our patient, the kappa immunoglobulin light chain was detected in her serum .
Our patient had both amyloid arthropathy and carpal tunnel syndrome. According to the systematic review of Wechalekar et al, cardiac involvement is the leading cause of organ injury, affecting approximately 50% of patients with AL amyloidosis, indicating that not all AL amyloidosis patients have cardiac involvement . Furthermore, Prokaeva et al published a case study of 191 patients with AL amyloidosis that showed the frequency of musculoskeletal disease was present in 42.9% of those cases, including macroglossia (23%), carpal tunnel syndrome (13.1%), amyloid arthropathy (3.7%) and pseudohypertrophy of the skeletal muscle (1.6%) . The clinical presentation resembled RA, but the serological markers, including anti-cyclic citrullinated peptide and rheumatoid factor, were negative. If active RA was the cause of the pain in our patient, the C-reactive protein level should have increased more than was observed. Consistent with our case, according to Randrianarisoa et al, previous studies have shown that several cases of amyloid arthropathy were initially diagnosed as seronegative RA .
Musculoskeletal imaging plays a crucial role in the diagnosis of the diseases. Distribution is frequently bilateral. Patients with large subchondral lesions have a high prevalence of pathologic fractures. In the past, the patient’s femurs were broken with a slight trauma which required surgery, and the surgeons had missed the chance to diagnose the cause of the disease. X-ray can show lytic lesions, which are spots of bone damage that result from cancerous plasma cells. In addition, on plain radiograph, findings of amyloid arthropathy are similar to an erosive arthropathy, due to the presence of juxtaarticular and subchondral erosions and juxta-articular osteoporosis . Distribution is frequently bilateral. Patients with large subchondral lesions have a high prevalence of pathologic fractures. Ultrasound of the joints can show synovial hyper-trophy, especially focal mixed echoic nodules like a mass. On MRI, amyloid arthropathy is characterized by extensive deposition in the synovial membrane, subchondral defects of a material which has low signal intensity on T1-weighted imaging, low to intermediate signal intensity on T2-weighted imaging, and mild peripheral enhancement following administration of intravenous gadolinium . This abnormal deposition can extend to periarticular soft tissue, and joint effusions are usually present [20–22]. Differential diagnoses include gout, pigmented villonodular synovitis, and hemophilia, which also demonstrate low signals on fluid-sensitive sequences [20,21].
Biopsy of a suspected organ is the most effective method of diagnosis. Today, there are a wide range of modern techniques and machines which ensure a high biopsy success rate, such as abdominal fat pat aspirate at 60% to 80%, rectal biopsy at 50% to 70%, bone marrow biopsy at 50% to 55%, and skin biopsy at 50% . The amyloid fibrils can be detected by Congo red staining of biopsied tissue, which is shown under polarized light with green birefringence .
This report has highlighted the importance of imaging, biopsy, and laboratory investigations in patients with arthropathy and musculoskeletal disease. In this case, the patient was seronegative for RA, and the presentation with very thick and nodular synovium supported an alternative diagnosis. The identification of musculoskeletal amyloid and amyloid arthropathy confirmed underlying multiple myeloma.
FiguresFigure 1.. Plain radiograph (A) and magnetic resonance imaging (MRI) (B–D) of the right shoulder. (A) Plain radiograph of shoulder shows lytic bone lesions (yellow arrow), multiple juxta-articular and subchondral cystic lesions (geodes), with well-defined sclerotic margins (black arrow). The joint space width is normal. (B) MRI with axial T1-weighted imaging (T1W), (C) sagittal T2-weighted fat-suppressed imaging (T2FS), and (D) axial T1W imaging after contrast (T1C+) show multiple nodular deposition in synovial membrane of an abnormal soft tissue that have the low signal intensity on T1W, intermediate signal intensity on T2FS, peripheral enhancement on T1C+ (white arrow). These substances also fill the subchondral defects (yellow arrow) and extend to periarticular soft tissue (yellow star). Figure 2.. Magnetic resonance imaging of the elbow. (A, B) Sagittal section (left to right T1-weighted [T1W], T2-weighted fat-suppressed [T2FS]). (C) Axial T1-weighted, (D) post-gadolinium contrast imaging. A slight effusion was present in the anterior and posterior recessus joint, with an hyperintense signal on T2W sequence (black arrow). There is extensive effusion of the bicipitoradial bursa, with synovial thickening that is low signal intensity on T1W and T2FS sequences and mild peripheral enhancement after contrast (D) (white arrow), consistent with bicipitoradial bursitis. Figure 3.. Histological findings from right shoulder specimen. (A, B) Hematoxylin-eosin staining: photomicrograph showing pink material deposition (green arrow), fibrous septal invasion by lymphocytes (black arrow), and increased stromal cellularity in part due to infiltrating large mononuclear cells. (C, D) Show amyloid deposition by Congo red staining: (C) red deposits as seen in un-polarizing light, and (D) typical apple-green birefringence seen under polarizing light. Figure 4.. Imaging the peak of kappa chain by immunofixation analysis (in red circle). Figure 5.. Bone marrow plasma cells. (A) The increase of plasma cells (black arrow) in the bone marrow (Giemsa staining, ×10). (B) Abnormal (atypical) plasma cells (black arrow) (Giemsa staining, ×100).
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