|CASE BASED REVIEW
|Year : 2022 | Volume
| Issue : 2 | Page : 180-185
Childhood-onset enthesitis-related arthritis leading to nephrotic syndrome due to secondary amyloidosis complicated by acute pulmonary embolism - The domino effect
Vishal Mangal1, Bhaskar Datt2, Arun Hegde3, AW Kashif4, Ankit Kumar1, Jaspreet Kaur4, Nidhi Goel1, Anil Shankar Menon1
1 Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Nephrology, Command Hospital Southern Command, Pune, Maharashtra, India
3 Department of Rheumatology, Command Hospital Southern Command, Pune, Maharashtra, India
4 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||26-Jul-2021|
|Date of Acceptance||12-Dec-2021|
|Date of Web Publication||28-Mar-2022|
Dr. Vishal Mangal
Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
The prevalence of Juvenile idiopathic arthritis (JIA) in India is 0.001% among the population under 16 years old and 0.00029% among the total population. Of the total JIA population, enthesitis-related arthritis (ERA) constitutes 35% of the cases. In the past, chronic infections, mainly, tuberculosis were the most common cause of AA amyloidosis in India; however, chronic inflammatory arthropathies have become the most common cause of AA amyloidosis in India over the past three to four decades. In 95% of the patients with AA amyloidosis, the kidney is the most affected organ presenting as proteinuria of nephrotic syndrome. The prevalence of AA amyloidosis in JIA is estimated to be 7.7% and 3.1% among the ERA group, making it an infrequent association. This translates to one case of AA amyloidosis secondary to ERA per 1,00,000,00 population in India. Similarly, the incidence of pulmonary thromboembolism in patients with nephrotic syndrome is 7.8%. We present a case of a young male who was diagnosed with JIA-ERA at the age of 13 years with multiple flares in childhood had now developed nephrotic syndrome secondary to AA amyloidosis demonstrated on renal biopsy complicated by acute pulmonary embolism and occult hepatitis B infection. He was managed with anti-tumor necrosis factor inhibitor therapy with a favorable outcome. This is the first such case of multiple rare associations occurring together in a single patient to the best of our knowledge.
Keywords: Amyloidosis, case report, enthesitis-related arthritis, infliximab, nephrotic syndrome
|How to cite this article:|
Mangal V, Datt B, Hegde A, Kashif A W, Kumar A, Kaur J, Goel N, Menon AS. Childhood-onset enthesitis-related arthritis leading to nephrotic syndrome due to secondary amyloidosis complicated by acute pulmonary embolism - The domino effect. Indian J Rheumatol 2022;17:180-5
|How to cite this URL:|
Mangal V, Datt B, Hegde A, Kashif A W, Kumar A, Kaur J, Goel N, Menon AS. Childhood-onset enthesitis-related arthritis leading to nephrotic syndrome due to secondary amyloidosis complicated by acute pulmonary embolism - The domino effect. Indian J Rheumatol [serial online] 2022 [cited 2022 Aug 9];17:180-5. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/180/341048
| Introduction|| |
AA amyloidosis is a type of acquired, systemic disease due to deposition of the positive acute-phase reactant protein serum amyloid A (A-SAA) in the setting of chronic inflammation or infection. The most common diseases associated with AA amyloidosis are tuberculosis, osteomyelitis, Castleman disease, rheumatoid arthritis, axial spondyloarthropathies, and juvenile idiopathic arthritis (JIA). In Western countries, AA amyloidosis is the second most common type of amyloidosis with an estimated incidence of 1.6/million population; however, in India, it is the most common type of amyloidosis, but the exact incidence is not known. In the past, chronic infections, mainly, tuberculosis were the most common cause of AA amyloidosis in India; however, chronic inflammatory arthropathies have become the most common cause of AA amyloidosis in India over the past three to four decades. In 95% of the patients with AA amyloidosis, the kidney is the most affected organ presenting as proteinuria of nephrotic syndrome. However, amyloid deposits can be seen in the liver, spleen, gastrointestinal tract, and adrenals without leading to any organ dysfunction. The involvement of the heart and nerves is infrequent. In India, the estimated biopsy incidence of amyloid nephropathy is 1.9%. The most common cause of amyloid nephropathy in India is chronic inflammatory diseases, responsible for 48.2% of the cases, followed by chronic infections, which account for 34.4% of the cases. The prevalence of JIA in India is 0.001% among the population under 16 years old and 0.00029% among the total population. Of the total JIA population, enthesitis-related arthritis (ERA) constitutes 35% of the cases. The prevalence of AA amyloidosis in JIA is estimated to be 7.7% and 3.1% among the ERA group, making it a rare association. This translates to one case of AA amyloidosis secondary to the ERA per 1,00,000,00 population in India.
Similarly, the incidence of pulmonary thromboembolism in patients with nephrotic syndrome is 7.8%. We present a case of a young male who was diagnosed with JIA-ERA at the age of 13 years with multiple flares in childhood had now developed nephrotic syndrome secondary to AA amyloidosis complicated by acute pulmonary embolism and occult hepatitis B infection (OBI). This is the first such case of multiple rare associations occurring together in a single patient to the best of our knowledge.
| Case Report|| |
A 24-year-old male with a past medical history of JIA-ERA for the past 11 years not on regular medication and history of generalized swelling over the body, and frothy urine for the past 6 months now presented to our center with acute onset breathlessness on exertion for the past 7 days.
The course of disease till 2020
At the age of 13 years, the patient developed acute onset pain in the middle of the right foot associated with swelling and difficulty bearing weight. He did not have any history of trauma preceding the onset of pain. He consulted an orthopedic surgeon and was advised a below-knee Plaster of Paris cast for 4 weeks. One week after applying the cast, he developed alternating buttock pain associated with early morning stiffness (EMS) lasting more than 30 min. He was prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) and his symptoms subsided over the next few weeks. He was lost to follow-up, and at the age of 15 years, he developed pain and swelling of both the knee joints associated with stiffness and marked disability in the form that he could not walk without the support of two persons. This time, he was diagnosed as a case of JIA-ERA based on arthritis plus a history of inflammatory back pain, sacroiliac tenderness on examination, and onset of arthritis in a male more than 6 years of age. He was negative for rheumatoid factor at this time; however, antinuclear antibody and human leukocyte antigen (HLA)-B27 were not tested. His erythrocyte sedimentation rate (ESR) was 105 mm fall in 1 h with C-reactive protein of 2.4 mg/dL. He did not have enthesitis at that time. He was managed with tablet naproxen 500 mg three times a day and tablet sulfasalazine 500 mg twice a day. The patient responded well to therapy with remarkable improvement in his symptoms. He continued sulfasalazine for the next 3 years, and his ESR came down to 10 mm fall in 1 h. He stopped all the medication and was again lost to follow-up. At the age of 20 years, he developed pain and swelling of both the shoulder joints with marked restriction of the movements and inflammatory backache. It was associated with EMS for more than 30 min. His ESR was 110 mm fall in 1 h. He was again started on NSAIDs and sulfasalazine, which he continued for 1 year and then stopped. He remained in remission for the next 2 years.
The course of disease in 2021
At the age of 23 years, he started developing swelling over both feet, first noticed when he could not wear his slippers because of swollen feet. This swelling progressed over the next 2 weeks to involve genitalia, lower abdomen, and back. He also noticed early morning swelling around the eyes. He also gave a history of passing frothy urine at the same time. He denied any history of blood in urine, fever, and sore throat; however, he gave the history of increased urine output. Initial laboratory parameters are presented in [Table 1]. He was diagnosed with nephrotic syndrome based on anasarca, proteinuria, hypoalbuminemia, hypertriglyceridemia, normal blood pressure, and absence of hematuria. He underwent ultrasonography of the abdomen, which revealed the right kidney measuring 12 cm with increased cortical echogenicity and left kidney measuring 3 cm. He was managed with oral glucocorticoids and loop diuretics by the physician at a different center. His symptoms subsided over the next 1 month; however, during follow-up, he was noticed to have an increase in proteinuria [Table 1]. He was advised to continue the same medications. He continued the medication and developed breathlessness on exertion, first noticed while playing cricket. The patient did not seek any medical attention at this time; however, his symptoms gradually worsened over the next 1 week when he used to get breathless even after getting out of bed. He reported at our center with complaints of breathlessness on exertion. He denied any history of chest pain, palpitations, cough, expectoration, and hemoptysis. On examination, he had tachycardia with a blood pressure of 118/76 mm of Hg, respiratory rate of 22/minute, and oxygen saturation of 96% on room air. He had bilateral pitting pedal edema localized to the ankles. His metrology on admission suggested restricted modified Schober's test and lateral flexion with normal intermalleolar distance and tragus to wall distance with normal cervical rotation. The initial laboratory workup is presented in [Table 1]. Chest radiograph on admission showed oligemia in bilateral upper and middle zones [Figure 1]a. The electrocardiogram showed sinus tachycardia. With the background of recently diagnosed nephrotic syndrome and acute onset breathlessness, the clinical diagnosis of pulmonary thromboembolism was considered. The patient underwent computed tomographic pulmonary angiography, which showed hypodense filling defects in the main pulmonary artery and right pulmonary artery extending to involve the third-order branches bilaterally suggestive of acute pulmonary artery thromboembolism. We did not test him for inherited or acquired thrombophilias. The patient was started on tablet apixaban 5 mg twice a day. His 24-h urinary protein was 5.5 gm. He was subjected to a renal biopsy which was consistent with secondary amyloidosis [Figure 2]. The short axis posterior view radiograph of the sacroiliac joints revealed bilaterally ankylosed sacroiliac joints [Figure 1]b. He was positive for HLA-B27 The detailed immunological workup is depicted in [Table 2]. The final diagnosis of JIA-ERA evolving to axial spondyloarthritis with solitary right kidney, secondary renal amyloidosis leading to nephrotic syndrome, and acute pulmonary embolism was established. He was managed with loop diuretics, angiotensin receptor blockers, statins, and novel anticoagulants. He was administered anti-tumor necrosis factor inhibitor (TNF) infliximab. As a prerequisite for infliximab administration, he was screened for latent tuberculosis and hepatitis B. He was negative for latent tuberculosis; however, he was found to have OBI (normal liver enzymes, hepatitis B surface antigen (HBsAg)-negative, anti HBc total-positive, and hepatitis B virus (HBV) DNA quantitative level-target not detected) [Table 2]. He was started on tablet entecavir 0.5 mg once daily because of the prolonged requirement of immunosuppression and higher risk of reactivation with biologics therapy compared to steroid therapy for prolonged use (>04 weeks). He was discharged with advice for regular follow-up.
|Figure 1: (a) Chest radiograph: the red arrows show pulmonary oligemia. (b) The radiograph of the sacroiliac joints: the red arrows show the complete ankylosis of the bilateral sacroiliac joints|
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|Figure 2: (a) An enlarged glomerulus showing eosinophilic, amorphous, hyaline deposits in the mesangium, and glomerular basement membrane (yellow arrow, H and E, ×400). (b) These deposits are weakly periodic acid–Schiff-positive and are seen to be present within the vessel wall (yellow arrow, periodic acid–Schiff stain, ×400). (c) The deposits are nonargyrophilic (yellow arrow, periodic Schiff-Methenamine Silver stain, ×400). (d) The deposits are congophilic and show apple-green birefringence under polarized light (yellow arrow, Congo red stain, ×400)|
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| Discussion|| |
Amyloidosis term is used to describe a group of disorders characterized by protein misfolding and extracellular deposition of protein fibrils in various tissues. Amyloid diseases are classified based on the nature of the misfolded protein, whether the deposition is systemic or localized, and the etiology such as acquired or inherited. AA amyloidosis is caused by the deposition of SAA in tissues and organs. SAA is a normal acute phase reactant in the human body with a mean plasma concentration of <3 mg/L in healthy individuals. It is a high-density lipoprotein binding apolipoprotein, its role in healthy individuals was unknown for years; however, the recent discovery of SAA messenger ribonucleic acid expression in extrahepatic tissues such as atherosclerotic plaques, endothelial cells, epithelial cells, lymphocytes, and synovial tissue in rheumatoid arthritis patients has opened a whole new world of possibilities. The level of SAA can increase up to 1000 times of the normal value under chronic inflammatory conditions, thus leading to deposition in various tissues.
The diagnosis of amyloidosis involves a multidisciplinary approach which starts with a high index of suspicion on clinical evaluation, hematological, and biochemical investigations, various imaging techniques, histopathology of the biopsied tissue, characteristic apple-green birefringence under polarized light on Congo red staining, and immunohistochemistry (IHC) for identifying the specific type of amyloid protein and genetic analysis. Serum amyloid P component (SAP) scintigraphy is an imaging technique that uses 123iodine SAP to image the visceral amyloid, and it also quantifies the load of amyloid deposits, which can be monitored serially. However, limited availability is the reason why it has not gained popularity.
Our patient had a history of childhood-onset JIA-ERA with poor compliance to treatment and multiple flares in childhood. He had presented with an anasarca. His initial laboratory parameters and clinical presentation suggested nephrotic syndrome. The nephrotic syndrome in a young adult with a history of chronic inflammation in the past 10 years, as evident by his past medical records, made us suspect AA amyloidosis. His kidney biopsy and abdominal fat pad biopsy showed features characteristic of AA amyloidosis [Figure 2]. The IHC of the kidney biopsy identified the SAA protein. Two-dimensional echocardiography did not show any features of restrictive cardiomyopathy. Cardiac magnetic resonance imaging can also be used in cases of suspected cardiac involvement, which shows characteristic late gadolinium enhancement. Our patient also had OBI. It is documented in the literature that chronic hepatitis B infection can very rarely lead to amyloidosis and nephrotic syndrome. To the best of our knowledge, there are only three cases reported in the literature with AA amyloidosis associated with chronic hepatitis B infection., However, the association of OBI and amyloidosis has never been reported in the literature. Furthermore, the patient should be a carrier for at least a substantial period for developing the Nephrotic Syndrome as in a case report by Jiang et al. where the patient was a carrier of Hepatitis-B for 30 years which is not the case in the present patient. Chronic hepatitis-B infection can increase the risk of thrombosis by various mechanisms such as (1) infection-mediated inflammation, (2) hemostatic impairment, (3) prothrombotic state associated with chronic liver disease, and (4) antiphospholipid antibodies. However, in the present case, pulmonary thromboembolism occurred as a complication of nephrotic syndrome, and the patient did not have a chronic hepatitis-B infection; instead, he had an OBI, which does not increase the risk of thrombosis. Hence, the hepatitis-B-amyloidosis-nephrotic syndrome pathway leading to pulmonary thromboembolism is less apt to this case as compared to the JIA-ERA-amyloidosis-nephrotic syndrome pathway leading to pulmonary thromboembolism.
The primary treatment modalities for JIA-ERA are NSAIDs, disease-modifying antirheumatic drugs (DMARDs), and biological compounds of anti-TNF drugs. Our patient was initially managed with NSAIDs followed by sulfasalazine. However, multiple episodes of loss to follow-up despite ongoing chronic inflammation, as evidenced by the persistently raised ESR, might have led to the onset of secondary amyloidosis within 10–12 years of JIA-ERA diagnosis. Another DMARD used in the management of ERA is methotrexate, usually in the dose of 10–15 mg/m2 once a week. The anti-TNF agents approved for ERA management are etanercept and adalimumab. However, they provide only symptomatic relief after the onset of sacroiliitis or evidence of joint damage on radiographs and do not halt the disease progression. Our patient did not receive biological agents for the management of ERA.
Anti-TNF agents such as etanercept and infliximab have been used in the past to treat systemic AA amyloidosis. Anti-TNF therapy significantly reduces the proteinuria and markers of chronic inflammation along with improvement in renal function. This response is independent of the duration of rheumatic disease, amyloidosis, age, and baseline renal function. Recently, it has been described that Interleukin-6 (IL-6) is one of the inflammatory cytokines responsible for releasing SAA and subsequent AA amyloidosis. A few case reports have demonstrated successful treatment of AA amyloidosis using IL-6 receptor antibodies such as tocilizumab. We administered infliximab to our patient for the management of proteinuria, to which he responded well. This fact further confirms the likelihood of the JIA-ERA-amyloidosis-nephrotic syndrome pathway leading to pulmonary thromboembolism. Our patient received infliximab with prior prophylactic antiviral therapy with entecavir to prevent the reactivation of hepatitis B. According to Perrillo et al., there is the reactivation of hepatitis B in HBsAg-negative, anti-HBc-positive patients in 0%–5% of cases in patients receiving moderate risk immunosuppression such as biologics therapy with TNF-alpha inhibitors. However, there is a paucity of data suggesting the definitive role of antivirals in such patients. However, the American College of Gastroenterology recommends that antivirals may be used to prevent reactivation in such patients. Because of his young age, he was given prophylactic antivirals to prevent HBV reactivation, and he is being followed up to look for reactivation.
| Conclusion|| |
JIA-ERA is an uncommon disease. The lack of knowledge and poor follow-up by the patient, delay in diagnosis by the general physician, and poor access to specialized care led to the domino effect of one event leading to another. In our case, JIA-ERA led to AA amyloidosis, which further contributed to nephrotic syndrome leading to acute pulmonary embolism. Early diagnosis and adequate management of JIA-ERA could have prevented these complications. The rarity of this event reinforces the need to have awareness about this entity so that adequate measures at the appropriate time may halt the potential occurrence of fatal events.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]