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CASE BASED REVIEW
Ahead of print publication  

Adult-onset Still's disease: A great masquerader triggered by hepatitis A infection


 Department of Medicine, AIIMS, Raipur, Chhattishgarh, India

Date of Submission17-Jun-2020
Date of Acceptance22-Jul-2020

Correspondence Address:
Jhasaketan Meher,
Department of Medicine, AIIMS, Raipur - 492 099, Chhattisgarh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_155_20

  Abstract 


Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology. The varied clinical presentation of the disease mimicking many other diseases makes it difficult to diagnose. Various infectious triggers in a genetically susceptible host have been described in literature. We report a case of a 25-year-old female who presented with fever, rash, and arthralgia and diagnosed to be AOSD triggered by hepatitis A infection after excluding other differentials. She was managed with corticosteroids with dramatic response and continued to be in remission even after steroid withdrawal.

Keywords: Adult-onset Still's disease, hepatitis A virus, infection



How to cite this URL:
Meher J, Nagpure KB, Siddiqui MS, Vishnu Dev A M. Adult-onset Still's disease: A great masquerader triggered by hepatitis A infection. Indian J Rheumatol [Epub ahead of print] [cited 2020 Dec 4]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=298854




  Introduction Top


Adult-onset Still's disease (AOSD) is an inflammatory disorder of unknown etiology characterized by quotidian (daily) fevers, arthritis, and an evanescent rash and multiorgan involvement.[1] The etiology of AOSD remains unknown. Here, we describe a case of AOSD triggered by hepatitis A virus infection.


  Case Report Top


A 25-year-old unmarried female presented with a history of high-grade fever, polyarthralgia, and myalgia for 15 days accompanied by sore throat and maculopapular rashes over the trunk and extremities for 10 days. She had been referred to us as a case of acute undifferentiated febrile illness. She had no other systemic symptoms. At the time of admission, she was febrile − 102°F, pulse rate – 120/min, blood pressure – 100/70 mmHg, and no pallor, icterus, lymphadenopathy, or pedal edema. Pharynx was erythematous without any exudate. Erythematous maculopapular rashes were present over the trunk, arm, hand, thigh, and legs. Systemic examination was unremarkable. Routine biochemical investigation and infective etiology workup were sent and started on empirical antibiotic ceftriaxone.

Laboratory data revealed elevated inflammatory marker (neutrophilic leukocytosis – 15,700/cu mm with 84% neutrophilia, erythrocyte sedimentation rate [ESR] – 66 mm in 1st h, and high C-reactive protein – 77 mg/dl) and raised liver enzymes (aspartate aminotransferase – 218 U/L and alanine aminotransferase – 157 U/L). Renal function, serum bilirubin, and coagulation profile were normal. Repeated blood culture and urine culture showed no growth of any organism. Chest X-ray was normal. Ultrasonography of the abdomen and pelvis showed mild hepatomegaly. Serology for malaria, dengue, scrub typhus, enteric fever, hepatitis B, hepatitis C, hepatitis E, and HIV was negative, but hepatitis A virus immunoglobulin Ig (IgM) antibody (enzyme-linked immunosorbent assay) was found to be positive. Serum ferritin level was markedly raised (1462 mg/dl). Antinuclear antibodies (ANAs), rheumatoid factor (RF), and antistreptolysin-O antibodies were negative. She continued to be febrile and symptomatic even after 10 days of admission with persistently elevated inflammatory marker.

Based on the clinical and laboratory profile, she was diagnosed to have AOSD as per Yamaguchi's criteria, triggered due to hepatitis A infection. Treatment was started in the form of corticosteroids (tablet prednisolone 1 mg/kg/day). Over few days, there was defervescence of fever; however, rash and arthralgia persisted. Therefore, prednisolone was continued till the resolution of symptoms, which was attained in subsequent 1 month and then gradually tapered off. On follow-up after 1 month, she was asymptomatic and off steroid.


  Discussion Top


In 1897, 22 children with symptoms of juvenile onset idiopathic arthritis similar to AOSD were described by Sir Still.[2] Later in 1971, Bywaters reported 14 adult cases with similar symptoms and coined the term the AOSD.[3]

AOSD is a low prevalent disease (1.5 cases /1 lac-10lac population), affecting male and female equally. There is a bimodal age distribution, with one peak between the ages of 15 and 25 and the second between the ages of 36 and 46.[4] The etiology of adult Still's disease is unknown, supposed to be triggered by both genetic factors and infectious agents. In a study in Korea, AOSD patients had more frequent DRB1*12 and DRB1*15 and less frequent HLA-DRB1*04. The patients with the monocyclic systemic type had more frequent DRB1*14 alleles.[5] The DRB1*15:01 and DR5 association with AOSD have been found in Japanese subjects.[6]

It has been hypothesized that AOSD may be triggered by various infectious agents in a genetically predisposed host and a variety of organisms have been proposed in literature. Multiple case reports and small series are implicating that broad range of viruses such as rubella, mumps, echovirus 7, cytomegalovirus, Epstein–Barr virus, Coxsackie virus B4, adenovirus, human herpes virus 6, parvovirus B19, hepatitis B, and hepatitis C are contributing to the pathogenesis of AOSD. Till date, only one case of AOSD triggered by hepatitis A infection has been reported.[1],[7],[8],[9] Microbial agents such as Mycoplasma pneumoniae, Chlamydia pneumoniae,  Yersinia More Details enterocolitica 3 and 9,  Brucella More Details abortus, and Borrelia burgdorferi all have been proposed in the pathogenesis of AOSD.[4],[10]

Various activated cytokines have been found in disease pathogenesis and progression. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6, IL-18, interferon gamma, IL-8, and soluble IL-2 receptor have been found to be elevated in patients with active AOSD. Among the various cytokines, IL-1β seems to be a key regulator in the pathogenesis of AOSD, involved in inflammatory pathway, and also associated with active and severe disease.[11]

AOSD typically manifests symptoms complex that include high-spiking fever (95%), evanescent salmon-pink maculopapular eruption, predominantly found on the proximal limbs and trunk (51%–87%), and arthritis/arthralgia (64%–100%). Other symptom includes myalgia, liver abnormalities, sore throat, splenomegaly, pleuritis, and pericarditis.[1] Our patient had the typical presentation with symptoms and sign comprising fever, rashes, arthralgia, sore throat, and liver involvement.

Diagnosis of AOSD is difficult in the early stages of the disease. It is a prerequisite to rule out infections, malignancies, and other rheumatic diseases such as systemic vasculitis before making a diagnosis of AOSD. Laboratory studies show marked ESR elevation and leukocytosis with predominance of neutrophils. Disproportionately elevated serum ferritin is characteristic of AOSD.[12] Our patient had raised ESR, neutrophilic leukocytosis, and raised ferritin level. AOSD was suspected after excluding infection, autoimmune disease, and lymphoreticular disease.

Diagnosing AOSD is often difficult due to the presence of several nonspecific symptoms and the absence of characteristic serological biomarkers. The Yamaguchi criteria are the most widely cited criteria and are shown to be the most sensitive one (93%).[13] The major and the minor criteria of the Yamaguchi criteria are as follows.

Major criteria are as follows:

  1. Fever of at least 39°C for at least a week
  2. Arthralgia or arthritis for at least 2 weeks
  3. Nonpruritic salmon colored rash on trunk/extremities
  4. Granulocytic leukocytosis (10,000/μL or greater with neutrophilia >80%).


Minor criteria are as follows:

  1. Sore throat
  2. Lymphadenopathy
  3. Hepatomegaly or splenomegaly
  4. Abnormal liver function tests
  5. Negative tests for RF and ANA.


Diagnosis requires at least 5 features, with at least 2 of these being major diagnostic criteria. Our patient had all 4 of the major criteria and all of the minor criteria except lymphadenopathy.

Nonsteroidal anti-inflammatory drugs or aspirin are the initial treatment in AOSD, but the response rate has been low. Corticosteroids remain the first-line treatment for AOSD, prednisolone being the preferred among steroids. Disease-modifying antirheumatic drugs, such as methotrexate, azathioprine, cyclosporine, and cyclophosphamide, are often used for maintenance therapy of the disease.[1],[14]

Biologic agents can be used in refractory AOSD as different cytokines such as TNF-alpha, IL-1, and IL-6 are implicated in the pathogenesis of AOSD. Anti-TNF agents (infliximab, etanercept, and adalimumab) have been used with varying success in refractory AOSD.[15],[16],[17] IL-1 inhibition is considered the mainstay of treatment for refractory AOSD, leading to significant improvement in both clinical and laboratory parameters.[18] Among the three IL-1 antagonists, anakinra has been used more frequently. Anakinra is particularly efficient in the rapid relief of systemic symptoms. In the event of an insufficient response to anakinra, canakinumab can be considered because they have longer half-lives and can be administered every week or every 8 weeks, respectively.[19] Tocilizumab is another monoclonal antibody directed against the IL-6 receptor that has been shown to induce remission in patients with AOSD refractory to standard treatment from several case studies.[20] Plasma exchange and intravenous Igs are other treatment options in refractory AOSD patients.[21],[22]


  Conclusion Top


AOSD is a rare inflammatory systemic disease mimicking many diseases triggered by various common infectious agents like hepatitis A. Therefore, high index of suspicion is needed for early diagnosis and management.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still's disease. Ann Rheum Dis 2006;65:564-72.  Back to cited text no. 1
    
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Bywaters EG. Still's disease in the adult. Ann Rheum Dis 1971;30:121-33.  Back to cited text no. 3
    
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[PUBMED]  [Full text]  
5.
Joung CI, Lee HS, Lee SW, Kim CG, Song YH, Jun JB, et al. Association between HLA-DR B1 and clinical features of adult onset Still's disease in Korea. Clin Exp Rheumatol 2003;21:489-92.  Back to cited text no. 5
    
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Asano T, Furukawa H, Sato S, Yashiro M, Kobayashi H, Watanabe H, et al. Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still's disease. Arthritis Res Ther 2017;19:199.  Back to cited text no. 6
    
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Meijvis SC, Endeman H, Geers AB, ter Borg EJ. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still's disease. Neth J Med 2007;65:212-4.  Back to cited text no. 12
    
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Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992;19:424-30.  Back to cited text no. 13
    
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Kokkinos A, Iliopoulos A, Greka P, Efthymiou A, Katsilambros N, Sfikakis PP. Successful treatment of refractory adult-onset Still's disease with infliximab. A prospective, non-comparative series of four patients. Clin Rheumatol 2004;23:45-9.  Back to cited text no. 15
    
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Husni ME, Maier AL, Mease PJ, Overman SS, Fraser P, Gravallese EM, et al. Etanercept in the treatment of adult patients with Still's disease. Arthritis Rheum 2002;46:1171-6.  Back to cited text no. 16
    
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Kötter I, Wacker A, Koch S, Henes J, Richter C, Engel A, et al. Anakinra in patients with treatment-resistant adult-onset Still's disease: Four case reports with serial cytokine measurements and a review of the literature. Semin Arthritis Rheum 2007;37:189-97.  Back to cited text no. 18
    
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Kontzias A, Efthimiou P. The use of Canakinumab, a novel IL-1β long-acting inhibitor, in refractory adult-onset Still's disease. Semin Arthritis Rheum 2012;42:201-5.  Back to cited text no. 19
    
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Ortiz-Sanjuán F, Blanco R, Calvo-Rio V, Narvaez J, Rubio Romero E, Olivé A, et al. Efficacy of tocilizumab in conventional treatment-refractory adult-onset Still's disease: Multicenter retrospective open-label study of thirty-four patients. Arthritis Rheumatol 2014;66:1659-65.  Back to cited text no. 20
    
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