Adult-Onset Still's Disease: Is This Truly a Diagnosis of Exclusion?

Abstract

Adult-onset Still's Disease is a rare, idiopathic, inflammatory disorder characterized by arthralgia, evanescent, salmon-colored rash, and daily fevers as well as lymphadenopathy, pharyngitis, splenomegaly, myalgias, and serositis. The inciting etiology of this syndrome is unknown, though it has been hypothesized that infection triggers an autoimmune response. The Yamaguchi Criteria, the most sensitive and widely used diagnostic criteria, requires both a minimum set of criteria to be met as well other potential etiologies to be excluded. By definition, evidence of concomitant infection, malignancy, vasculitis, or connective tissue disease precludes the diagnosis of Adult-onset Still's Disease from being made. We present a very rare case of a patient who met all diagnostic criteria for Adult-onset Still's Disease, had a protracted course refractory to numerous immunosuppressant treatments, and also had evidence of coxsackie B infection with fourfold rise in viral titers on two occasions (both associated with disease flare). Although coxsackie B virus has been linked to Adult-onset Still's Disease at disease presentation, this case is unique in its protracted course and serological evidence of infection temporally related to disease flare. While accepted diagnostic criteria call for this disease to be a diagnosis of exclusion, our case supports the fact that ongoing infection may in fact be an important antigenic driver in persistent and refractory Adult-onset Still's Disease.

Introduction

Adult-onset Still's disease (AOSD) is a rare, idiopathic, inflammatory disorder characterized by arthralgia, evanescent, salmon-colored rash, and quotidian or double quotidian fevers. Lymphadenopathy, pharyngitis, splenomegaly, myalgias, and serositis are also commonly seen with this disease. Frequently seen laboratory abnormalities include leukocytosis, transaminitis, elevated ferritin levels, increased acute phase reactant concentrations, and aberrant production of proinflammatory cytokines.¹ While the inciting etiology of this syndrome is unknown, both viruses and bacteria have been isolated in patients with AOSD leading to the hypothesis that infection triggers an autoimmune response. A number of different diagnostic criteria have been published, with the most sensitive and widely used being the Yamaguchi Criteria.^1,2 However, this set of criteria requires both a certain number of major and minor criteria to be met as well other potential etiologies to be excluded, as demonstrated in Table 1.² Thus, by definition, evidence of concomitant infection, malignancy, vasculitis, or connective tissue disease precludes the diagnosis of AOSD from being made.

Table 2.

Coxsackie B Viral Titers

Coxsackievirus Serotype	Day 11	Day 21	Day 151	Day 471
Coxsackievirus B1 Ab	<1:10	<1:10	<1:10	<1:10
Coxsackievirus B1 Ab	<1:10	<1:10	<1:10	<1:10
Coxsackievirus B1 Ab	1:40	1:160	1:10	1:160
Coxsackievirus B1 Ab	1:160	>1:160	1:80	>1:640
Coxsackievirus B1 Ab	1:10	1:40	<1:10	>=1:640
Coxsackievirus B1 Ab	<1:10	<1:10	<1:10	<1:10

We present a rare and interesting case in which a patient met all major criteria and three of the four minor criteria (and later in his disease met the fourth minor criteria), yet had proven coxsackie B viral infection with fourfold rise in antibody titer. His disease was atypical as it remained refractory for over eighteen months to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), oral disease modifying antirheumatic drugs (DMARDs) (except for prednisone), TNF-alpha agents, and anakinra. A disease flare over one year into treatment was associated with repeat fourfold rise in coxsackie B titer, though he definitively responded to initiation of tocilizumab several months after this flare. It has been hypothesized that an infectious etiology initiates a cascade of immunological insults which results in the clinical syndrome of AOSD. Investigators in the past have demonstrated persistence of viral antigens in patients with AOSD, thus raising the question of antigenic stimulation driving the ongoing immune response.^3,4 We present the following case of a patient with classic AOSD and elevated coxsackie B viral titers on two separate occasions (both associated with increased disease activity) as further evidence that continuing antigenic stimulation is a driving force in refractory disease, and that AOSD may not truly be a diagnosis of exclusion.

Case

A 29-year-old previously healthy Puerto Rican man presented with pharyngitis (culture negative), chills, and knee pain. The patient was empirically treated with doxycycline followed by azithromycin though his symptoms continued to worsen. He was admitted to inpatient care at that time and was noted to have documented fever to 39.4C, an evanescent rash of the inner thighs which spread to his arms and chest, myalgias, arthralgias with joint effusion, and pleuritic chest pain with an echocardiogram showing pericardial effusion. Labs were notable for elevated CRP to 32mg/L, ESR greater than 100mm/hr, negative ANA/RF, leukocytosis, transaminitis, ferritin of 3596 mcg/L, and elevated coxsackie B viral titre (B4 1:160, drawn 11 days into his illness).

The patient's diagnosis was initially unclear as he met four major and three minor Yamaguchi criteria in the setting of elevated coxsackie B viral titers. He was initially started on naproxen 500mg twice daily to which he responded well, though with residual symptoms for which he was switched to prednisone 40 mg/day. A coxsackie B viral panel drawn ten days after the initial panel demonstrated fourfold increase of coxsackie B3 from 1:40 to 1:160, with continued elevation of B4 at >1:160, as demonstrated in Table 2. The patient's symptoms initially responded to high dose prednisone with decrease in ESR to 5mm/hour 121 days after disease onset. coxsackie B titer drawn 151 days after disease onset showed decreasing B3 and B4 serotypes, as demonstrated in Table 2?. He was definitively diagnosed with AOSD at this time, though he suffered recurrent fevers and arthralgia/synovitis upon cessation of steroids. He was tried on various courses of DMARDs to include plaquenil, colchicine, methotrexate, and adalimumab, though his symptoms always returned after prolonged discontinuation of prednisone. Fifteen months after disease onset he was hospitalized a second time with recurrent fevers, myalgias, synovitis of left hand/wrist, and new lymphadenopathy as demonstrated in Figures 1 and 2. Coxsackie panel drawn at that time was notable for over fourfold increase of B3 (1:160) and B4 (>1:640). Biopsy of the lymph node showed only reactive hyperplasia (Figure 3). He was started on etanercept upon discharge, though he was still unable to wean from prednisone and was thus switched to anakinra, though elevated inflammatory markers and large joint arthritis requiring intra-articular steroid injection persisted through this treatment. The patient was finally tried on tocilizumab in combination with methotrexate which led to an extended disease remission that has persisted for over two years despite complete steroid taper.

Figure 1.

Extensive Synovitis and Soft Tissue Swelling of Left Hand.

Figure 2.

PET Avid Left Inguinal Lymph Node, SUV 7.9 Measuring 9mm

Figure 3.

Germinal Center from Left Inguinal Node Biopsy Sample Demonstrating Reactive Follicular Hyperplasia.

Discussion

Adult onset Still's disease is a rare, multisystem inflammatory disorder characterized by arthralgia, evanescent, salmon-colored rash, and daily fevers. While the true etiology and pathology of the disease process is not well defined, it is likely multifactorial and the result of complex interplay between host factors and antigenic insults.¹ The immunopathogenic mechanism of this disease can be seen with elevated levels of proinflammatory cytokines such as tumor necrosis factor-alpha, interferon-gamma, interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-18.^5,6 Given the abrupt onset of symptoms and high fever, an infectious etiology has been postulated. A study in Nijmegen, Netherlands evaluated for potential infectious etiology through broad serological evaluation in five patients with AOSD. Two of the cases were thought to be secondary to rubella reinfection (based upon high IgG titres) while the disease in a third patient was attributed to Echovirus 7 as supported by positive culture from a throat swab as well as four-fold antibody titer increase.⁷ Another study evaluated 19 children with chronic rheumatic disease and isolated rubella virus from the lymphoreticular cells of seven of these patients, including one with Still's Disease.³ Other implicated viruses include cytomegalovirus, Epstein-Barr virus, parainfluenza, parvovirus B19, human immunodeficiency virus, hepatitis A, B, and C virus, adenovirus, human herpes virus 6 and coxsackie B virus. Bacterial infectious agents to include Yersinia enterocolitica, Chlamydia trachomatis, Chlamydia pneumonia, Campylobacter jejuni, and Mycoplasma pneumoniae have also been implicated.^6,8,9,10

Coxsackie B virus, an enterovirus consisting of an icosahedral capsid surrounding a single-stranded RNA genome, is a well known cause of febrile arthritis.¹¹ Acute coxsackie viral infection is oftentimes indistinguishable from AOSD, and there have been few reports discussing the presence of coxsackie infection in patients ultimately diagnosed with Still's disease. One study from 1983 evaluating three patients with febrile arthritis found elevated but stable coxsackie B antibody titer in two patients and a fourfold rise in viral titer in a third patient.¹² A study from 1986 found significant rise in neutralizing antibody to coxsackie B4 virus in two patients with evanescent macular rash, constitutional symptoms, high spiking fever, and polyarthritis/synovitis. Both patients also had elevated inflammatory markers, transaminitis, and neutrophilic leukocytosis.¹³ A case of Still's disease and elevated initial titers to coxsackie B2 and B4 with progression to hemophagocytic syndrome was described in a 12-year-old girl in New Zealand in 1985.¹⁴

Our case is unique in the prolonged and refractory nature of the disease with elevated coxsackie B titers noted twice during the course, both times temporally associated with increased disease activity. These findings support either coxsackie viral reinfection or viral persistence/chronic infection as an antigenic driver to the immune dysregulation inherent to AOSD. Persistent enteroviral infection has been implicated in several chronic diseases to include insulin-dependent diabetes mellitus, dilated cardiomyopathy, chronic inflammatory myopathy, and chronic fatigue syndrome.^11,15 This has been shown in both humans as well as animal models. Persistence of coxsackievirus B3 was noted in both the acute and chronic phase of myocarditis in an immunocompetent mouse model.¹⁶ Another study evaluating eight patients with chronic fatigue syndrome and positive enteroviral sequences by PCR were evaluated for viral persistence at a five-month interval. Four of the eight patients were found to have an identical nucleotide sequence in both samples, which was indicative of viral persistence as opposed to reinfection.¹⁷ While no study has directly addressed persistence of coxsackie virus in patients with AOSD, a previous study from 1994 found that AOSD patients carry a four-fold greater load of rubella viral genome than do normal controls, and that the genome is found primarily in monocytes and B cells. This suggests the possibility that patients suffering from AOSD may be unable to effectively clear viral infection from their mononuclear cells.⁴

While our case is unique in describing elevated coxsackie viral titers temporally associated with increased disease activity, it does not definitively prove the presence of coxsackie infection as neutralizing antibody titer against coxsackie B virus lacks specificity. Viral culture or PCR would have offered more definitive evidence of infection. Also, nucleotide sequence by PCR would have been useful in determining whether the patient had persistent infection versus reinfection at the time of his disease flare.

Conclusion

While previous reports have associated AOSD with infectious triggers, there have been relatively few reported cases of concomitant coxsackie B infection. This case is unique in reporting a four-fold rise in coxsackie B antibody titers on two separate occasions during a prolonged, refractory course of AOSD, both temporally associated with disease flare. Previous literature has established that coxsackie B can persist in a number of chronic infections, though this has not been proven with AOSD. While the low specificity of viral titers in our case cannot prove the link between coxsackie infection and increased disease activity in AOSD, it supports that evidence of coxsackie B infection should potentially be considered an antigenic driver of AOSD rather than an exclusion criteria.

Table 1.

Yamaguchi Criteria

Major Criteria	Minor Criteria
Fever >39°C of one week or longer	Sore throat
Arthralgia or arthritis of greater than 2 weeks	Lymphadenopathy
Typical Rash	Hepatomegaly/Splenomegaly
Leukocytosis >10,000/mm3	Abnormal liver function tests
Exclusion Criteria	Negative antinuclear antibody and RF
Infections
Malignancies
Other rheumatic disease

Disclaimer

The views expressed in this abstract/manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

Conflict of Interest

None of the authors identify a conflict of interest.