Bilateral dacryoadenitis in adult-onset Still’s disease: A case report

Abstract We present an unusual case of bilateral dacryoadenitis in a middle-aged patient with adult-onset Still’s disease (AOSD). We reviewed relevant clinical studies addressing the association between lacrimal lesions and AOSD. A 50-year-old Chinese woman with a 4 year history of recurrent fever and rashes was admitted to the hospital. She had also developed nodules on both eyelids 10 months before admission. After undergoing resection of the left lacrimal gland, the patient received steroids and immunosuppressive therapy. The patient showed good postoperative recovery during the 20 month follow-up. In this case, the pathological examination conducted after orbital surgery helped clinicians differentiate between dacryoadenitis and other orbital lesions. In a review of the literature, dacryoadenitis occurred after the onset of AOSD, and all cases showed non-granulomatous chronic inflammation by histopathology, which indicated that the lacrimal gland may be an inflammatory target and is affected by systemic inflammation in AOSD.


Background
Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology, characterized by recurrent high-spiking fever, an evanescent salmon pink rash, arthralgia, and multiorgan involvement [1]. Other common manifestations include myalgia, liver abnormalities (hepatomegaly and abnormal liver biochemistry), pleuritis, pericarditis, and splenomegaly are seen less commonly [2]. AOSD sometimes involves ophthalmic manifestations, such as uveitis, keratitis, ptosis, oculomotor disorders, erythema, chemosis, and orbital pseudotumor [3]. Dacryoadenitis has also been linked to AOSD, the most common form of idiopathic orbital inflammation. However, little is known about lacrimal gland involvement in AOSD patients.
Here we report a middle-aged Chinese woman diagnosed with AOSD who developed bilateral lacrimal gland lesions. We also review and summarize relevant literature on dacryoadenitis in AOSD patients with the aim of improving our understanding of this disease.

Case presentation
A 50-year-old Chinese woman was admitted to our hospital with complaints of recurrent high fever, rash, and joint pains in the 4 years prior to admission. She had also developed nodules on both eyelids in the 10 months prior to hospitalization.
Her physical examination showed maculopapular eruption on the back of her hands, upper limbs, neck, and back, with enlarged superficial lymph nodes in the neck, axilla, and inguen. Laboratory tests revealed a white blood cell count of 14,020 per mm 3 , neutrophil percentage in granulocytes of 92.3%, and C-reactive protein level of 19.80 mg/L, with negative rheumatoid factor and antinuclear antibody tests. Visual acuity was measured to be 20/25 in the right eye and 20/100 in the left eye. Palpation showed the distinct presence of nodules on both eyelids ( Figure 1). Although the anterior segment and fundus were normal, enhanced magnetic resonance imaging (MRI) of the eye showed thickened soft tissue around the orbit with heterogeneous enhancement (Figure 2). Based on the clinical symptoms and MRI scans, the patient was diagnosed as AOSD with dacryoadenitis.
The patient underwent surgery for resection of the left orbital mass. During surgery, we observed a superior lateral lacrimal and orbital mass that adhered closely to the orbital periosteum and subcutaneous tissue. The excised mass was solid and tan-white in color ( Figure 3). Pathological examination showed foam cell granuloma with lymphocytes and plasma cell infiltration. The biopsy stained positive for CD163, propylene glycol mannate sulfate (PGMS), plasma cell CD138, multiple myeloma oncogene 1 (MUM1), IgG4 (sparse positive, 16/high-power field), lymph cell CD20 (partially positive), and CD3 (partially positive) ( Figure 4).
After undergoing surgery, methylprednisolone and cyclosporine were given for 20 months, during which she showed good postoperative recovery, with resolution of eyelid nodules ( Figure 5). The fever, joint symptoms, and skin rash were also relieved.
Informed consent: Informed consent has been obtained from all individuals included in this study.
Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors' institutional review board or equivalent committee.

Discussion
AOSD is a multisystemic autoinflammatory disorder of unknown etiology. It was first described in 1971 based on the similarity between clinical symptoms presented by 14 adults and those observed in children with Still's disease [4]. There are only two previous reports of dacryoadenitis occurring with AOSD. Our patient developed bilateral dacryoadenitis after systemic presentation of AOSD. Considering the Yamaguchi classification criteria [5], our case met all the major criteria: fever of at least   39°C, intermittent, lasting 1 week or longer; arthralgias, lasting 2 weeks or longer; typical rash; leukocytosis (>10,000 per mm 3 ), with 80% or more granulocytes; and met two minor criteria: lymphadenopathy and negative rheumatoid factor and antinuclear antibody. After undergoing resection surgery, and receiving steroid and immunosuppressive therapy, the patient showed good postoperative recovery. Orbital surgery and pathophysiology helped our understanding of lacrimal lesions complicated by AOSD.
Our review of the literature identified 2 reports of dacryoadenitis in women with AOSD [6,7], involving 2 Japanese, 1 French, and 1 Chinese woman who ranged in age from 26 to 62 years (mean age 45.8 ± 15 years; Table 1). In all four patients, dacryoadenitis occurred after the onset of AOSD: two developed symptoms in both eyes, and the others developed symptoms in only one eye. All four patients showed non-granulomatous chronic inflammation by histopathology, which indicated that the lacrimal gland may be an inflammatory target and is affected by systemic inflammation in AOSD. The immunohistochemical staining was helpful to differentiate from infectious disease, xanthoma, and Rosai-Dorfman disease. After resection, these patients received either steroid or interleukin-1 (IL-1) inhibitor therapy. All patients showed good postoperative recovery ( Table 1). Unlike previously reported patients, serum ferritin level in our patient was not elevated, may be due to the long course of disease, and previous intermittent treatment with steroids before admission [8].
Clinicians often find it difficult to diagnose and treat AOSD because of the wide range of differential diagnoses and clinical manifestations associated with it [9]. Current therapies for AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, anti-rheumatic drugs, polyvalent intravenous immunoglobulins, IL-1 receptor antagonists (anakinra), and anti-human IL-6 monoclonal antibodies [1,2,9]. NSAIDs often fail to control the symptoms of AOSD and many patients experience adverse events; corticosteroid therapy is considered the first-line treatment, but dependency occurs in approximately 45% of cases. Methotrexate can reduce the daily corticosteroid intake, but remission speed is slow, and it can cause severe adverse events, including liver toxicity and pneumonitis. Biologic drugs can  be administered in cases refractory to the above treatments, but it is expensive for patients in developing countries [10,11]. To date, the treatment of AOSD has relied on empirical data from prospective or retrospective studies. Double-blinded randomized trials with suitable sample sizes are required to develop effective treatments for patients with AOSD.

Conclusion
We report a rare case of bilateral dacryoadenitis in a middle-aged Chinese woman with AOSD. This diagnosis was supported by pathological examination after lacrimal resection, which helped exclude other orbital diseases. The histopathological findings of non-granulomatous chronic inflammation indicated that the lacrimal gland may be an inflammatory target and is affected by systemic inflammation in AOSD. Our case highlights the need for long-term follow-up to prevent recurrence of dacryoadenitis. Future research must focus on ophthalmic manifestations to gain a better understanding of the diagnosis and treatment of patients with AOSD. Additionally, the development of practical serological or molecular diagnostic marker(s) that could be utilized for the early diagnosis of atypical bilateral dacryoadenitis is recommended.
Funding information: Authors state no funding involved.
Author contributions: Weimin He conceived, designed, and coordinated the study. Qing Huang analyzed the data and drafted the manuscript. All authors read and approved the final manuscript.