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Elderly-onset adult Still’s disease

Adult-onset Still’s disease is a rare inflammatory disorder usually affecting young adults. Elderly-onset Still’s disease (EOSD) is reported in some cases, commonly in Japan, the USA and Europe. One of the most commonly used criteria for diagnosing EOSD is Yamaguci criteria. In elderly patients more severe course of the disease and more complications may be expected than in the younger group of patients with Still’s disease. The lungs involvement is rather rare manifestation of this disease. In our article we discuss the problem of both the development of Still’s disease in the elderly and interstitial lung changes in the course of the disease, based on available literature and own cases from one centre.


Introduction
Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology with an estimated prevalence of 1 to 10 cases per million [1,2]. It usually affects young patients between 16 and 35 years old, but some cases of elderly patients have been reported [3][4][5][6][7]. AOSD clinical presentation includes four main symptoms: spiking fever, arthralgia or arthritis, skin rash and leukocytosis ≥ 10,000 cells/µl with neutrophils ≥ 80%.
An elevation in the total and glycosylated ferritin levels is suggestive of AOSD but is not pathognomonic [2]. Many other manifestations are possible, making diagnosis challenging, especially in the elderly [3,4]. Several features have been found to be associated with this category of patients with a higher frequency of complications and poor survival [3,4]. However, the number of elderly-onset Still's disease (EOSD) cases remains insufficient to explore their clinical features.
We aim through this article to highlight the fact that the elderly can develop typical AOSD with some characteristic features and discuss these characteristics for this age group by reviewing the literature.

Material and methods
The aims of this case-based review were to report three cases of EOSD (among 21 patients with AOSD) and to perform a literature review of EOSD case reports and series.
Inclusion criteria included case reports or series reporting specific characteristics of EOSD (age ≥ 60 years old) fulfilling the diagnostic criteria proposed by Yamaguchi [2]. Only English reports (full texts or abstracts) were considered. The references of the studies obtained were also examined to identify additional reports.
The C-reactive protein (CRP) was 354 mg/l and the erythrocyte sedimentation rate (ESR) was 104 mm/hour. The white blood cell count (WBC) was elevated to 14 500 cells/µl. There were hepatic cytolysis and cholestasis. Serum protein electrophoresis showed polyclonal hypergammaglobulin at 16.7 g/l.
Histopathology of the liver biopsy found periportal non-specific inflammation. Joint radiography was normal. We diagnosed EOSD according to the Yamaguchi criteria. Initially, the patient was treated with glucocorticoids (GCs) 1 mg/kg/day, obtaining remission and stopping treatment after 14 months.
The patient relapsed 3 and 4 years later. The treatment with GCs 0.5-1 mg/kg/day has been applied. The complication of GCs treatment was weight gain and developement of arteruial hypertension. A control CT of the lungs showed diffuse pulmonary nodules at the upper and middle right lobe of the lung. Methotrexate (MTX) at the initial dose 12.5 mg/week was initiated 5 years later with a good outcome over a 3-year follow-up.

Case 2
A 68-year-old woman, with no pathological history, presented for 6 weeks deterioration of the general state, fever, evanescent maculopapular rash on the trunk, sore throat and tenosynovitis of the hands.
The CRP was 230 mg/l and the ESR was 80 mm/hour. The WBC was elevated to 14 600 cells/µl. Normochromic  normocytic anemia at 10.8 g/dl was found. Serum protein electrophoresis showed polyclonal hypergammaglobulinemia. The serum ferritin was 11.420 ng/ml.
There was no biological evidence of infections. RF, ACPA and ANA antibodies were not present. Cardiac ultrasound was normal. Thoraco-abdominopelvic CT showed diffuse interstitial lung infiltrates. Joint radiography was normal.
We diagnosed EOSD according to the Yamaguchi criteria. The patient was treated with indomethacin without clinical improvement. Corticosteroid therapy at 0.5 mg/kg/day was initiated with a good outcome over a 2-year follow-up.

Case 3
A 70-year-old man was admitted with fever, deterioration of the general condition, weight loss and myalgia. He had hypertension treated with irbesartan hydrochlorothiazide, diabetes mellitus treated with oral antidiabetics and a history of colonic adenocarcinoma treated a year earlier and in remission.
The described patient had high elevated inflammatory parameters including CRP of 183 mg/l and ESR of 130 mm/hour. The procalcitonin level was 0.148 ng/ml. The WBC was 17 800 cells/µl with neutrophils ≥ 80%. Serum protein electrophoresis did not indicate monoclonal gammopathy or hypogammaglobulinemia. The microbiological assessment did not confirm any infections. The serum ferritin was 1000 ng/ml. There was no presence of RF, ACPA, ANA antibodies or neutrophilic anticytoplasmic (cANCA) in the patient's serum.
The cardiac ultrasound was normal. Thoracic-abdominopelvic CT showed reticulation and honeycombing involving mainly the lung periphery, without other abnormalities. The endoscopic examination showed antro-fundal gastritis and no malignancy was identified in the biopsies. The colonoscopy was normal. Doppler ultrasound and temporal artery biopsy were normal. The bone marrow biopsy was normal. The glucocorticosteroid therapy at dose a 1 mg/kg/day was prescribed as an initial dose with subsequent dose reduction and good outcome over a 3-year follow-up.

Discussion
Usually, the onset of AOSD is in early adulthood, but in our 3 cases the onset was at an advanced age. EOSD is reported in some cases , and its frequency is still increasing because of the aging of society.
According to a Japanese study in 2016, about 23% developed EOSD at ≥ 65 years old and about 16% at ≥ 75 years old among AOSD cases [53]. According to a review of the literature, EOSD has been described more of-ten in Japan (27/43 articles), the USA (7/43 articles) and Europe (2/38 articles) (Table I)  .
One case was reported from North Africa (Tunisia) [51] and it was associated with squamous cell carcinoma. The mean age of onset was 73.5 ±7 years and 79.5% were female.
A study compared the clinical features between 25 EOSD cases (age ≥ 70 years) and a group of 166 AOSD cases [3]. In this literature review, the overall AOSD group included less than 10-20% EOSD cases because reports of AOSD included all ages [3]. The mean age of onset was 76.6 ±4.9 and 24-46 years in the EOSD and AOSD groups, respectively [3]. Seventy-five percent of the patients were female [3]. Elderly-onset Still's disease showed similar clinical signs and laboratory findings to overall AOSD [3]. Indeed, patients often presented with fever (higher than 39°C), evanescent rash, lymphadenopathy, sore throat, arthralgia/arthritis, myalgia, and serositis [7] (Table I).
Another recent Japanese study demonstrated that EOSD (> 60 years old) patients less often had typical skin rashes and sore throat and more often had pleuritis than AOSD [4].
In case 3, the patient presented deterioration of the general condition and weight loss, which is rarely reported in the literature [7,44]. Neoplasia, infections and systemic diseases need to be ruled out before the diagnosis is established.
Parenchymal lung involvement (PLI) was found in the 3 patients. In the literature, two cases were reported in EOSD with severe respiratory failure [5,22] and coma [22]. However, two other patients in the 7 th decade showed pleuritis and pneumonitis according to an abstract not included in the literature review (lack of information) [54]. Gerfaud-Valentin et al. [55] reported that PLI occurred in nearly 5% of AOSD cases. In the parenchymal lung involvement group, the patients were younger at AOSD onset compared with the non-PLI group. The distribution of PLI was equivalent between men and women [55]. The chest X-ray and CT revealed unilateral or bilateral interstitial hyperdensities in 72% and alveolar hyperdensities in 50% with an air bronchogram in 33% [55].
However, the frequency of macrophage activation syndrome (MAS) was similar between the AOSD and EOSD groups [3,4]. The Yamaguchi criteria have been used to aid in the diagnosis with high sensitivity (above 93%) and specificity (92.1%) [7]. So, as elderly patients can develop typical AOSD, physicians should not exclude EOSD from the differential diagnosis.
As for the medications, corticosteroids at 0.5-1 mg/ kg/day were given for our 3 patients, and methotrexate was useful for controlling the disease and for corticosteroid-sparing treatment in our first case. According to our literature review and that of Suda et al. [3], corticosteroids were commonly used in EOSD (95.1% in the reviewed case reports), and methylprednisolone therapy was used in about one-third of cases. Methotrexate and biologics were prescribed in 17.7% of cases (Table I).
Another Japanese study found that corticosteroids (including methylprednisolone), methotrexate, and biological agents were not different between the two groups. However, cyclosporine and plasma exchange was more frequently used in the elderly-onset group due to the higher prevalence of complications [4].
Regarding the evolution, it was polycyclic in our first case and monocyclic in our two subsequent cases. In the literature, the comparison of rates of remission, relapse and death between AOSD and EOSD is controversial. It was similar for Suda et al. [3], but the observation period was longer in the overall AOSD group.

Conclusions
Adult Still's disease should not be overlooked in elderly patients. However, it remains a diagnosis of elimination, particularly in the presence of fever or deterioration of the general condition. Parenchymal pulmonary involvement, found in the three described patients, is seldom encountered in adult and elderly Still's disease.
Unlike our cases, the clinical features of the literature review were characterized by a higher frequency of complications that need immunosuppressive drugs. However, these treatments should be used with extreme caution in elderly-onset patients because of the risk of serious adverse events.
The authors declare no conflict of interest.