Interleukin-18 as a diagnostic marker of adult-onset Still’s disease in older patients: a case report and review of the literature
Adult onset Still’s disease is a systemic auto-inflammatory condition of unknown etiology characterized by intermittent spiking high fever, an evanescent salmon-pink or erythematous maculopapular skin rash, arthralgia or arthritis, and leukocytosis. Recently, a high level of interleukin-18 has been reported as a new characteristic marker. On the other hand no reports have been published on high interleukin-18 as a marker in older patients. We report a case of adult onset Still’s disease in an older patient successfully treated with steroids in which interleukin-18 was a useful marker of disease activity.
A 66-year-old Asian woman presented to our hospital with fever and arthralgia. We diagnosed adult onset Still’s disease based on Yamaguchi criteria and a history of a high spiking fever, salmon-colored rash, and bilateral pain to shoulders, knees, and wrists. In this case, a high serum level of interleukin-18 was a diagnostic parameter. Administration of 40 mg of prednisolone followed by subcutaneous administration of 200 mg cyclosporine daily resulted in a dramatic resolution of our patient’s febrile episodes 2 months after admission. Prednisolone was tapered to 5 mg/day every 2 weeks and cyclosporine 200 mg/day was continued. Her serum interleukin-18 level was prominently decreased, and she was discharged 3 months after treatment.
Serum interleukin-18 level may be a good diagnostic biomarker to monitor adult onset Still’s disease activity in older patients, measuring levels in both the acute and convalescent phases.
KeywordsInterleukin-18 Adult-onset Still’s disease Diagnostic marker Elderly patients Older patients
Adult-onset Still’s disease
Adult onset Still’s disease (AOSD) is a systemic auto-inflammatory condition of unknown etiology, characterized by intermittent spiking high fever, an evanescent salmon-pink or erythematous maculopapular skin rash, arthralgia or arthritis, and leukocytosis . High serum ferritin levels, elevated erythrocyte sedimentation rate, high C-reactive protein levels, and an absence of antinuclear antibody (ANA) and rheumatoid factor are common laboratory findings . A high level of interleukin (IL)-18 has recently been reported as a new characteristic marker; however, no such report focusing on older patients has been published [3, 4].
Discussion and conclusions
The criteria for AOSD diagnosis proposed by Yamaguchi include high spiking fever and salmon-like evanescent rash. In addition, joint involvement and myriad nonspecific symptoms may occur . AOSD diagnosis remains one of exclusion, ruling out infectious, autoimmune, or malignant conditions, and is defined by Yamaguchi classification criteria. The pivotal role of the macrophage is cell activation and release of Th1-type inflammatory cytokines . It remains difficult, however, to determine predictive factors of outcome and to draw guidelines for patient management.
AOSD is rare and exhibits a bimodal age distribution with one peak incidence between ages of 15 and 25 and a second peak between ages of 36 and 46 years . The frequency of AOSD in older people is unknown . The immune system in older patients undergoes a functional remodeling. After menopause, the incidence of chronic inflammatory disease in women approaches or exceeds that observed in men. The immune system of aged individuals is quite different from that of a young or middle-aged adult, and these differences correlate with increased susceptibility to various infections, the reduced efficacy of some vaccinations, and a greater risk of chronic disease driven by chronic inflammation . In this case our patient was greater than 65 years of age and was, therefore, likely to have some degree of immunological impairment, which could have induced AOSD. The number of older patients with AOSD is likely to increase in the future because this age group is susceptible to immunological dysfunction; therefore, awareness of this disease should be increased.
IL-18 was first described in 1999 . The main source of IL-18 in humans is mononuclear cells, such as monocytes, macrophages, dendritic cells, and lymphocytes B . Macrophage activation is a hallmark of AOSD, and serum from patients with AOSD discloses a dramatic increase in growth and differentiating factors for macrophages . This cytokine plays effector and regulatory roles in a variety of early inflammatory responses. It is also expressed at sites of chronic inflammation, in autoimmune disease, a variety of cancers, and the context of numerous infectious diseases . The dramatic effects of cytokine storms are now well documented in AOSD. The serum level of IL-18 was reported to be correlated with disease activity and ferritin serum level . IL-18 could play a central role in AOSD, and systemic expression may be responsible for tissue damage in target organs such as liver, spleen, and synovial membrane . This suggests an important role in resistance to intracellular pathogens that can develop inside immune cells, including macrophages . Our previous report demonstrated that IL-18 reduced viral infection due to enhancement of interferon-gamma and natural killer cell activity in an animal model .
Higher serum IL-18 levels were related to AOSD disease activity, and a positive significant correlation was confirmed between IL-18 serum levels and disease activity . Furthermore, these levels were higher than those in rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus, whose IL-18 levels were lower than 3000 pg/mL . In a previous article, serum concentration of IL-18 was suggested as a diagnostic marker of AOSD; and in patients with active AOSD, it was higher than the highest value in healthy individuals and its cutoff point was 312.5 pg/mL for detection of AOSD . In this case, it was greater than 100,000 pg/mL at admission.
We report the first case of AOSD in an older patient with rash typically associated with Still’s disease in which serum IL-18 level was a good biomarker of AOSD activity in both acute and convalescent phase. Serum IL-18 level could be a diagnostic marker in AOSD in older patients.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
YF is the physician who handled the case; DU is a major contributor to the writing of the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This case report was approved by the Kanazawa Medical University Himi Municipal Hospital ethics committee, and carried out in conformance with the principles of the Declaration of Helsinki. Both verbal and written informed consent were obtained from the patient before submission.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors declare that they have no competing interests.
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