Adult-onset Still’s disease in an elderly patient – case report

INTRODUCTION

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder characterized by a triad of symptoms: a febrile state that includes daily temperature spikes that can reach up to 40°C, a characteristic transient maculopapular rash that most often appears during temperature spikes and predominantly occurs on the trunk and extremities, as well as arthralgias or arthritis, most often in the knees, ankles, wrists, and shoulders. (1)

Adult-onset Still’s disease and systemic juvenile idiopathic arthritis (sJIA) are terms used for similar clinical conditions that have different ages of onset, meaning that the first symptoms of the disease appear at different ages. If the disease occurs before the age of sixteen, that is considered to be the case of systemic juvenile arthritis. In other cases, the commonly used term is adult-onset Still’s disease. (2)

In patients with adult-onset Still’s disease, two age ranges have been observed in which the first symptoms of the disease most often appear: between 15 and 25 years of age and between 35 and 46 years of age. The incidence of the disease is estimated to be between 0.16 and 0.4 cases per 100,000 people. No male or female predominance of the disease has been determined. (3) The occurrence of Still’s disease after the age of 60 is extremely rare and is then referred to as elderly-onset Still’s disease (EOSD). (4)

The disease pathogenesis remains unknown, but it is believed that genetic predisposition, autoinflammatory cascade reaction due to an inadequate innate immune response, and infectious agents as triggers for the development of the disease are the key factors. Genetic background and environmental triggers such as PAMP (pathogen-associated molecular pattern) and DAMP (damage-associated molecular pattern) are the starting points of inflammation in AOSD. They promote macrophage stimulation and activate NLPR3 inflammasomes. Following that, NLRP3 inflammasomes facilitate the activation of caspase-1, which leads to the proteolytic cleavage of pro-interleukin-1 beta (pro-IL-1β) and pro-interleukin 18 (pro-IL-18) into their bioactive and mature forms, which further generate a burst of cytokine storm with interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-α) involvement. Neutrophils are also extensively activated in AOSD and release more neutrophil extracellular traps (NETs), which can further stimulate NLRP3 activation. (5)

Numerous microorganisms have been reported as triggers for adult-onset Still’s disease, including rubella virus, Epstein-Barr virus, cytomegalovirus, parvovirus B19, hepatitis viruses, and the following bacteria: Mycoplasma pneumoniae, Yersinia enterocolitica, Chlamydia pneumoniae, Campylobacter jejuni, and Borrelia burgdorferi. (6-8)

In addition to the classic triad of symptoms, sore throat, myalgia, splenomegaly, hepatomegaly, liver disease, pleural and pericardial effusion, and lymphadenopathy may also occur individually, depending on the case. Laboratory findings typically include leukocytosis with a predominance of neutrophils, increased C-reactive protein levels and erythrocyte sedimentation rate, and elevated ferritin levels. Affection of the liver commonly includes increased aspartate aminotransferase and alanine aminotransferase levels. (1)

Disease complications can occur due to the development of cytokine storm and macrophage activation syndrome (MAS) with multiorgan failure, which is a life-threatening condition. (9)

Establishing a diagnosis of AOSD is challenging because it is necessary to exclude other clinical entities such as infections, neoplastic and paraneoplastic syndromes, and other autoimmune and anti-inflammatory diseases. The diagnosis is most often made on the basis of Yamaguchi’s or Fautrel’s criteria. Both lists of criteria showed high specificity and sensitivity, with the fact that, unlike Fautrel’s criteria, Yamaguchi’s criteria also contain the exclusion criteria. (10)

Initial treatment of AOSD depends on the severity of clinical symptoms. In mild forms of the disease, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or indomethacin are recommended over glucocorticoids. (11) If there is no patient response to NSAIDs or if the clinical symptoms of adult-onset Still’s disease are moderate to severe, the introduction of a biologic is recommended. If a biologic is not available, glucocorticoids are introduced into the therapy in doses of 20–60 mg per day, orally. The use of parenteral glucocorticoids is recommended depending on the clinical features according to the preference of the attending physician. If the development of macrophage activation syndrome (MAS) is suspected, it is recommended that these patients be treated with anakinra and pulse glucocorticoid therapy (1000 mg of methylprednisolone, intravenously) for one to three days. In maintenance therapy, disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and leflunomide, can be introduced. Among other biologics, canakinumab, rilonacept, tocilizumab and infliximab are also used in the treatment of AOSD. (12-14)

CASE REPORT

A 73-year-old patient was admitted to the Department of Rheumatology due to a prolonged febrile state with a body temperature of up to 40°C, accompanied by a maculopapular rash on the trunk (Figure 1) and swelling and pain in the joints. The patient had a history of coronary artery disease with a triple bypass graft, which was preceded by a myocardial infarction. The patient also had a history of hypertension, diabetes, and stage 2 kidney disease. He was previously hospitalized at another hospital where he was treated with broad-spectrum antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs), but his condition did not improve and was referred to our institution. In the patient’s family history, it is stated that he had not previously experienced similar joint problems. He states that there is a positive family history of autoimmune diseases. His sister died of complications of systemic lupus erythematosus at a young age. His brother suffers from ankylosing spondylitis. On admission, the patient was almost motionless, with swelling and pain in all metacarpophalangeal and proximal interphalangeal joints, as well as pain and swelling in the ankle joints. Laboratory findings show signs of leukocytosis, with a white blood cell count of 27.10 x 10^9 leukocytes/L (reference range of 4 – 10 x 10^9 leukocytes/L) with a predominance of neutrophil granulocytes of 96.2% in the differential blood count, elevated fibrinogen values ​​of 6.2 g/L (reference range of 1.8 – 3.5 g/L), elevated ferritin values of 3880 ng/mL (reference range of 17.9 – 464 ng/nL), slightly elevated values of the D-dimer, nitrogenous substances and transaminases and elevated C-reactive protein values of 117.9 mg/L (0.0 – 5.0 mg/L). Given the patient’s age, we first treated the patient’s condition as an infectious syndrome and, in consultation with an infectious disease specialist, we initiated empirical dual-antibiotic therapy. The patient continued to have fever with progression of the clinical features. Blood cultures were taken at the fever spikes; however, the results of several blood cultures were sterile. In the control laboratory findings, there were still signs of persistent leukocytosis with a predominance of neutrophilic granulocytes, anaemia, elevated transaminases, elevated ferritin values of up to 15750 ng/mL (reference range of 17.9 – 464 ng/nL), without a drop in C-reactive protein values. Bone marrow biopsy was performed, which showed signs of reactive bone marrow hyperplasia. Urine cultures were sterile. Physiological microflora was isolated from the throat and nasal swabs. Given the laboratory findings and the progression of the clinical features, a working diagnosis of Still’s disease with the life-threatening development of macrophage activation syndrome was made. Methylprednisolone in moderately high doses (alternately 60 and 80 mg) was included in therapy and administered intravenously along with other forms of supportive therapy. Three days after initiating glucocorticoid therapy, the patient became afebrile and the joint swelling subsided.

Ultrasound of peripheral lymph nodes confirmed the finding of reactive lymphadenopathy. Immunological findings showed a negative rheumatoid factor result, anti-citrullinated protein antibodies and anti-streptolysin antibodies (ASO), negative double-stranded DNA antibodies (anti-dsDNA), low titre positive antinuclear antibodies with a negative ENA-8 test.

Tumour markers were negative. Abdominal ultrasound showed signs of splenomegaly. X-ray of the hands and feet did not show any erosive changes (Figure 2). Considering all laboratory findings and the patient’s clinical features, the diagnosis of adult-onset Still’s disease was made using Yamaguchi’s criteria. The patient was treated with moderately high doses of glucocorticoids administered parenterally for three weeks with the use of antimalarials, and after the administration of the aforementioned therapy the clinical features and laboratory parameters improved. When the patient was discharged from hospital, his laboratory findings showed a white blood cell count of 8.10 x 10^9 leukocytes/L (reference range of 4 – 10 x 10^9 leukocytes/L), with persistent anaemia, slightly elevated transaminase values, and a drop in CRP levels to 29.3 mg/L (reference range of 0.0 – 5.0 mg/L). At the follow-up examination after one month, the patient did not report any subjective complaints, during the physical examination there were no signs of swollen joints, and in the laboratory findings the inflammatory parameters were unremarkable, as were the liver enzyme levels. Given the presence of kidney disease, we decided not to include methotrexate in the therapy, but we have opted for the inclusion of leflunomide in a dose of 20 mg/day.

After receiving the prescribed therapy for three months, the patient showed no signs of disease relapse at the follow-up examination.

DISCUSSION

The occurrence of Still’s disease in elderly patients is extremely rare. Due to this, it was challenging to make an initial diagnosis of the disease. In this case, the patient had a classic triad of symptoms including fever, transient maculopapular rash, and arthralgias. However, given that these are symptoms that may individually be of limited specificity, and which occur more often as part of certain infectious syndromes, and given the patient’s age, the disease was treated as an infectious syndrome for the first two days. Suspicion of elderly-onset Still’s disease (EOSD) was based on the persistence of the clinical features, with leukocytosis, further elevation of ferritin values, and elevated values ​​of C-reactive protein.

In the literature review of 25 presented cases with a diagnosis of EOSD, the age at which symptoms first appeared was 76.6 ± 4.9 years of age, which corresponds to the age of the patient in our case report. (4)

In a 10-year retrospective study conducted by Sheng Li et al., patients diagnosed with EOSD had similar symptoms of fever and arthralgia compared to patients diagnosed with Still’s disease at a young age. Fewer patients with EOSD reported sore throat as their initial symptom, and they also reported having less pronounced skin rash. (15)

The acute phase of patients with Still’s disease is most often accompanied by leukocytosis with a predominance of neutrophil granulocytes. Before the inclusion of glucocorticoids in the therapy, the patient underwent a bone marrow biopsy to rule out the existence of a hematopoietic neoplasm. It is important to note that hemophagocytic activity was not verified during the bone marrow biopsy. Hypercellular bone marrow of the reactive type was verified in about two-thirds (63.6%) of patients in a Korean study conducted on 40 patients diagnosed with Still’s disease. (16)

Elevated ferritin levels are present in as many as 90% of patients with AOSD. Ferritin levels are not only a good indicator of the disease, presence but also play an important role in the disease pathogenesis, and are a predictor of further development of macrophage activation syndrome according to a study conducted by Jia et al. (17)

Suda et al. compared the clinical symptoms and laboratory findings of 25 patients with EOSD described individually in the literature with those of patients with AOSD and no significant difference was found between the two groups, other than the fact that elderly patients more often developed disseminated intravascular coagulation (DIC) as a disease complication and had a more frequent tendency to develop opportunistic infections (OIs). (4)

In addition to the classic triad of symptoms, our patient had splenomegaly (verified through an ultrasound scan) lymphadenopathy, liver disease with elevated transaminases, and pleural effusion (verified through an X-ray). All of these findings, in addition to the negative tumour markers and negative immunological findings, except for the low titre positive antinuclear antibodies, which can also be found in healthy older populations, resulted in the final diagnosis of EOSD based on the Yamaguchi’s criteria.

Although the presence of another autoimmune disease is the exclusive criterion for diagnosing Still’s disease according to Yamaguchi’s criteria, we found a case report in the literature of an elderly patient who, in addition to a previous diagnosis of systemic lupus erythematosus, was also diagnosed with EOSD. (18)

The therapy protocol we applied in our case was conditioned by the unavailability of drugs such as anakinra and the presence of comorbidities in the patient including coronary artery disease, diabetes mellitus and kidney disease. Given the serious clinical features and the lack of adequate response to NSAIDs, we decided to include methylprednisolone administered parenterally in moderately high doses.

In the absence of other therapeutic options, the combination of leflunomide and hydroxychloroquine may be used in the treatment of patients with AOSD. (19)

In a study conducted by Sheng Li et al, patients with EOSD had an equally good response to initial glucocorticoid therapy as patients with AOSD. The frequency of relapses and disease complications in patients with EOSD was similar to that in patients with AOSD. A higher mortality rate was observed in patients with EOSD even though they had more moderate disease activity compared to patients with AOSD. (15)

CONCLUSION

Establishing the diagnosis of Still’s disease in adulthood is challenging in elderly patients because it is an extremely rare condition. Early symptom recognition and differential diagnostic inclusion of this diagnosis is important in order to initiate treatment in a timely manner and prevent complications of the disease such as the development of macrophage activation syndrome. Although the clinical symptoms and the course of the disease in elderly patients do not differ from those in younger patients according to the available literature, the treatment of these patients is often further complicated by the presence of other comorbidities.

Author Contributions: Conceptualization/draft, data curation, formal analysis and interpretation: I.M.; writing of the original draft, critical revision of the significant part of the intellectual content: I.M., S.M., L.G., M.M., E.Č.

Acknowledgments: The authors report no acknowledgments.

Funding: For this work authors did not receive any funding.

Conflict of interest statement: The authors declare that they have no conflict of interest relevant to this manuscript.

REFERENCES / LITERATURA

<jrn>11. Franchini S, Dagna L, Salvo F, Aiello P, Baldissera E, Sabbadini M. Efficacy of Traditional and Biologic Agents in Different Clinical Phenotypes of Adult-Onset Still’s Disease. Arthritis Rheum. 2010;62:2530–5.https://doi.org/10.1002/art.27532PubMed</jrn>

<jrn>12. Lenert A, Oh G, Ombrello MJ, Kim S. Clinical characteristics and comorbidities in adult-onset Still’s disease using a large US administrative claims database. Rheumatology (Oxford). 2020;59(7):1725–33.https://doi.org/10.1093/rheumatology/kez622PubMed</jrn>

<jrn>13. Kalyoncu U, Solmaz D, Emmungil H, Yazici A, Kasifoglu T, Kimyon G, et al. Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still’s disease: Data from a large multicenter cohort. J Autoimmun. 2016;69:59–63.https://doi.org/10.1016/j.jaut.2016.02.010PubMed</jrn>

<jrn>14. Cavalli G, Franchini S, Aiello P, Guglielmi B, Berti A, Campochiaro C, et al. Efficacy and Safety of Biological Agents in Adult-Onset Still’s Disease. Scand J Rheumatol. 2015;44:309–14.https://doi.org/10.3109/03009742.2014.992949PubMed</jrn>

<jrn>15. Li S, Ying S, Bai J, Wang Y, Yang C, Sun Q, et al. Clinical characteristics and outcome of elderly onset adult-onset Still’s disease: A 10-year retrospective study. J Transl Autoimmun. 2023;6:100196.https://doi.org/10.1016/j.jtauto.2023.100196PubMed</jrn>

<jrn>16. Kim HA, Kwon JE, Yim H, Suh CH, Jung JY, Han JH. The pathologic findings of skin, lymph node, liver, and bone marrow in patients with adult-onset still disease: a comprehensive analysis of 40 cases. Medicine (Baltimore). 2015;94(17):e787.https://doi.org/10.1097/MD.0000000000000787PubMed</jrn>

<jrn>17. Jia J, Wang M, Meng J, Ma Y, Wang Y, Miao N, et al. Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis. Nat Commun. 2022;13(1):6804.https://doi.org/10.1038/s41467-022-34560-7PubMed</jrn>

<jrn>18. Hirooka Y, Okuda S, Sugiyama M, Shiga T, Nozaki Y, Kinoshita K, et al. Case Report: A Rare Case of Elderly-Onset Adult-Onset Still’s Disease in a Patient With Systemic Lupus Erythematosus. Front Immunol. 2022;13:822169.https://doi.org/10.3389/fimmu.2022.822169PubMed</jrn>

<jrn>19. Pirildar T. Treatment of adult-onset Still’s disease with leflunomide and chloroquine combination in two patients. Clin Rheumatol. 2003;22(2):157.https://doi.org/10.1007/s10067-002-0667-0PubMed</jrn>

Figure 1. Salmon-pink maculopapular rash on the patient’s back

Figure 2: X-ray of the hands and feet: no clear signs of erosive changes