KEYWORDS
adult onset Still’s disease, COVID-19 vaccine, SARS-CoV2, ulcerative colitis
INTRODUCTION
Adult-onset Still’s disease is a systemic autoinflammatory illness characterized by recurrent spiking fever, fleeting salmon-pink skin rashes, and polyarthritis.1 Although the etiology of adult-onset Still’s disease remains elusive, dysregulation of immune cells, particularly macrophages and T cells, and the release of various proinflammatory cytokines such as interleukin (IL)-18 may play significant roles in its development.2 Reportedly, vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could induce a hyperinflammatory state by triggering the production of spike proteins3; however, the correlation between SARS-CoV-2 vaccination and hyperinflammation remains to be elucidated. Moreover, the coexistence of adult-onset Still’s disease with ulcerative colitis, an inflammatory intestinal disease involving the colon, is extremely rare. Only one case of adult-onset Still’s disease with ulcerative colitis has been reported to date.4 Herein, we report a case of a patient with stable ulcerative colitis who developed adult-onset Still’s disease after receiving the first dose of a SARS-CoV-2 vaccine and was treated using nonsteroidal anti-inflammatory drugs (NSAIDs) alone.
CASE HISTORY/EXAMINATION
A woman in her 50s with a history of stable ulcerative colitis for over 20 years presented to our hospital with a complaint of migratory joint pain. One week before presentation, she experienced arthralgia in her elbow and right hip, accompanied by throat pain, skin rashes, and intermittent daily fever that started abruptly. She developed intermittent migratory rashes on her limbs following daily fever spikes (up to approximately 38 ℃), demonstrating a possible temporal relevance between the rashes and fever. Bilateral ankle pain and loss of appetite followed, leading her to seek medical care at a hospital, where acetaminophen (400 mg as needed) was prescribed. Although the joint pain in her elbows and hip disappeared, acetaminophen was not effective for relief of the ankle pain. Furthermore, she experienced bilateral wrist pain and visited another hospital for further pain relief. Celecoxib (100 mg two times/day) was prescribed and was partially effective for pain relief. She was subsequently referred to our hospital for further treatment.
The patient had no significant medical history other than ulcerative colitis, which was diagnosed in her 30s and managed using salazosulfapyridine (3000 mg per day). The patient showed no acute deterioration under this treatment, and her annual colonoscopy showed no flares in her intestines. Her family history was insignificant and she had no allergies, travel history, history of insect exposure, or history of sexual activity that may explain the migratory rashes and arthralgia.
On her first visit, she presented with an afebrile status accompanied by tachycardia (105 beats per minute). Salmon-pink maculopapular rashes with abrasions were observed on her forearms, abdomen, and lower legs (Figure 1A). Her anterior neck lymph nodes showed painless lymphadenopathy (maximum diameter, 15 mm). She reported tenderness in multiple joints, including the wrists and ankles, and the pain was intensified with active joint movement.
DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS AND TREATMENT
Laboratory tests performed on admission revealed leukocytosis (16,700 cells/mm3) with neutrophilia (14,863 cells/mm3), a C-reactive protein level of 35.2 mg/dL, an erythrocyte sedimentation rate of 98 mm/h, and a ferritin level of 1651.5 ng/mL. Positron emission tomography-computerized tomography (PET-CT) indicated 18F-fluorodeoxyglucose uptake in the lymph nodes (neck, axillary, mediastinal, inguinal, and liver), spleen, and bone marrow. Axillary lymph node biopsy revealed reactive lymphoid follicular hyperplasia with no malignant changes.
The presence of granular cast and microscopic hematuria prompted admission for fear of acute kidney failure. An anti-streptolysin titer returned negative results. Twelve days after admission, the patient’s ferritin levels increased to 2382.6 ng/mL and her IL-18 levels (131000 pg/mL) were extremely high.
Hepatitis B surface antigen, anti-human parvovirus B19 immunoglobin M, and interferon gamma assays for tuberculosis showed negative results. Autoimmune-related assessment, including antinuclear antibody, rheumatoid factor, anti-citrullinated peptide antibody, anti-ds DNA antibody, anti SS-A antibody, and anti-neutrophil cytoplasmic antibodies tests, showed normal results.
Ceftriaxone as an empiric antibiotic therapy was started immediately after admission because the nephrologists considered the risk of infection-related acute glomerular nephritis. However, we discontinued the antibiotics five days later after confirming negative blood culture results and rapid improvement in urine sediment with no pathognomonic casts, which is not compatible with the indications of acute kidney injury that requires kidney biopsy.
Diagnosis of adult-onset Still’s disease requires a thorough clinical investigation to rule out other possible inflammatory diseases, including malignancies, infections, and other rheumatic diseases. Malignant lymphoma is a fatal condition that mimics adult-onset Still’s disease. Biopsies of the patient’s lymph nodes and skin showed no malignant cells, and her good response to NSAIDs was incompatible with the outcomes of malignant lymphoma. Results of a PET-CT scan did not suggest any solid malignant tumor. In addition, cancer screening, including a pap smear, ruled out cervical cancer.
Considering the patient’s negative blood culture results and lack of apparent exposure, infectious diseases characterized by skin rashes and fever, including Lyme disease, syphilis, and acute hepatitis B, were ruled out. Autoimmune diseases associated with relevant antibodies, including systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-related vasculitis, and rheumatoid arthritis, were also ruled out by negative blood test results, which did not meet the classification criteria for each disease.
The patient’s medical history, physical examination findings, and lab test results indicated that the diagnostic criteria for adult-onset Still’s disease were met (Yamaguchi’s criteria5; three of four major criteria [arthralgia/arthritis, typical rash, and leukocytosis] and four of five minor criteria [sore throat, lymphadenopathy, abnormal liver function test results, and negative rheumatoid factor and antinuclear antibody assays] were met). Furthermore, her serum IL-18 levels increased to 131,000 pg/mL, and her ferritin levels increased as her symptoms worsened, which strongly supported the diagnosis of adult-onset Still’s disease. PET-CT findings showing high absorption in the bone marrow demonstrated a typical pattern for adult-onset Still’s disease. Thus, new-onset Still’s disease was considered the most likely diagnosis.
We initially considered restarting acetaminophen instead of NSAIDs to relieve the patient’s joint pain, even though NSAIDs are generally contraindicated for patients with ulcerative colitis because they may trigger a relapse.6,7 We finally decided to continue the NSAID therapy considering that the severe arthralgia that was affecting her motor function was improving with the use of celecoxib.
We started the patient on loxoprofen and gradually increased its dose while continuing salazosulfapyridine and confirming the absence of hematochezia or abdominal pain, a sign of relapsing ulcerative colitis. If treatment failed, we planned to intensify the dose of steroid or tocilizumab treatment, which is reportedly effective for adult-onset Still’s disease. The patient responded to the NSAID therapy with loxoprofen (180 mg daily [maximum dose]) and showed a gradual and significant improvement in the fever, rashes, and fatigue. She was subsequently discharged from our hospital within three weeks.
OUTCOME AND FOLLOW-UP
Figure 2 shows the clinical course of the case. NSAID therapy was significantly and continuously effective in relieving the patient’s joint symptoms. She was discharged nine days after admission following significant improvement in her symptoms. We continued the usual recommended dose of NSAIDs (loxoprofen 60 mg three times/day), and no side effect or reactivation of ulcerative colitis, bloody diarrhea, or abdominal pain occurred. Follow-up endoscopy performed nine months later showed no abnormalities in the patient’s large intestine.
Considering the significant improvements in arthralgia, edema, and fever, as well as the normalized inflammatory indicators within three months of NSAID monotherapy (loxoprofen 60 mg three times/day), administration of steroids or tocilizumab was deemed unnecessary. The rashes also disappeared within three months (Figure 1B). We gradually decreased the dose of loxoprofen considering the possible risk of recurrent ulcerative colitis, and finally discontinued the NSAID therapy within 12 months. All joint symptoms, fever, and rashes disappeared, and the patient’s ferritin, C-reactive protein, and IL-18 levels normalized at the completion of follow-up in one year.
With regard to anti-SARS-CoV2 vaccination status, the patient commented as follows (The following perspective was translated by the author as English is not the patient’s native language): “I was worried about the joint symptoms, as they interfered with my daily activities. However, pain killers relieved my joint pain gradually but significantly. The possible relationship between my disease and coronavirus disease 2019 vaccination is a bit worrisome, and I contemplated whether I should receive another shot. I will consider the consensus of the doctors and the prevalence of coronavirus disease 2019 when deciding.”
DISCUSSION
Development of adult-onset Still’s disease following mRNA SARS-CoV-2 vaccination suggests that the vaccine can cause a hyperinflammatory response. Multiple cases of new-onset adult-onset Still’s disease following SARS-CoV-2 vaccination have been documented.8-13 Flares of adult-onset Still’s disease have also been reported, suggesting a possible correlation between the disease and SARS-CoV-2 vaccines.14-17 The reported cases of new occurrence of adult-onset Still’s disease after SARS-CoV-2 vaccination, including the present case, are summarized in Table 1.
TABLE 1 New-onset adult-onset Still’s disease following the patient’s first SARS-CoV-2 vaccination