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