A previously healthy 16-year-old girl presented in September 2019 to our clinic for bilateral eyelid swelling within the past 2 months. She had neither edema of the lower limbs, nor fever, sore throat, erythra and oliguria. Also, she had no known drug allergy, with no history of recent medication, travel, exposure to sick persons, blood transfusions, major illness or previous surgery. She had no previous personal or family history of autoimmune disease. On physical examination, the temperature was 36.8°C, the blood pressure 106/70 mmHg, the pulse 84 beats per minute, the respiratory rate 20 breaths per minute. Physical examination demonstrated bilateral eyelid edema and cervical lymph nodes enlargement. Review of chest, lung, abdomen and nervous system was negative. Initial laboratory examinations revealed normal routine blood test, serum electrolytes and albumin, liver and renal function and rheumatoid factor (RF). Urinalysis indicated proteinuria (2+) and 24-hour proteinuria was 1259mg.
Subsequent blood work revealed elevated erythrocyte sedimentation rate (ESR 31mm/h), increased IgG (18.8g/L) and globulin (38.0g/L) levels, low C3 (0.64g/liter), high titers of anti-nuclear antibody (ANA) (1:1000), positive anti-SSA(Ro52/60) and anti-SSB auto-antibody. HIV, HBV and HCV were tested to be negative. Comprehensive laboratory test results are shown in Table 1. Cardiac ultrasonography revealed normal global cardiac function and right-ventricular size, no evidence of a pericardial effusion. Ultrasonography of the abdomen and urinary system revealed normal structure. Enhanced computed tomography (CT) of the chest was also performed and no abnormalities were identified. Due to the proteinuria, hypocomplementemia and high titers of ANA, systemic disease of lupus cannot be excluded. Therefore, renal biopsy was performed. Nevertheless, renal biopsy showed minimal change disease (MCD) without immune complex deposits.
Table 1
Laboratory Test Results upon First and Second Admission
Variable | Reference Range | First Admission | Second Admission |
Blood Routine Test | | | |
White cell count (per mm3) | 4000−15,000 | 6670 | 10,730 |
Neutrophils | 50–70 | 56.3 | 58.6 |
Lymphocytes | 20–40 | 30.9 | 34.1 |
Platelet count (per mm3) | 100,000−550,000 | 155,000 | 318,000 |
Hemoglobin (g/dl) | 11–16 | 12.6 | 14.4 |
Renal Function | | | |
Creatinine (µmol/liter) | 9–88 | 57 | 47 |
Liver Function | | | |
Albumin | 35–50 | 37.4 | 18.2 |
Globulin | 18–32 | 38.0 | 28.9 |
Inflammatory Markers | | | |
C reactive protein (mg/L) | < 8 | 2 | 14 |
Erythrocyte sedimentation rate (mm/hr) | 0–20 | 31 | 49 |
Auto-antibody Test | | | |
Antinuclear antibody | Negative | 1:1000 | 1:320 |
Anti-RNP antibody (U/ml) | Negative | Negative | Negative |
Anti-Smith antibody (U/ml) | Negative | Negative | Negative |
Anti–SS-A/Ro52 antibody (U/ml) | Negative | Positive | Positive |
Anti–SS-A/Ro60 antibody (U/ml) | Negative | Positive | Positive |
Anti–SS-B antibody (U/ml) | Negative | Positive | Positive |
Anti–double-stranded DNA | Negative | Negative | Negative |
Anticardiolipin antibody (U/ml) | Negative | Negative | Negative |
p-ANCA | Negative | Negative | / |
c-ANCA | Negative | Negative | / |
Complement (g/liter) | | | |
C3 | 0.9–1.8 | 0.64 | 0.73 |
C4 | 0.1–0.4 | 0.14 | 0.19 |
RF (IU/ml) | < 15.9 | 13 | / |
Urine | | | |
Protein | Negative | 2+ | Negative |
Red cells (per high-power field) | 0–3 | 0–2/HP | 0/HP |
24 hour urine protein (mg/24h) | 40–225 | 1259 | 91 |
Coombs test | | | |
Direct Coombs test | Negative | Negative | / |
Indirect Coombs test | Negative | Negative | / |
Immunological Evaluation | | | |
IgG (g/L) | 7.2–15.6 | 18.8 | 7.97 |
IgM (g/L) | 0.50–2.55 | 2.29 | 3.50 |
IgA (g/L) | 0.67–3.14 | 2.49 | 1.88 |
IgE (IU/ml) | < 100 | 76.80 | 91 |
Pathogen Test | | | |
TSPOT | Negative | / | Negative |
Blood Culture | Negative | / | Negative |
EBV-DNA (copies/ml) | < 5*103 | / | Negative |
CMV-DNA (copies/ml) | < 500 | / | Negative |
In the setting of positive anti-SSA/Ro and anti-SSB/La autoantibodies, there was concern for SS as the etiology of her presentation. Labial glands biopsy was then performed, suggesting mild atrophy of labial glands with two lesions of inflammatory lymphoplasmacytic infiltrates. On the basis of her evaluation, the patient was diagnosed with childhood-onset SS according to the proposed pediatric criteria pointed out by Bartunkova in 1999 and the 2016 ACR/EULAR Classification Criteria. The patient was then treated with daily oral prednisone and total glucosides of paeony (TGP, a capsule of extracts of traditional Chinese medicine).
The disease was stable until 5 months after the patient’s initial hospitalization when there was obvious edema of the lower limbs. She also complained of transient chest pain as well as arthralgias affecting knees and ankles, in the absence of sicca symptoms. With these new-onset symptoms and on-going oliguria, she was admitted for hospitalization again. Vital signs included tachycardia to 108 beats per minute, tachypnea of 28 breaths per minute as well as enlarged cervical lymph nodes, eyelid edema and dependent edema of the lower extremeties. Review of chest, lung, abdomen and nervous system only revealed mild abdomen distention and shifting dullness.
Laboratory work revealed a decreased serum albumin level of 18.2 g/L, yet with negative proteinuria. Comprehensive laboratory test results are also shown in Table 1.
A chest and abdomen computed tomography scan revealed atelectasis in the left lobe and extensive bilateral pleural effusion as well as massive ascites (Fig. 1). Cardiac ultrasonography revealed pericardial effusion yet normal global cardiac function. Considering extensive bilateral pleural effusion and massive ascites, thoracentesis was performed and identification of hydrothorax revealed 9.0*106 cells/L with protein level of 16.2g/L and negative Rivalta test, confirming transudates rather than exudates. Intravenous albumin (11 consecutive days) and immunoglobulin (5 consecutive days) was given subsequently. No organisms grew from the fluid, and broad infectious testing results were negative, so antibiotics were not considered. Repeated immunological parameters revealed a positive antinuclear antibody level, with a titer of 1:320 in a speckled pattern, and positive anti-SSA/Ro and anti-SSB/La antibody levels, with decreased levels of C3 (0.73g/L). Pertinent negative findings included negative anti-double stranded DNA, anti-Smith, and anti-phospholipid antibody levels. Salivary gland ultrasound (SGUS) imaging was obtained of her bilateral parotid and submandibular glands and revealed global inhomogeneity of the tissue in her parotid and submandibular glands, consistent with subclinical salivary gland involvement. Malignant tumors that can present as systemic illness, which could be considered in this rapidly progressive case, include non-Hodgkin’s lymphoma and plasma-cell myeloma. However, bone marrow puncture and cervical lymph nodes biopsy were normal and excluded the possibility. SS activity score by EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) was 40 upon this hospitalization.
Since the diagnosis of SS was confirmed and extensive bilateral pleural effusion as well as massive ascites were due to SS itself rather than other diseases, the patient was then given intravenous methylprednisolone therapy (50mg daily) and MMF. Meanwhile, the patient also received intravenous albumin and immunoglobulin therapy for hypoproteinemia consecutively. Nevertheless, extensive pleural effusion persisted despite these treatment. Again, thoracentesis was repeated and analysis of hydrothorax revealed 283.0*106 cells/L with protein level of 33.7g/L and positive Rivalta test, indicating exudates instead of transudates this time, which was contrary to previous one. Static tremors were also unexpectedly observed occasionally, which, we assumed, was most likely caused by SS itself after excluding other factors including hypocalcemia, drug factors and etc. On the fifth hospital day, cough occurred and aggravated, thus repeated chest CT scanning indicated bilateral pulmonary infection. Treatment with oral cefdinir, azithromycin, intravenous methylprednisolone (pulse therapy of 500mg daily for 3 days, followed by 40mg daily for 15 days) was initiated.
The patient responded well to the immunosuppression therapy, with obvious reduction of hydrothorax and normalization of complement levels and serum albumin. She was able to wean off prednisone 7 months after her initial diagnosis. Two years and seven months after disease onset, she undergoes MMF therapy and has shown no clinical signs including fatigue, edema, arthralgias, rash or fever.