Autoimmune Polyendocrine Syndrome Type 4 with Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome
A 50-year-old Chinese woman presented with a complex medical history spanning over two decades, characterized by intermittent fever, xerostomia, xerophthalmia, paroxysmal loss of consciousness, and other systemic symptoms. Her case was ultimately diagnosed as Autoimmune Polyendocrine Syndrome Type 4 (APS-4) in conjunction with Systemic Lupus Erythematosus (SLE) and Anti-Phospholipid Syndrome (APS). This report provides a comprehensive analysis of her clinical presentation, diagnostic journey, and therapeutic management.
Clinical Presentation and Initial Evaluation
The patient first experienced intermittent fever (38–39°C) every 2 to 3 months, which resolved spontaneously without intervention, 24 years prior to her first rheumatological evaluation. Twenty-three years ago, she suffered an episode of epilepsy accompanied by abdominal pain, leading to severe weight loss, fatigue, weakness, skin pigmentation, and hypotension (80/45 mmHg). Laboratory tests at that time revealed hyponatremia (133 mmol/L, normal range 135–145 mmol/L), low serum cortisol (0.56 mg/mL, normal range 4.40–9.20 mg/dL), low 24-hour urine-free cortisol (259.6 mg/d, normal range 370.0–639.0 mg/d), and elevated adrenocorticotropic hormone (ACTH) (128.37 pg/mL, normal range 7.20–63.30 pg/mL). She also exhibited anemia (hemoglobin 77 g/L), thrombocytopenia (platelet count 70–90 x 10^9/L), and a dramatically prolonged activated partial thromboplastin time (APTT) (105.1 s, normal range 22.7–31.8 s). Serum creatinine was elevated (110–135 mmol/L, normal range 44–133 mmol/L). Blood cultures and purified protein derivative tests were negative.
Initial Treatment and Response
The patient was initiated on prednisolone 30 mg daily along with supportive therapy, which normalized her blood pressure, resolved her fever, and reduced serum creatinine to 120 mmol/L. Her fatigue and skin pigmentation improved, but she experienced shedding of armpit and pubic hair. Autoimmune tests revealed positive anti-nuclear antibodies (ANA) at 1:1000 and anti-SSA antibodies, while serum complement levels were normal. She was diagnosed with autoimmune adrenal insufficiency (AI) and maintained on prednisone replacement therapy (5 mg 8 AM and 5 mg 4 PM daily) for over 20 years.
Neurological Manifestations and Further Evaluation
Eleven years prior to admission, the patient began experiencing episodes of loss of consciousness with limb twitching, lasting approximately 3 minutes. Despite treatment with levetiracetam 1 g daily for the past two years, the episodes increased in frequency over the last year. Brain MRI showed minor lacunar infarction, and electroencephalogram revealed focal epilepsy discharge. Increasing the levetiracetam dosage to 1 g twice daily did not alleviate the symptoms. The neurologist referred her to endocrinologist and rheumatologist for further evaluation.
Additional Diagnostic Findings
Physical examination revealed multiple decayed teeth and dry mouth mucosa without hyperpigmentation. Laboratory tests confirmed distal renal tubular acidosis (blood gas analysis pH 7.3, PO2 98 mmHg, PCO2 33.4 mmHg, HCO3– 17.3 mmol/L, urinary titratable acid 8.4 mmol/L, normal range >10.5 mmol/L) with a normal anion gap. Thyroid-related antibodies, including anti-thyroglobulin, anti-thyroperoxidase, and anti-thyrotropin receptor antibodies, were negative. Coombs test was also negative. Positive ANA, anti-SSA, anti-SSB, and anti-histone antibodies were detected, while anti-double-stranded DNA was negative. Anti-cardiolipin antibody (IgG) was elevated at 36.07 U/mL (normal range <12.00 U/mL), anti-β2-glycoprotein-1 antibody (IgM) was 26.06 U/mL (normal range <20.00 U/mL), and lupus anticoagulant was positive at 2.0 (normal range 0.8–1.2). APTT was prolonged at 52.8 s (normal range 27.0–37.6 s). Complement 3 (C3) was low at 0.547 g/L (normal range 0.6–1.5 g/L), while C4 was normal. Immunoglobulins and IgG4 levels were normal. Schirmer test showed less than 5 mm of tear production in both eyes. Lumbar puncture revealed elevated cerebrospinal fluid pressure, cell count, protein, IgG index, and positive oligoclonal banding. Ultrasound showed a normal thyroid, while computed tomography revealed atrophy of bilateral adrenal glands. MRI showed a normal pituitary body and increased signals in the white matter on T2-weighted images.
Diagnosis and Management
The patient was diagnosed with APS-4, characterized by Addison disease (low body temperature, hypotension, hyponatremia, low cortisol, and high ACTH) and gonadal failure. Long-term prednisone replacement therapy led to tertiary or secondary AI. No elevated thyroid-stimulating hormone in response to low thyroxine (T4) suggested autoimmune hypophysitis. She was also diagnosed with SLE, Sjogren syndrome, and APS. Treatment with prednisone 60 mg daily, hydroxychloroquine, aspirin, and sodium bicarbonate resulted in significant improvement. During a 6-month follow-up, she remained asymptomatic for seizures or loss of consciousness, allowing discontinuation of anti-epileptics. Prednisone was tapered to 10 mg daily, and she continued on hydroxychloroquine, aspirin, and sodium bicarbonate, remaining stable.
Discussion
This case highlights the complexity of diagnosing and managing APS-4 in the context of SLE and APS. APS-4 is a rare condition involving multiple endocrine disorders, with Addison disease being a prominent component. The patient’s initial presentation with AI, followed by the development of SLE and APS, underscores the interplay between autoimmune endocrine and non-endocrine diseases.
Sjogren Syndrome and SLE Diagnosis
The patient’s initial symptoms of xerostomia, xerophthalmia, and positive anti-SSA/SSB antibodies fulfilled the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for primary Sjogren syndrome. Her subsequent development of fever, thrombocytopenia, seizure, positive anti-phospholipid antibodies, and low C3 met the 2019 EULAR/ACR classification criteria for SLE. The inclusion of fever in the new classification system aids in the early diagnosis of SLE, particularly in cases with neuropsychiatric manifestations.
Anti-Phospholipid Syndrome and Endocrine Involvement
APS is characterized by the presence of anti-phospholipid antibodies and recurrent thrombosis or fetal losses. Endocrine abnormalities, particularly AI, are uncommon in APS. The etiology of AI in APS may involve thrombosis leading to hemorrhagic infarction of the adrenal gland, which is vulnerable due to its single venous drainage. This case is unique in reporting APS with involvement of multiple endocrine glands.
Central Nervous System Involvement
The patient’s neurological symptoms, including seizures and loss of consciousness, were likely due to SLE and/or APS. High-dose steroid therapy improved her seizures, highlighting the role of autoimmune mechanisms in central nervous system involvement.
Conclusion
This case illustrates the diagnostic and therapeutic challenges of managing APS-4 in conjunction with SLE and APS. The patient’s clinical course underscores the importance of a multidisciplinary approach in diagnosing and treating complex autoimmune conditions. Further research is needed to elucidate the relationship between autoimmunity and endocrine diseases, particularly in rare syndromes like APS-4.
doi.org/10.1097/CM9.0000000000000708
Was this helpful?
0 / 0