Systemic lupus erythematosus presenting as right-sided massive pleural effusion with autoimmune hypothyroidism and medium vessel vasculopathy

Abstract

Segmental involvement of medium-sized vessels are lesser-known manifestations of systemic lupus erythematosus (SLE) vasculopathy. Medium vessel vasculopathy and peripheral vascular disease (PVD) mimicking manifestations of SLE, although rare, have been reported, particularly in Asian women mostly under the age of 30 years. This is due to metabolic disadvantages in their ethnicity, with high incidence of insulin resistance and resulting metabolic syndrome, leading to lower high-density lipoprotein cholesterol levels, higher triglyceride levels and small dense low-density lipoprotein, increased proinflammatory cytokines, endothelial dysfunction and procoagulant tendency. Owing to the longer duration of the disease with the simultaneous use of steroids, vessels are often affected. SLE may also present with thyroid manifestations against a background of a proinflammatory immune state, where autoimmune thyroid diseases, such as Hashimoto’s thyroiditis, may coexist. Here, we describe the case of a young woman who presented with progressive shortness of breath, right leg pain and cough with amenorrhoea and was diagnosed with SLE.

Case presentation

A woman in her 20s presented with a dry cough which she had had for 6 weeks associated with progressive shortness of breath for 4 weeks, followed by right leg pain for 2 weeks. These events occurred sequentially, one after the other. The cough was persistent and dry in nature. Shortness of breath was preceded by pleuritic chest pain in the right hemithorax and progressed from modified Medical Research Council grade 1 to grade 4 within 4 weeks, requiring admission to hospital. The patient had also observed pain in her right leg, initially noticed when walking. Later, the intensity of pain increased intensity at night and even when at rest. She had no history of the following:

• Fever, haemoptysis, wheezing, nasal congestion, postnasal drip, heartburn or any history of a cough requiring drug treatment

• Joint pain, rash, haematuria and decreased urinary output or associated glandular swelling

• Leg swelling, discolouration, ulcers or any features of Raynaud’s phenomenon

• Contact with tuberculosis or weight loss

• Diabetes, alcohol consumption, smoking, recent travel, blood transfusions or keeping pets

• Long-term medication or use of immunosuppressive drugs.

She had amenorrhea for 2 months, but no history of miscarriage. Before coming to the hospital, she had received a few courses of oral antibiotics, with no relief.

Clinical examination disclosed a slight pallor. She was tachycardic with a heart rate of 110 beats/min, had a regular rhythm with impalpable pulsations in the right radial and femoral arteries, while the other pulses were normal on palpation.

In view of the above clinical symptoms and findings, a chest X-ray scan was taken, showing a right-sided massive pleural effusion with contralateral mediastinal displacement (figure 1). Routine blood tests were performed (table 1). Serology for hepatitis C virus and hepatitis B virus was negative and non-reactive for human immunodeficiency virus types 1 and 2. Sputum for acid-fast bacilli was negative in two specimens; sputum for Gram stain and culture showed no growth. Urinalysis showed traces of albumin and red blood cells—1/hpf. There was no growth in culture and sensitivity; 24-hour urine protein was 37 mg/day. An abdominal ultrasound scan was normal. Two-dimensional echocardiography showed minimal pericardial effusion.

Figure 1.

Chest radiographic imageshowing right-sided massive pleural effusion with obliteration of the bilateral costophrenic angle.

Table 1.

Full investigation panel

Investigations	Results	Reference range
Routine blood investigations
Haemoglobin (g/dL)	10.4	Male: 13–18  Female: 11.5–16.5
Total leucocyte count (/mm3)	5100	4000–11000
Differential leucocyte count	n=53%, L=15%, M=01%, E=01%	n=40–60%, L=20–40%, M&E=2–8%
Platelet count (/mm3)	2 90 000	1 50 000–4 00 000
Serum urea (mg/dL)	12	5–20
Serum creatinine (mg/dL)	0.8	Male: 0.74–1.35  Female: 0.59–1.04
Total protein (g/dL)	6.8	5.5–7.5
Serum albumin (g/dL)	3.8	3.5–5.5
Fasting blood sugar (mg/dL)	78	<110
Thyroid function tests profile
Serum thyroid stimulating hormone (mU/L)	19.7	0.4–5.6
Free T4 (ng/dL)	0.28	0.58–1.20
Thyroid peroxidase antibody (U/mL)	59	0–35
Thyroglobulin antibody (U/mL)	131	0–40
Autoimmune screening panel
Serum antinuclear antibody with HEp-2 substrate	Reactive 1: 320 dilution 4 + homogeneous
Anti-dsDNA	Positive: 1:10
Serum complement 3	64.5	90–180
Serum complement 4	17.8	10–40
Antineutrophil cytoplasmic antibodies	Negative
Antiphospholipid antibodies	Negative
Lupus anticoagulant	Negative
Pleural fluid antinuclear antibody (Hep-2)	Reactive1: 640 dilution 4 + homogeneous
Pleural fluid titre	Pleural fluid titre > serum titre

Pleural fluid was aspirated daily (800 mL/day straw fluid) for the first 3 days. Pleural fluid analysis was performed (table 2). An intercostal tube was placed to relieve shortness of breath despite repeated aspiration on day 3 of admission (figure 2). After drainage of the intercostal tube, respiratory distress worsened, and the patient was ventilated for 3 days. A CT scan of the chest was performed (figure 3). Finally, the patient was successfully weaned from ventilatory support, followed by removal of the intercostal tube. Due to the recurrence of symptoms, the patient was admitted to the hospital for further investigation.

Table 2.

Pleural fluid analysis

Parameters	Right side	Left side
Appearance	Pale, straw and coagulum present.	Pale, straw and coagulum present.
Cells	Nucleated cells=2000/mm3, n=98%, neutrophilic	Nucleated cells=800 cell/mm3, n=55%, neutrophilic
Glucose (mg/dL)	82	122
Protein (g/dL)	3.8	3.7
Nature	Exudative	Exudative
ADA	8.9	11.7
Malignant cells	Negative	Negative
Microbiology	No acid-fast bacilli. No growth in Gram stain and aerobic culture.	No acid-fast bacilli No growth in Gram stain and aerobic culture.

ADA, adenosine deaminase.

Figure 2.

Chest radiographic image after the third day of pleural fluid aspiration and intercostal drainage.

Figure 3.

CT scan of thorax showing pleural effusion.

Differential diagnosis

The differential diagnoses considered in this case were tuberculous pleural effusion with tuberculous arteritis, malignant effusion (lymphoma/metastatic malignancy) with tumour embolism, collagenosis or pulmonary thromboembolism. Other causes of effusions include congestive heart failure, cirrhosis, kidney disease or failure, anaemia, subphrenic abscess, actinomycosis, rheumatic fever, SLE, viral pneumonia and Meigs’s syndrome.¹

Further analysis produced a profile of the thyroid function that was congruent with the presence of autoimmune hypothyroidism. An ultrasound scan of the thyroid was normal. After consultation with endocrinology, treatment of the patient with thyroxine replacement therapy was started and full autoimmune screening was carried out (table 1).

An ultrasound scan with Doppler of all four limbs showed segmental stenosis of the distal part of the right radial artery and stenosis of the proximal part of the right femoral artery without stenosis of the profunda femoris artery, which was complemented by lower limb angiography, with similar findings (figure 4). A nerve conduction velocity study was normal for all four limbs. The rheumatology department was consulted, and the patient was advised to have an arterial biopsy, but she did not consent. Treatment was then started with low molecular weight heparin and oral anticoagulants. She was also given intravenous methylprednisolone (500 mg) for 3 days, followed by oral prednisolone, which was started at 1 mg/kg/day. Additionally, she received hydroxychloroquine (200 mg) once daily, and mycophenolate mofetil 500 mg, initially twice daily and then increased to 1000 mg twice daily.

Figure 4.

Lower limb angiographic image showing narrowing of the proximal part of the right femoral artery without any narrowing of the profunda femoris artery.

Outcome and follow-up

The patient was diagnosed with SLE presenting as a right-sided massive pleural effusion with autoimmune hypothyroidism and middle vessel vasculopathy. She gradually recovered and the follow-up chest X-ray scan showed no accumulation of pleural fluid (figure 5). She is currently followed up twice a year and has resumed her daily activities.

Figure 5.

Follow-up chest radiographic image showing resolution of pleural fluid collection.

Discussion

The most common thoracic manifestation of SLE is pleurisy.² Pleuritic pain occurs in approximately 45–60% of patients, with or without pleural effusion.³ However, clinically obvious and massive refractory pleural effusions are rare.⁴ They are usually bilateral but can be unilateral and evenly distributed between the left and right hemithorax. Pleural effusions in patients with SLE may also be secondary to renal failure, pulmonary embolism, infection or congestive heart failure. Lupus pleurisy in SLE is thought to result from the deposition of immune complexes, complement activation and direct binding of anti-dsDNA antibodies to the mesothelium.⁵ Pleural effusions are invariably exudative with either lymphocytic or neutrophilic dominance and have higher glucose and lower lactate dehydrogenase levels than those found in rheumatoid arthritis. Antinuclear antibodies, anti-DNA antibodies and lupus erythematosus cells are usually found in the pleural fluid. Lupus erythematosus cells appear to be relatively specific.^6–9 Pleural biopsies have rarely been performed in SLE, and are primarily indicated to rule out alternative causes. Findings are non-specific, showing lymphocyte and plasma cell infiltration, fibrosis and fibrinous pleurisy.¹⁰ Thoracoscopy tends to show nodules on the visceral pleura, and immunofluorescence of biopsy specimens of these nodules often shows immunoglobulin deposits.¹¹

Treatment for pleural disease depends on the severity of symptoms. Small asymptomatic effusions may not require special treatment. Non-steroidal anti-inflammatory drugs can be effective for mildly symptomatic pleurisy. Patients with more severe disease or those already receiving corticosteroids often require higher doses of corticosteroids.¹² Long-term treatment may involve the use of antimalarial drugs, such as hydroxychloroquine. Invasive measures such as talc pleurodesis should be used when systemic measures fail or when pleural effusion is the only manifestation of lupus.¹³ If a refractory pleural effusion is part of an exacerbation of lupus, systemic treatment is preferred, such as an immunosuppressive therapy with high-dose steroids and cyclophosphamide. Intravenous immunoglobulin can also be considered.¹⁴

As the life expectancy of patients with SLE continually increases, PVD has become an important cause of morbidity. The broad spectrum of vascular manifestations associated with SLE includes vasculitis, thromboembolism or vasospasm.¹⁵ The relative contribution of each component is difficult to assess given the overlapping pathophysiology. PVD is an area of vascular morbidity in SLE that has received little attention in the past. Kao et al have shown that the occurrence of PVD is influenced by longer duration of both the disease and steroid use.¹⁶ Apart from disease-related variables such as dyslipidaemia or atherosclerosis, ethnicity might play a role, as Asian Indians are known to be a metabolically disadvantaged group. They have high incidence of insulin resistance and resulting metabolic syndrome leading to lower high-density lipoprotein cholesterol levels, higher triglyceride and small dense low-density lipoprotein levels, increased proinflammatory cytokines, endothelial dysfunction and procoagulant tendency.¹⁵

Various modalities can be used to detect vascular disease in lupus. Theodoridou et al used an abnormal Ankle-Brachial Index, while Lin et al using xenon-133 muscle washout showed that muscle perfusion is significantly reduced in the lower extremities of patients with SLE.^{17 18} Thallium-201 muscle perfusion scans have also shown reduced perfusion reserve in distal muscles in asymptomatic patients with SLE.¹⁹ Doppler ultrasonography and angiography can also be used. They can detect disorders of the upper and lower extremities and have the advantage of delineating structural lesions. 18-Fluorodeoxyglucose-positron emission tomography CT scans can also be used to assess the extent of vasculitis involvement. However, in this case the CT angiogram of the lower extremity showed no changes indicative of any vasculitis or inflammatory changes, therefore not necessitating any further investigation (figure 4).

Primary hypothyroidism is the most common thyroid manifestation, occurring in 15–19% of patients with SLE. It is unclear how the proinflammatory immune state caused by SLE affects thyroid function, but a strong commonality between thyroid disease and SLE appears to be the immune dominance of T-helper 1 cells that produce interferon γ. Both SLE and autoimmune thyroid diseases, such as Hashimoto’s thyroiditis and Graves' disease, share common elevations in interferon γ and its associated chemokines.²⁰ Although patients with SLE have autoantibodies to thyroid peroxidase (TPO), IgG from sera in patients with SLE does not inhibit TPO activities, as it does in patients with thyroid diseases. This finding suggests that the specificities of anti-TPO autoantibodies in SLE differ from those in thyroid disease. These autoantibodies to TPO should be considered when searching for associations between SLE and autoimmune thyroid disease.²¹ Based on the thyroid profile, thyroxine supplementation is beneficial in these cases. Hypothyroidism can cause pleural effusions, but most of these are either mild or bilateral or sometimes unilateral, but rarely severe.^4–6 In our patient, the hypothyroidism was probably secondary to the common spectrum of autoimmune disorders that can coexist with SLE.

Conclusion

The above case examines a spectrum of three factors associated with SLE. There is a massive pleural effusion associated with medium vessel vasculopathy affecting the right lower extremity together with autoimmune thyroiditis in a background of hypothyroidism. These manifestations of segmental medium vessel involvement and peripheral vascular disease in SLE, although rare, have been reported specifically in young Asian women. Taking into account the given association, we made our final diagnosis. Subsequent treatment with corticosteroids and thyroxine supplementation, with supportive medication such as hydroxychloroquine, helped us to manage this case. Cyclophosphamide was not used in our patient, mainly owing to concerns about fertility. At the same time, there was no evidence of any life-threatening organ dysfunction, such as diffuse alveolar haemorrhage, acute interstitial nephritis, lupus nephritis or neurological involvement. The vasculopathic changes in the lower extremity also did not contribute to acute extremity ischaemia. This therefore did not require a graded immunosuppressive regimen of 1 g (high-dose) methylprednisolone.

Learning points.

• Pleural effusion may be the sole manifestation of systemic lupus erythematosus (SLE) in some cases.

• Pleural effusion in SLE may be extensive, requiring repeated aspiration or sometimes even intercostal tube drainage.

• Young women of Asian descent may present with claudication of limbs, which might be due to SLE-induced vasculopathy.

• Clinical hypothyroidism in young patients might occur owing to an autoimmune disease (such as autoimmune thyroiditis) that may be associated with SLE.

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