Overview

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease in which your body’s immune system mistakenly starts attacking healthy tissues. It affects the skin, joints, kidneys, and other organs. Lymphopenia occurs in lupus, and it serves as a sign of kidney involvement in the affected individual.¹

Lymphopenia is defined as a low level of lymphocytes in the body, and SLE causes it. Lymphopenia serves as a marker for active SLE disease, suppressed immunity, and risk of infections in the affected people. It may also occur due to medications used in the treatment, such as corticosteroids.^1,2,3

In this article, we will discuss why lymphopenia occurs in lupus and how it causes further disease progression. We will also learn how to manage this condition in a person affected by lupus.

What is SLE?

SLE is a chronic disease in which the body’s immune system starts attacking the healthy tissues and organs. It is an autoimmune condition that primarily affects young people assigned female at birth (AFAB). It may occur at any age, but most cases are reported between the ages of 15 and 45. Lupus causes inflammation throughout the body, and the person affected may experience periods of active disease (flares) and periods of remission (wellness).^1,4 

Signs and symptoms of SLE

Symptoms of lupus vary from person to person. It may affect a single organ or your whole body. The symptoms may be mild or severe, depending on the organs that are affected. It usually affects the skin, joints, kidneys, brain, lining of lungs and heart, and blood cells.¹

Common symptoms:^1,3

• A butterfly rash: a rash that appears on the face, extending from the nose to the cheeks
• Photosensitivity
• Arthritis: a condition that causes painful and stiff joints (especially in the morning)
• Tiredness
• Headache
• Depression 
• Fever
• Hair loss
• Mouth ulcers 
• A scaly rash that may occur anywhere on the body
• Swollen eyes and legs
• Bluish fingers and toes (Raynaud’s phenomenon)
• Abdominal pain
• Swelling in the glands

Why does lymphopenia occur in SLE?

Lymphopenia occurs in the majority of patients suffering from Lupus. The mechanism is complex, and it involves the following processes:¹

• The immune system makes autoantibodies that attack CD4+ T-cells
• Uncontrolled apoptosis of T-cells (destruction of cells)
• Increased destruction of T-cells by the complement system
• Impaired formation of new T-cells
• Abnormal lymphocyte sequestration (a process in which lymphocytes accumulate in lymphoid organs such as the spleen and are temporarily removed from the blood) – in SLE, the normal process is disturbed due to the destruction of lymphocytes by immune cells¹

How does lymphopenia contribute to SLE progression?

Lymphopenia is a common finding in severe and active SLE. The anti-Ro antibodies target the CD4+ T cells (immune cells) and destroy them. The IgM and IgG antibodies, along with the complement system, also kill T-cells, causing lymphocyte depletion.²

This active episode (flare) of lupus is associated with a decline in lymphocyte count in the circulating blood. It increases the risk of opportunistic infections in the affected person. The infections further cause a decrease in lymphocytes, causing disease progression. Moreover, high doses of immunosuppressive drugs such as cyclophosphamide and glucocorticosteroids also contribute to lymphopenia.^2,3

How are different types of lymphocytes affected in SLE?

Both B-cell and T-cell lymphocytes are affected in lupus. They are involved in the spread of SLE in the body. The NK (natural killer) cells of the body present damaged antigens to T-cells. These T-cells produce a distorted gene. It causes Interleukin 2 (IL-2) to increase the production of altered T-cells in the body. These abnormal T-cells activate cytokines and autoantibodies against them, causing further damage and activation of SLE. The naïve B lymphocytes are more affected than the memory B cells. These cells show increased activation and production of autoantibodies that damage the different tissues and organs of the body.²

Effects of lymphopenia in lupus

Lymphopenia is a marker of active or severe SLE. In the body of the affected person, lymphopenia can be associated with:³

Leukopenia and thrombocytopenia 

Leukopenia means the low count of white blood cells, mainly neutrophils, and this causes an increased risk of infections. Thrombocytopenia is given by a low level of platelet count in the blood, resulting in an increased risk of haemorrhage.^2,3

Increased risk of infections

Active episodes of SLE lead to depleted immunity. This causes an increased risk of opportunistic infections in the affected individual.

The infections are:

• Bacterial infections: These infections are caused by Staphylococcus aureus (skin and tissues), Streptococcus pneumoniae (respiratory), and Escherichia coli (urinary tract)
• Viral infections: Herpes zoster (shingles) infections
• Fungal infections: severe pneumonia caused by Pneumocystis jirovecii⁴

Arthritis 

Lymphopenia can be associated with lupus arthritis. It affects all joints of the body. In most cases, the hand and knee joints suffer the most. The joints become inflamed. This causes stiffness in the morning.^2,5

Lupus nephritis

Lupus nephritis is a renal disease that causes inflammation in the kidneys. The glomeruli are severely affected, and this may lead to kidney failure if left untreated.^1,3

Neuropsychiatric lupus

Neuropsychiatric lupus consists of a range of neurologic and psychiatric conditions that can occur to people affected by SLE. This happens when the immune-mediated injury affects the central and peripheral nervous system – the brain, spinal cord, and peripheral nerves. The neuropsychiatric lupus-associated syndromes are divided into two categories:⁶

The Central Nervous System manifestations (CNS)

• Headaches
• Seizures
• Mood disorders
• Aseptic meningitis
• Anxiety disorders
• Psychosis
• Cerebrovascular diseases
• Movement disorders (chorea)
• Demyelinating syndromes

The Peripheral Nervous System manifestations (PNS)

• Autonomic disorders
• Mononeuropathy
• Polyneuropathy 
• Cranial neuropathy 
• Myasthenia gravis
• Gullian-Barré syndrome
• Plexopathy 

Lymphopenia has been identified to be associated with neurological involvement in patients affected by lupus. They show a higher risk of neuropsychiatric manifestations.⁷ 

How is lymphopenia diagnosed in SLE?

Your doctor may diagnose lymphopenia with a CBC test (Complete blood count). This test shows the lymphocyte count in the blood. According to the National Institutes of Health (NIH), lymphopenia is diagnosed in a person when their lymphocyte levels are less than 1500 cells/microlitre.⁴

Other diagnostic tests are:

• Flow cytometry: When the CBC shows lymphopenia, this test measures the levels of different types of lymphocytes in the blood, e.g, the B-cells, T-cells, and the NK cells 
• Indirect immunofluorescence: ALA (Antilymphocytic antibodies) are likely to be detected in a person with active SLE and can present higher levels in SLE patients with lymphopenia⁸

How to manage lymphopenia in SLE?

Lymphopenia is commonly used as a biomarker of disease activity in active or severe lupus. Management of lymphopenia in SLE patients focuses on treating the underlying manifestations of active disease and reviewing the medications that may influence the lymphocytes – for example, if the patient undergoes immunosuppressive therapy (cyclophosphamide, glucocorticoids). Lymphopenia itself in SLE patients has no specific treatment, but if the lymphopenia is severe, the focus will be to reduce the risk of infections.²

Emerging treatments and research in lupus (SLE)

Research is ongoing for the blood abnormalities that occur in SLE disease. Rituximab shows a positive response in reducing haematological conditions in SLE-affected individuals.² Similarly, another drug named Belimumab was also tested, but there are fewer reports on its success.⁹

Bortezomib (proteasome inhibitor) is a drug used to treat multiple myeloma and was also tested in SLE patients. It has shown benefits in severe or refractory SLE cases, reducing disease activity and autoantibody levels (including anti-dsDNA). But this option remains an experimental treatment and is taken into consideration in case of a difficult case.^2,10

Summary

• Lymphopenia is defined as low levels of lymphocytes in the blood, and SLE is frequently associated with it
• It is considered a marker of SLE severity or activity, but the role it plays in the disease pathogenesis and progression is not yet completely understood
• Lymphopenia in SLE can be identified using investigational tests such as CBC, flow cytometry, and indirect immunofluorescence (for antilymphocyte antibodies) 
• No specific therapy for lymphopenia is indicated in a person affected by lupus, except for the prevention and treatment of opportunistic infections. Research into new treatments for haematological abnormalities in SLA is ongoing