The Four Subgroups of Systemic Lupus

Although all Lupus Warriors stand together under the same banner, understanding the differences between the subtypes of SLE can help us understand and better treat lupus.

Lupus is an inflammatory disease that effects organs throughout the body through immune system cells called “auto-antibodies.”

There are many types of lupus:

• Cutaneous lupus affects the skin
• Lupus nephritis attacks the kidneys
• Drug-induced lupus occurs as a reaction to certain medications
• Neonatal lupus is a lupus-like condition that occurs in newborns

and Systemic Lupus Erythematosus, which affects organs throughout the body, and can occur alongside other forms of lupus. SLE is the broadest type of lupus. Women less than 40 years of age with high levels of anti-nuclear antibodies (ANA) are most likely to develop SLE, and though they will often have symptoms in common, each patient has a set of symptoms unique to them.

Early on, however, doctors determined that these symptoms of SLE are not completely random. There are distinct patterns: Some people with full systemic lupus have more severe kidney problems. Others will have more symptoms related to the muscles, bones, and joints, or they might experience more neurological symptoms.

What are Autoantibodies?

Antibodies are key to lupus and autoimmune diseases in general. They are immune system cells that attach to invading cells such as bacteria and viruses. These act as “flags” that signal the immune system to attack and destroy these cells. Autoantibodies mark the body’s own cells to be attacked by the immune system.

Autoantibodies are not always bad.  Healthy people have autoantibodies available, and they help fight diseases that involve the body’s own cells, such as viruses and cancer. Normally, though, most autoantibodies are “filtered out.” In SLE, this filter seems to not be working properly for a variety of reasons. You can read more about B cells here.

In autoimmune diseases such as lupus, these antibodies latch onto the body’s healthy cells, and the immune system starts attacking organs and tissues throughout the body. The damage releases particles that signal that the body is under attack, and that causes more immune system activity. This feedback loop causes the disease can become more entrenched or worsen over time, especially when it is triggered.

Researchers have determined what types of autoantibodies are involved in lupus, and what their targets are. There are certain patterns of autoantibodies that show up in people who develop autoimmune diseases. ds-DNA antibodies, anti-ribosomal antibodies, anti-histone antibodies, and anti-phospholipid antibodies, for example, target parts that healthy and unhealthy cells have in common.

There are several blood tests for autoantibodies, such as C-reactive protein tests which assess nearly 15 different immune system proteins responsible for causing immune system reactions, and ANA Tests, measures the level of antinuclear antibodies, which target proteins found in the nucleus – the center – of healthy cells.

What are the Four Subtypes of Lupus?

Systemic Lupus Erythematosus (SLE) is a broad term, encompassing any form of lupus that effects organs throughout the body. It is so broad that, as research has progressed, it has become clear that SLE is not a single disease, but a collection of different conditions with similar symptoms, involving different types of autoantibodies.

SLE has long been recognized as having two distinct types: Type 1 and Type 2, but because several different routes may lead to SLE, many researchers sought to break these types down further. Initially, researchers thought that there were three subtypes, but recent research implies that there are actually four! These four subtypes are physically different from each other, involving different types of autoantibodies and affecting the body in different ways. Researchers think that these four subgroups indicate that SLE has at least four different disease pathways, or ways that SLE can arise in a person.

Different levels of the common antibodies have been found between different people with lupus. It has been difficult to find differences between the symptoms that people experience and break it into groups in that way, but looking at the autoantibodies themselves, at least four different types of SLE have been revealed.

The Four Subtypes of Lupus

In a study involving 911 patients in the US and Sweden, researchers assessed data involving blood samples, clinical manifestations, self-reports of symptoms and symptom intensity. Autoantibodies were determined for all of the patients by analyzing their blood samples and then putting these samples through genome sequencing. The subgroups occurred evenly in the study group, and very likely is evenly distributed in the general population as well.

Subgroup 1: The primary antibodies are Anti-SSA/Ro60/Ro52 and Anti-dsDNA and Anti-RNPA. Subtype 1 made up 29.3% of the study population. This subtype is similar to the autoantibodies found in Sjogren’s syndrome; an autoimmune disease sometimes found alongside lupus. 

Subgroup 2: The primary antibodies are anti-nucleosome, anti-SmRNP, anti-dsDNA, and anti-RNPA antibodies. People with Subtype 2 were diagnosed as young adults (ages 27-31.) Subgroup 2 comprised 28.7% of the people in the study. Most (13% of the population) male patients with lupus in the study population had subgroup 2 SLE and were more likely to have lupus nephritis. Although the subtypes were equally represented, the researchers believe that subtype 2 is the form of SLE most commonly diagnosed as SLE, since it was associated with many of the common symptoms that people report.

Subgroup 3: The primary antibodies are anti-CL/IgG/IgM and anti-β2GPI/IgG. 23.8% of the people in the study had subgroup 3, and shared some features with primary antiphospholipid syndrome, also known as pAPS. anti-β2GPI is associated with a lot of cardiovascular symptoms, which means that it will be important to identify this subgroup early and begin treatment to protect the heart. People with lupus are at more than twice the risk of ischemic stroke (Blood clots) and are at three times greater risk of hemorrhage (brain bleeds.) These types of symptoms can be devastating, but when caught early, they can be controlled and prevented.

Subgroup 4: The primary antibodies are this group had patients who were negative for all 13 of the autoantibodies the researchers were looking for. 18.2% fell into this group and were diagnosed in early middle age (32-45) more often than the others and had the lowest numbers of males (7.3%.) Disease symptoms were generally milder, but serositis and arthritis occur in a higher proportion.

These autoantibodies are similar to each other, and a few are different forms of the same autoantibody. They each target something present on healthy cells, such as proteins in the cell membrane or normal cell DNA. These apparently small differences can be quite profound:

People with lupus use a wide range of different medications, and often go through several combinations before finding the combination that works for their symptoms. Determining the subtype might lead to more efficient and targeted treatment at the start. For example, Subtype 1, which may be Sjogren’s like, may benefit more from medications that block the activity of interferon, which are made by the immune system to target viruses. Other subtypes may benefit more from drugs involving the immune system’s ability to regulate itself.

Limitations of the Study

Only people of white/European origin were in this study, and 911 people is a relatively low number of patients for a study. These two traits limited researcher’s ability to find differences between the four types.

However, it is a hint as to what the patterns might be. The four distinct autoantibody-defined phenotypes appeared to be associated with certain clinical manifestations and symptoms. There are differences in genetic background, cytokine levels, disease activity, and the organs effected.

There are also studies that indicate that there may be many more subtypes that have yet to be found.

A Lupus Warrior’s Takeaway

The more we learn about the autoantibodies involved in lupus, the closer we come to therapies that can send lupus into remission and better understand how to diagnose and treat lupus. Different subtypes may explain why some people do well when tapering off of medications like hydroxycloroquine and why some do not.

Knowing these subtypes might also help to make better monoclonal antibody therapies. Essentially, these lab-produced artificial antibodies target the autoantibodies themselves, marking them for destruction! The immune system “learns” these new targets and can start clearing out the autoantibodies. While current monoclonal antibody therapies are imperfect, they are a valuable tool for dealing with lupus.