Introduction

Disorders of the immune system are defined by the inability of our body’s defense mechanism to function as intended. In immune system conditions, the mechanisms responsible for protecting our body from infection mistakenly target and attack the body’s own tissues, causing a wide range of symptoms. An example of a human immune system disorder is Pyoderma Gangrenosum (PG), where minor skin trauma causes the formation of a spot, which then rapidly transforms into a large, painful necrotic ulcer.¹ Pyoderma Gangrenosum is rare—it is estimated to affect less than 10 out of one million people every year. Nevertheless, its severe symptoms and possible health complications are detrimental to people living with the condition.²

Like the majority of immune disorders, the exact cause of PG is not entirely understood, due to how rare it is, but also because such conditions involve complex interactions between several factors.³ The lack of a clearly defined cause, a specific diagnostic procedure and effective treatment options have driven researchers to identify the cause of PG by looking at other conditions that share the mechanism of action seen in Pyoderma Gangrenosum.⁴

Evidence shows that systemic (affecting several organs) autoimmune disorders, specifically rheumatoid arthritis (RA) and Lupus, also known as Systemic Lupus Erythematosus (SLE), are strongly associated with PG.^5,6 This article explores the link between Pyoderma Gangrenosum, Rheumatoid Arthritis and Lupus, showing the disease profile and suspected causes of each condition, as well as the possible overlaps in their biological mechanisms.

Pyoderma Gangrenosum

The term Pyoderma Gangrenosum refers to pus-filled (pyo-) lesions on the skin (derma) accompanied by necrotic tissue (gangrene). Pyoderma Gangrenosum (PG) is an inflammatory disorder that is linked to immune system dysfunction and is characterised by severe symptoms on the skin of affected individuals, presenting large and painful open sores.

Presentation and potential causes

Early-stage PG may show up on the body as a spot, such as a pustule, nodule, or common pimple, in the location where the injury happened. This spot is often surrounded by a purple border with asymmetrical edges, which quickly becomes an open sore, often referred to as an ulcer. The ulcer typically grows rapidly in size and forms a painful lesion with dead cells, often referred to as necrotic tissue. The necrosis (death) of previously healthy tissue occurs due to a phenomenon called pathergy, where trauma to the skin triggers an abnormal inflammatory response in the body, and the immune system attacks its own cells at anomalous rates. The PG ulcers usually present a sheet of pus covering them, caused by the recruitment of neutrophils (the white blood cells responsible for the body’s first line of defense against infection). Pyoderma Gangrenosum is not infectious, but the open wound may become infected, ultimately leading to further disease.⁷

The exact cause of pyoderma gangrenosum is still unknown, and for this reason, diagnosis is complicated. However, its development has been linked to the following factors:

• Neutrophil Dysfunction: abnormal population of neutrophils to the lesion site, classifying PG as a neutrophilic dermatosis
• Associations with Autoimmune Disorders: It is suggested that a compromised immune system can lead to PG
• Genetic factors: links to mutations causing disruptions⁸ 

Rheumatoid Arthritis (RA) and its clinical association with PG

Rheumatoid Arthritis (RA) is categorised as a chronic systemic autoimmune disease that primarily affects the joints while also causing damage to the vascular system and lungs. People with RA typically experience pain in the hands and wrists, with swollen, warm, and stiff joints, while severe cases show deformities and impaired movement.⁹

Meanwhile, Pyoderma Gangrenosum is associated with underlying illnesses, while there has been a significant association with Rheumatoid Arthritis.⁵ Understanding the overlap in the underlying immune dysregulations of these conditions may help improve diagnosis and treatment approaches.

Why could PG and RA be linked?

• Cytokine Dysregulation: Both conditions are driven by abnormal immune system reactions. PG and RA have common pathways of inflammation that are driven by cytokines (signalling proteins ensuring protection against inflammation), such as TNF-α, IL-1, and IL-17⁵
• Dysfunction of Neutrophils: Neutrophils are significantly important in the development of both conditions. Neutrophils causing PG are hyperactive and gather on the surface of the skin in abnormally large populations, causing ulcers to form. Whereas in RA, neutrophils release substances that contribute to joint degradation¹
• Clinical Correlation: A significant number of individuals with PG are also affected by an arthritis condition, with RA making up half of the arthritis cases found in individuals with PG.¹⁰ Additionally, people with rheumatoid arthritis have a three times higher risk of developing PG. In most cases, symptoms of PG follow after years of joint complications caused by RA¹¹

Systemic Lupus Erythematosus (SLE) and its link to PG

Systemic Lupus Erythematosus, commonly known as lupus, is also categorised as a chronic systemic autoimmune disease. Lupus does not target a specific type of healthy tissue but can cause inflammation and damage to multiple organs, including the skin, kidneys, heart and central nervous system. Lupus typically presents itself in patterns of increased illness and remission, called flares. Symptoms may vary from fatigue and skin rashes to kidney malfunction and issues disrupting normal neurological function.¹²

Although PG is less commonly observed in people with lupus than those with RA, lupus's association with PG is based on unusual immune responses that lead to inflammation.^6,13 Reports of the conditions co-occurring are relatively recent and quite rare. However, studying their similarities can offer us a deeper understanding of Pyoderma Gangrenosum.

Why could PG and Lupus be linked?

• Dysfunction of Neutrophils: Neutrophil activation plays a crucial role in both Lupus and PG. In Lupus, neutrophils are overly sensitive and create traps for identified pathogens, which are called Neutrophil Extracellular Traps (NETs). Impaired NETs in lupus identify nuclear material (antigens), leading the dysregulated immune system to target its own tissues.¹⁴ In a similar way, neutrophils in PG recruit in abnormal amounts and cause inflammation
• Autoantibody production: In lupus, impaired antibodies (proteins) called autoantibodies are released. Autoantibodies direct the immune system to the body’s own tissues, leading to inflammation and damage. Although autoantibody action is not directly linked to PG, the constant dysregulation of the immune system may intensify the formation and expansion of PG ulcers

Diagnosis

Diagnosis of PG follows a process of elimination for potential factors causing ulceration. Pyoderma gangrenosum is commonly misdiagnosed as necrotising fasciitis, hence the attempt to be surgically removed. However, this only triggers the PG ulcer to expand, therefore strongly suggesting a PG diagnosis.¹⁵

In individuals with rheumatoid arthritis or lupus, as well as other autoimmune disorders, attention to any minor trauma due to incidents or surgical procedures is crucial, as they may be predisposed to triggering PG through pathergy.

Treatment options

• Corticosteroids: systemic use of corticosteroids reduces inflammation and promotes ulcer healing for patients with PG alone, PG with rheumatoid arthritis and PG with lupus. (e.g. prednisone- first-line medication with PG)¹⁶
• Immunosuppressants: administered to patients resistant to corticosteroids or to reduce steroid dependency (e.g., methotrexate (effective in RA), cyclosporine (RA and lupus))^5,17 
• TNF inhibitors: inhibit TNF-α, effective in cases of co-occurrence (e.g., infliximab)
• Pulse Steroid Therapy: report of control and improvement of lupus-PG co-occurrence¹⁸
• Pain and discomfort relief: loose dressings and meticulous ulcer care, NSAIDs and narcotics may be required

Why linking PG to rheumatoid arthritis and lupus is important

Establishing a solid link between the occurrence of pyoderma gangrenosum and rheumatoid arthritis, as well as lupus, has the potential to significantly improve diagnosis and treatment. Conditions caused by immune system dysfunctions are significantly complicated to diagnose and treat, while the weakened immune state caused by one condition may predispose the patient to the development of a different autoimmunity-associated disease. This comprehensive approach can lead to a deeper understanding of the underlying causes of these conditions and provide early detection for additional autoimmune disorders, as well as targeted combinational treatments.

Summary

People affected by Pyodergma Gangrenosum experience painful ulcers and other debilitating symptoms that may decrease their quality of life. Like many immune system disorders, the exact cause of the condition, as well as effective, targeted treatment, has not been found. Clinical cases have shown an association between PG and autoimmune disorders, specifically Rheumatoid Arthritis and Lupus. Finding the link between PG and other immune disorders that rely on the same mechanisms has the potential to reveal important information that may improve living with PG, as well as early diagnosis.