Polyarteritis Nodosa: Symptoms, Types, Causes and Treatment

Polyarteritis nodosa (PAN) is a rare yet serious form of vasculitis—a condition marked by inflammation of blood vessels—that can affect a wide spectrum of organs and tissues. While its exact cause often remains a mystery, advances in research have improved our understanding of PAN’s diverse clinical presentations, underlying mechanisms, and modern treatment strategies. In this article, we’ll explore the essential aspects of PAN, including its symptoms, types, causes, and current approaches to treatment.

Symptoms of Polyarteritis Nodosa

Polyarteritis nodosa can present with an array of symptoms, ranging from subtle skin changes to severe multi-organ dysfunction. Recognizing these symptoms early is crucial for timely diagnosis and management. The manifestations depend on the type of PAN (systemic or cutaneous), the organs involved, and the severity of vessel inflammation.

Symptom	Organ/System	Typical Features	Source(s)
Subcutaneous Nodules	Skin	Tender, palpable bumps	1 2 3 8
Livedo Reticularis	Skin	Net-like purplish discoloration	1 2 3 8
Ulcers/Necrosis	Skin	Painful sores, mainly on legs	1 2 3 8
Myalgia/Arthralgia	Muscles/Joints	Muscle aches, joint pain	1 4 8
Neuropathy	Nervous System	Paresthesia, mononeuritis multiplex	2 5 7
Fever/Malaise	Systemic	General unwellness, fever	1 8
Organ Involvement	Kidneys, GI, Heart	Hypertension, GI pain, cardiac issues	4 6 7 12

Table 1: Key Symptoms

Skin Manifestations

Skin involvement is among the most recognizable symptoms of PAN, especially in cutaneous variants. Patients often develop:

• Tender subcutaneous nodules: These are firm, painful bumps under the skin, mostly on the legs or lower limbs 1 2 3 8.
• Livedo reticularis: This is a lace-like, reddish-purple pattern on the skin, reflecting impaired blood flow 1 2 3 8.
• Ulcers and necrosis: Painful skin ulcers, often slow-healing, may appear and can progress to tissue death if untreated 1 2 3 8.
• Atrophie blanche lesions and purpura: White, scar-like patches and small purple spots may also be seen 2.

Musculoskeletal and Neurological Symptoms

• Myalgia and arthralgia: Muscle aches and joint pain are frequent, sometimes severe enough to hinder mobility 1 4 8.
• Peripheral neuropathy: Nerve involvement can result in numbness, tingling (paresthesia), or weakness. Mononeuritis multiplex—a condition where multiple individual nerves are affected—is a classical neurological finding, especially in systemic disease 2 5 7.
• CNS symptoms: Less common but potentially serious, including headaches, stroke-like features, and seizures when brain vessels are involved 5 7.

Systemic and Organ-Specific Symptoms

• Fever and malaise: Non-specific but common, contributing to the general feeling of being unwell 1 8.
• Kidney, gastrointestinal, and cardiac involvement: In systemic PAN, the disease may cause high blood pressure (hypertension), abdominal pain, GI bleeding, heart attacks, and more 4 6 7 12.
• Ocular findings: Eye inflammation, retinal vasculitis, or even vision loss in rare cases 15.

Types of Polyarteritis Nodosa

PAN is not a single disease, but a spectrum with distinct clinical types. Understanding these types helps guide diagnosis and therapy decisions.

Type	Defining Feature	Systemic Involvement	Source(s)
Systemic (Classic) PAN	Multiorgan vasculitis	Yes	6 7 12 14
Cutaneous PAN (CPAN)	Vasculitis limited to skin	No (or minimal)	1 2 3 8
HBV-associated PAN	Linked to hepatitis B infection	Variable	6 7
Monogenic PAN (DADA2)	Genetic ADA2 deficiency	Variable	9 10 13

Table 2: Main Types of Polyarteritis Nodosa

Systemic (Classic) Polyarteritis Nodosa

• Overview: The most recognized form, systemic PAN involves necrotizing inflammation of medium-sized arteries throughout the body, potentially affecting kidneys, gastrointestinal tract, heart, peripheral nerves, and more 6 7 12 14.
• Clinical features: Multisystem symptoms, including severe hypertension, abdominal pain, neuropathy, and organ dysfunction.

Cutaneous Polyarteritis Nodosa (CPAN)

• Overview: Primarily affects the skin and subcutaneous tissues, with minimal or no internal organ involvement 1 2 3 8.
• Symptoms: Painful nodules, ulcers, and livedo reticularis, generally confined to the lower limbs 2 8.
• Prognosis: Often has a benign, chronic, and relapsing course; rarely progresses to systemic disease 2 8.

HBV-associated Polyarteritis Nodosa

• Overview: A subtype triggered by hepatitis B virus infection 6 7.
• Features: May resemble classic PAN but often requires a tailored approach to treatment, focused on antiviral therapy 6.

Monogenic/Hereditary PAN (DADA2)

• Overview: Caused by biallelic mutations in the ADA2 gene (Deficiency of Adenosine Deaminase 2, or DADA2) 10 13.
• Epidemiology: Often presents in childhood or in familial clusters 10.
• Clinical overlap: Can mimic both systemic and cutaneous PAN; recognition is important as tumor necrosis factor (TNF) inhibitors are particularly effective in DADA2-associated vasculitis 13.

Causes of Polyarteritis Nodosa

The underlying causes of PAN are diverse and, in many cases, remain only partially understood. Both environmental and genetic factors are implicated, with some well-established associations.

Cause/Factor	Role in PAN	Description/Notes	Source(s)
Idiopathic	Most common	No identifiable cause	6 7 9
HBV Infection	Major environmental trigger	Hepatitis B virus-related PAN	6 7
Genetic (DADA2)	Monogenic/familial cases	ADA2 gene mutations	10 13
Infectious Agents	Possible triggers	TB, bacterial hypersensitivity	2 12
Immune Mechanisms	Pathogenic process	Immune-mediated vessel damage	6 7
Renin-Angiotensin	Experimental models	Local angiotensin II role	11

Table 3: Main Causes and Risk Factors

Idiopathic PAN

• Definition: Most cases have no identifiable cause and are termed “idiopathic” 6 7 9.
• Pathogenesis: Thought to involve abnormal immune responses leading to vessel inflammation.

Infection-Associated PAN

• Hepatitis B Virus (HBV): Once a major cause, especially in regions with high HBV prevalence. The virus can trigger immune complex deposition in vessel walls, leading to vasculitis 6 7.
• Other infectious triggers: Evidence suggests prior exposure to Mycobacterium tuberculosis and bacterial antigens might play a role, particularly in cutaneous variants 2 12.

Genetic Factors

• Deficiency of ADA2 (DADA2): Recent genetic studies have identified ADA2 mutations as a cause of familial and childhood-onset PAN-like vasculitis 10 13.
• Clinical importance: DADA2 can closely resemble classic PAN, but requires different management (e.g., TNF inhibitors) 13.

Immune System Dysfunction

• Immune-mediated vessel damage: Most idiopathic cases appear to be driven by abnormal or uncontrolled immune responses targeting arterial walls, resulting in inflammation and necrosis 6 7.

Renin-Angiotensin System

• Animal models: Experiments in rats have shown that overactivation of the renin-angiotensin system can induce PAN-like vasculitis, suggesting a possible pathogenic role in humans, though direct evidence remains limited 11.

Treatment of Polyarteritis Nodosa

Treatment strategies for PAN depend on the disease type, severity, and presence of organ involvement. Advances in immunosuppression and antiviral therapy have significantly improved outcomes over the past decades.

Therapy Type	Indication	Main Agents/Approach	Source(s)
Corticosteroids	First-line, all types	Prednisone, methylprednisolone	6 7 14 15 16
Immunosuppressants	Severe/systemic cases	Cyclophosphamide, azathioprine	6 7 14 15
Antiviral Therapy	HBV-associated PAN	Antivirals + steroids	6
NSAIDs/Colchicine	Mild cutaneous PAN	NSAIDs, colchicine	1 8
Biologics	Refractory/monogenic	TNF inhibitors, tocilizumab	13 17
Adjunctive Therapies	Symptom control	IVIG, methotrexate, others	8 17

Table 4: Main Treatment Approaches

Corticosteroids

• Mainstay of therapy: High-dose corticosteroids are the first-line treatment for most forms of PAN, rapidly reducing inflammation and controlling acute symptoms 6 7 14 15.
• Pulse therapy: In severe or life-threatening cases, intravenous methylprednisolone “pulse” treatment may be used 16.

Immunosuppressive Agents

• Indications: Added for patients with critical organ involvement, severe disease, or those unresponsive to steroids alone 6 7 14.
• Examples: Cyclophosphamide (especially in induction), azathioprine, methotrexate, mycophenolate mofetil for maintenance 6 7 8 14.
• Survival benefit: Addition of immunosuppressants to steroids markedly improves long-term survival 14 15.

Antiviral Therapy

• For HBV-associated PAN: Antiviral agents (e.g., entecavir) are used in combination with short-course steroids to control both the infection and vasculitis 6.

Treatment of Cutaneous PAN

• Mild cases: NSAIDs, colchicine, and topical steroids are often sufficient 1 8.
• Moderate to severe or extracutaneous symptoms: May require oral steroids or additional immunosuppression 8.
• Favorable prognosis: Cutaneous PAN usually responds well and has a low risk of progression to systemic disease 1 2 8.

Biologic Agents

• DADA2-associated (monogenic) PAN: Tumor necrosis factor (TNF) inhibitors (such as etanercept) are highly effective for ADA2 deficiency 13.
• Refractory cases: Biologics targeting interleukin-6 (e.g., tocilizumab) or Janus kinase inhibitors (e.g., tofacitinib) have shown promise in difficult-to-treat PAN 17.

Adjunctive and Supportive Care

• IVIG, hydroxychloroquine, and others: Used in specific scenarios or when conventional therapy fails 8.
• Symptom management: Pain control, wound care for ulcers, and physical rehabilitation are important for quality of life 4 8.

Monitoring and Prognosis

• Prognosis: Improved dramatically with prompt diagnosis and aggressive treatment; untreated systemic PAN carries a poor prognosis 6 14 15.
• Relapses: Chronic or relapsing courses are possible, especially in cutaneous forms 1 2 8.
• Long-term follow-up: Regular monitoring is essential to detect relapses or complications from treatment.

Conclusion

Polyarteritis nodosa is a complex, heterogeneous vasculitic disorder with a wide range of clinical manifestations and outcomes. Increased awareness, advances in diagnosis, and tailored therapies have changed the landscape for affected patients.

Key takeaways:

• PAN presents with diverse symptoms, often involving skin, nerves, muscles, and internal organs, depending on the type and severity.
• The main types include classic systemic PAN, cutaneous PAN, HBV-associated PAN, and genetic forms like DADA2 deficiency.
• Causes are multifactorial, including idiopathic, infectious (notably HBV), genetic, and immune-mediated factors.
• Treatment is individualized: corticosteroids for most, immunosuppressants for severe cases, antivirals for HBV-PAN, and biologics for refractory or monogenic cases.
• Early recognition and intervention are crucial for improving survival and quality of life.

By understanding the complexities of PAN, clinicians and patients alike can better navigate the challenges of this rare but impactful disease.