Granulomatosis With Polyangiitis: Symptoms, Types, Causes and Treatment

Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a rare and potentially life-threatening autoimmune disease. It is characterized by inflammation of small- and medium-sized blood vessels, leading to damage in multiple organs—most notably the respiratory tract and kidneys. Despite its rarity, GPA has seen significant advances in diagnosis and management in recent decades. In this article, we provide a comprehensive look at the symptoms, different types, underlying causes, and treatment options for GPA, synthesizing the latest evidence-based research.

Symptoms of Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis is notorious for its diverse and often subtle onset, which can make early diagnosis challenging. Symptoms may mimic more common illnesses, leading to delays in recognition. Understanding the characteristic clinical features is essential for timely intervention and better outcomes.

System	Manifestation	Frequency/Details	Source(s)
ENT	Sinusitis, nasal crusting	70–100% of cases	2 6 9
Lungs	Nodules, cough, hemoptysis	Frequent, sometimes severe	2 6 13
Kidneys	Glomerulonephritis	Common, rapid progression	2 6 13
Eyes	Scleritis, orbital mass	Up to 50% of patients	4 12
Skin	Purpura, ulcers	Variable	3
Genitourinary	Prostatitis, ulcers	<1% of cases	5

Table 1: Key Symptoms of Granulomatosis With Polyangiitis

Major Organ Systems Involved

• Ear, Nose, and Throat (ENT):

  • GPA often starts with persistent sinusitis, nasal crusting, or nosebleeds.
  • Otorhinolaryngologic (head and neck) symptoms are the first sign in the majority of patients 2 6 9.
  • Other features include hearing loss, otitis media, and even destruction of nasal cartilage, leading to a saddle-nose deformity.

• Pulmonary (Lungs):

  • Patients frequently develop cough, shortness of breath, or chest pain.
  • Lung nodules—which may cavitate—are common, as is alveolar hemorrhage in severe cases 6 13.
  • Hemoptysis (coughing up blood) is a red flag symptom.

• Renal (Kidneys):

  • Rapidly progressing glomerulonephritis is a hallmark and a major determinant of prognosis 2 6 13.
  • Symptoms may be silent until advanced, but can include blood in urine or swelling due to kidney dysfunction.

• Ocular (Eyes):

  • Almost half of GPA patients experience eye involvement 4 12.
  • Manifestations include scleritis, conjunctivitis, orbital masses, and vision loss in severe cases.

• Skin:

  • Non-specific findings such as purpura, ulcers, or nodules can occur 3.

• Genitourinary:

  • Very rare (<1%), but can include prostatitis, urethritis, or genital ulcers 5.
  • Some urologic symptoms may also be caused by treatment complications.

Disease Course and Relapses

• GPA can be indolent (slowly progressive) or rapidly worsen.
• Relapses are common, seen in up to 50% of patients within five years 1 6.
• Chronic symptoms and repeated flares contribute to cumulative organ damage and morbidity.

Summary

GPA's symptoms are wide-ranging and can affect nearly any organ system. However, the classic triad involves the upper respiratory tract, lungs, and kidneys. Early recognition, especially of ENT and pulmonary symptoms, is crucial for prompt diagnosis and management.

Types of Granulomatosis With Polyangiitis

The clinical spectrum of GPA is broad, and classification is essential for guiding treatment decisions. GPA is part of a family of vasculitic diseases, and several subtypes—some overlapping—have been described.

Type	Main Features	Prevalence/Population	Source(s)
Generalized	Multisystem, kidneys involved	Most common in adults	6 7 13
Limited	Only ENT/respiratory tract	Often younger patients	6 7
Childhood	Onset <18 years, severe relapses	Rare, high morbidity	1
EGPA	Asthma, eosinophilia, vasculitis	Distinct entity	8 10 14

Table 2: Types of Granulomatosis With Polyangiitis

Generalized GPA

• Involves multiple organ systems, especially the kidneys, lungs, and respiratory tract.
• Can be severe, with risk of organ failure and high mortality if untreated 6 13.
• Most adult patients present with generalized disease.

Limited GPA

• Disease is restricted to the upper and/or lower respiratory tract, without kidney involvement 6 7.
• Patients may have a milder course, but still require close monitoring for progression.
• More commonly seen in younger individuals.

Childhood-Onset GPA

• Rare, but more severe in presentation and with higher relapse rates 1.
• Children often experience significant morbidity and require intensive therapy.
• Diagnosis can be delayed due to the overlap with other pediatric illnesses.

Eosinophilic Granulomatosis With Polyangiitis (EGPA)

• Though related, EGPA is a distinct type characterized by asthma, blood and tissue eosinophilia, and small-vessel vasculitis 8 10 14.
• EGPA has unique features (e.g., prominent eosinophilia, cardiac involvement) and is managed differently.
• It is important to distinguish EGPA from classic GPA due to differences in treatment and prognosis.

Subtypes by Severity

• Classification by severity (mild, moderate, severe) is used clinically to tailor immunosuppressive regimens 7.
• Severe disease is defined by organ- or life-threatening manifestations (e.g., kidney failure, alveolar hemorrhage).

Summary

Understanding the types of GPA helps clinicians predict disease course, tailor therapy, and counsel patients regarding prognosis. Accurate classification is essential for optimal care.

Causes of Granulomatosis With Polyangiitis

The underlying cause of GPA remains incompletely understood. However, research has highlighted the key roles of autoimmunity, genetic predisposition, and environmental factors.

Factor	Description	Evidence/Notes	Source(s)
Autoimmune	ANCA antibodies against neutrophils	Central to pathogenesis	2 7 11
Genetics	Genetic susceptibility required	Certain populations more affected	2 7
Environmental	Infections, environmental triggers	Incite disease in predisposed people	2 7
Cellular Immunity	Th17, Treg cell imbalance	Disease activity biomarkers	11

Table 3: Causes and Risk Factors of Granulomatosis With Polyangiitis

Autoimmunity and ANCA

• GPA is an autoimmune disease strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), especially cytoplasmic ANCA (c-ANCA, usually targeting proteinase 3) 2 7 11.
• ANCAs are believed to activate neutrophils, leading to inflammation and destruction of blood vessel walls.

Genetic Predisposition

• GPA can affect all races, but is more common in Caucasians and certain geographic regions (higher prevalence in Northern Europe) 2 7.
• Family studies suggest a genetic susceptibility, but no single gene has been identified.

Environmental Triggers

• Environmental and infectious factors may trigger the disease in genetically predisposed individuals 2 7.
• Upper respiratory tract infections are sometimes linked to disease onset or flares.

Immune Cell Imbalance

• Recent studies suggest an imbalance between pro-inflammatory Th17 cells and regulatory T cells (Tregs) as a contributing factor 11.
• Th17 cells may drive inflammation, while Tregs help suppress it; their ratio can reflect disease activity.

Pathology

• The disease is characterized by three main histological features: necrotizing vasculitis, granulomatous inflammation, and often necrotizing glomerulonephritis 2 7.
• These findings are confirmed on tissue biopsy, which remains a cornerstone for diagnosis.

Summary

GPA is a complex disease involving autoimmunity, genetics, and environmental triggers. ANCA antibodies are central to its pathogenesis, but not all patients are ANCA-positive. The interplay between immune cells and environmental factors shapes disease onset and progression.

Treatment of Granulomatosis With Polyangiitis

Advances in the treatment of GPA have dramatically improved survival and quality of life. Therapy is tailored to disease severity and aims for swift remission with the lowest possible toxicity.

Phase	Main Drugs/Therapies	Purpose/Notes	Source(s)
Induction	Corticosteroids + CYC or RTX	Achieve remission	2 6 9 13
Maintenance	Azathioprine, methotrexate	Prevent relapse, reduce toxicity	2 6 9 13
Biologics	Rituximab, mepolizumab (EGPA)	For refractory or relapsing disease	13 14
Supportive	Multidisciplinary care	Surgery, infection prevention	2 6 9 4

Table 4: Treatment Strategies in Granulomatosis With Polyangiitis

Induction of Remission

• Corticosteroids: High-dose steroids are the backbone of initial therapy to control inflammation swiftly 2 6 9 13.
• Cyclophosphamide (CYC): Traditionally used with steroids for severe, generalized GPA, especially with kidney involvement. Effective but associated with significant toxicity 2 6 13.
• Rituximab (RTX): A monoclonal antibody targeting B cells, now considered at least as effective as CYC for induction, with a potentially better safety profile, especially in relapsing cases or those intolerant to CYC 13.
• Children: Similar induction regimens are used, but with careful monitoring due to higher relapse rates and cumulative toxicity 1.

Maintenance Therapy

• After achieving remission, immunosuppression is tapered to maintenance drugs:
  • Azathioprine or Methotrexate: Preferred for long-term maintenance due to lower toxicity compared to CYC 2 6 9 13.
  • Steroids: Usually continued at the lowest effective dose.

Biologic and Targeted Therapies

• Rituximab: Increasingly used for both induction and maintenance, especially in refractory or relapsing cases 13.
• Mepolizumab (EGPA subtype): Anti-IL-5 antibody approved for eosinophilic granulomatosis with polyangiitis, significantly reduces relapses 14.
• Other biologics are under investigation, especially for those unable to tolerate standard immunosuppression.

Supportive and Multidisciplinary Care

• Surgical intervention: Considered for patients who do not respond to pharmacotherapy or have local complications (e.g., subglottic stenosis, orbital mass) 9 4.
• Infection prevention: Due to immunosuppression, patients are at increased risk for infections; prophylactic measures are important.
• Specialist involvement: Otorhinolaryngologists, rheumatologists, nephrologists, pulmonologists, and ophthalmologists all play vital roles 2 9 4.

Monitoring and Prognosis

• Regular monitoring for disease activity and treatment side effects is critical.
• Relapses are common (up to 50% at 5 years); long-term maintenance therapy is often required 1 6.
• Survival has improved dramatically, but kidney involvement and infection remain key determinants of prognosis 2 6.

Summary

Modern treatment of GPA uses a combination of immunosuppressive drugs tailored to disease severity. The goal is to induce and maintain remission while minimizing adverse effects. Biologic agents are increasingly important for refractory or relapsing cases, and multidisciplinary care is essential.

Conclusion

Granulomatosis with Polyangiitis is a complex autoimmune disease with diverse clinical manifestations and a variable course. Early diagnosis and aggressive, tailored treatment have transformed outcomes for many patients. Ongoing advances in immunology and therapy continue to improve quality of life and survival.

Key Points:

• GPA most commonly affects the upper respiratory tract, lungs, and kidneys, but can involve almost any organ 2 6 13.
• Classification into limited, generalized, childhood-onset, and EGPA subtypes guides prognosis and management 1 6 8.
• The disease is autoimmune in origin, closely associated with ANCA antibodies, but also influenced by genetics and the environment 2 7 11.
• Treatment involves induction with corticosteroids and immunosuppressants (CYC or RTX), followed by maintenance therapy; biologics are used for refractory disease 2 6 9 13 14.
• Multidisciplinary care and vigilant monitoring are essential for optimal outcomes.

Understanding GPA's symptoms, types, causes, and treatment options is critical for both clinicians and patients, paving the way for improved lives and hopeful futures.