Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a necrotizing vasculitis that affects small and medium cell vessels. The peak incidence of individuals diagnosed with GPA is 65 to 70 years of age, with Black individuals the least likely to be affected.1 Nonspecific signs and symptoms include fever, malaise, and weight loss (see Common clinical manifestations of GPA).1 A recent systematic review and meta-analysis reported 70% of patients with childhood-onset GPA were female, and ear, nose, and throat involvement were more common in childhood-onset GPA.2
A case review
JR, a 19-year-old Black male, presented to an outpatient primary care clinic on postoperative day 3 following split-thickness graft surgery. He presented with a nonhealing ulcer over his left shin, a fever of 103° F (39.4° C), and myalgia. JR recalled a minor cough over the past 2 weeks, but he otherwise reported being healthy and denied any recent travel, injury, or change in appetite.
A review of the patient's medical records revealed that he previously had two skin grafts performed at two different hospitals, and both grafts had failed. Following these episodes, his mother sought care for him at a different institution where the adolescent received a third skin graft. The postoperative course was unremarkable, and he went home on day 2.
Medical and family history
JR had a surgical history of skin grafts for nonhealing wounds on his lower extremities over the course of 1 year. His mother stated that he had a dry cough, but it did not disrupt daily activities. The patient reported a history of sinusitis, nasal crusting, aphthous ulcer, and resolved asymptomatic hematuria over the past 3 years. The patient had no history of diabetes mellitus or allergies and was not taking any prescription medications. He denied any recent travel, significant weight loss, or exposure to sick contacts. The patient was up-to-date on all immunizations. There was no family history of autoimmune disease, sickle cell disease, or diabetes mellitus.
Physical exam findings and diagnostic testing
When JR returned to the office, he was ill with a fever of 103° F (39.4° C), and other vital signs were as follows: heart rate 115 beats/minute, respiratory rate 25 breaths/minute, and BP 110/73 mm Hg. His weight was 205 lb (93 kg) and his oxygen saturation was 95% on room air. On clinical exam, there was no regional lymph node enlargement or splenomegaly. Upon examining the lower extremity, there was a 3 cm necrotic ulcerative lesion over the left tibia with erythematous edges.
The patient's testes were equal in size with no varicocele. Reflexes were 2+ and symmetric bilaterally. Lab values included a complete blood cell (CBC) count with differential, revealing leukocytosis and thrombocytosis with evidence of normochromic normocytic anemia. JR's erythrocyte sedimentation rate was 120 mm/h (normal = 0 to 15 mm/h), and he had a mildly elevated rheumatoid factor of 16 IU/mL.
JR had a negative tuberculosis skin test and a negative antinuclear antibody test. His liver function tests were all within normal limits. A positive antineutrophil cytoplasmic antibody (ANCA) test result led to a diagnosis of possible vasculitis. Histopathologic exam done from the tissue from the edge of the unhealed wound showed giant cells and small vessels consistent with necrotizing granulomatous vasculitis. A biopsy confirmed the diagnosis of GPA and was consistent with the history of multiple hospitalizations for unhealed wounds.
Because GPA usually involves the respiratory tract and the kidney, further workup was done. The patient's blood urea nitrogen, creatinine, blood glucose level, glomerular filtration rate, and urinary albumin excretion measurement were all within normal limits; however, the urinalysis showed red cell casts and protein. The patient's chest X-ray revealed a small number of nodular opacities in the lung. The lung tissue was biopsied, revealing early signs of GPA in the chest cavity secondary to cutaneous lesions.
GPA causes an inflammatory cascade that acts as a positive feedback loop, causing necrotizing vasculitis. Initially, cytokines instruct neutrophils to exert maximal phagocytic ability in a process known as “priming.” A primed neutrophil will expose a proteinase 3 (PR3) or myeloperoxidase (MPO) antigen on the membrane surface. As a result of the PR3 or MPO exposure, B cells produce ANCA. The production of these specific autoantibodies and antigens is the result of predisposing factors such as environmental agents, genetic factors, and therapeutic drugs.3
The binding of PR3 and ANCA in circulation is associated with GPA in 60% to 80% of cases, whereas MPO-ANCA are found in 26% of GPA cases.4 The antigen-antibody binding increases the release of cytokines and chemokines as well as the upregulation of adhesion molecules.3 Endothelial cells from a given origin present their specific proinflammatory cytokine profile, helping to identify susceptible tissue and aiding the recruitment of specific immune cells.5 As a result, there is an increase in endothelial cell permeability, allowing primed neutrophils to transmigrate into the vessel wall, producing reactive oxygen species (ROS).5 ROS causes hardening of the endothelium and tissue damage through the induction of necrosis.
Diagnosis and classification
GPA should be considered when a patient has recurrent sinus and ear complaints with constitutional symptoms.6 Criteria for pediatric vasculitis was created in 2006 and revised in 2008 by the Paediatric Rheumatology International Trials Organization (PRINTO) and Paediatric Rheumatology European Society (PReS). The revision was endorsed and supported by European League Against Rheumatism (EULAR).7,8 Classification of GPA should meet at least three of the following six manifestations: hematuria or proteinuria, granulomatous inflammation on biopsy, nasal sinus inflammation, subglottic or tracheal stenosis, abnormal chest X-ray or computed tomography (CT), and cytoplasmic ANCA (c-ANCA) staining.8
Before the EULAR/PRINTO/PReS publication, adult guidelines by the American College of Rheumatology were used.7,8 Studies often use the Chapel Hill Consensus Conference (CHCC) 2012 set of definitions to categorize different types of vasculitis. The CHCC definitions are not classification criteria, and as such, they are not considered a diagnostic tool.9
There is currently no diagnostic test for vasculitis. The Diagnostic and Classification Criteria in Vasculitis investigators are presently conducting a study to create such a tool to address this clinical gap. Nonspecific diagnostic tests used to support the diagnosis of GPA include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), CBC, and ANCA tests.
ANCA testing plays a vital role in detecting small-vessel vasculitis due to the vast majority of patients with severe GPA found to have a complete overlap of systemic manifestations and the presence of ANCA.10 However, researchers found that pediatric patients have a lower prevalence of ANCA- positive tests compared with adult populations.11 It is important to note that across the lifespan, a negative ANCA test does not exclude a diagnosis of GPA (see Common lab tests for GPA).
The case review revisited
Pediatrics is challenging because there are so many diseases that are more common in a particular age group. During late adolescence, it is essential to consider adult diseases when the disease process does not follow a specific pattern or does not improve. This case review is a classic example of the importance of widening the diagnostic possibilities when a patient presents with a disease process with an unusual course. The diagnosis of vasculitis, either primary or secondary to a disease process, was the most likely diagnosis when JR presented to the primary care office, as it is uncommon to see nonhealing ulcers in pediatric patients. Following the detection of ANCA and a biopsy of the nonhealing wound, JR was diagnosed with vasculitis, which resulted in hospital admission and a consult with a rheumatologist. GPA was the confirmed diagnosis.
Pediatric leg ulcers are uncommon and require a thoughtful, systematic approach because the etiologies can be vastly different. The evaluation requires a thorough history and physical exam, including a consideration of inheritable disorders. Differential diagnoses for nonhealing leg wounds in pediatric patients can fall under the categories of neurological, autoimmune/rheumatological, oncological, infectious, and hematological disease (see Common differential diagnosis for nonhealing leg ulcer).
Each patient needs an individualized treatment plan according to the involved body system. It is essential to pick therapeutic agents that target the affected system. The initial treatment begins by putting the disease into remission with induction therapy, which usually lasts 3 to 6 months, followed by 12 to 24 months of maintenance therapy to avoid relapse.9 The treatment for GPA involves the use of drugs that are not approved by the FDA for the treatment of pediatric patients with GPA. The usual medications used in the induction phase include glucocorticosteroids and either cyclophosphamide, an alkylating drug, or rituximab, a human monoclonal antibody.6
If the disease is untreated, there is a mortality of 90%.6 Maintenance therapy is necessary to prevent early GPA relapse and progressive organ failure. Azathioprine, an immunosuppressive antimetabolite; methotrexate, an antimetabolite; leflunomide, a pyrimidine synthesis inhibitor; and rituximab are all successfully used as maintenance therapy for GPA.12 Two add-on therapies include co-trimoxazole, taken as prophylaxis three times a week, and plasma exchange to remove ANCA from the peripheral circulation.1 Infection is the most commonly reported adverse reaction, followed by damage to various organ systems due to chronic glucocorticosteroid and cyclophosphamide use.2 The leading cause of death in children with GPA is respiratory-related complications.2
Role of the NP
Although treatment guidelines for adults with GPA are available, pediatric-specific antibody-associated vasculitis treatment guidelines are lacking. EULAR/PRINTO/PReS recommendations and resources such as hospital-specific protocols, pediatric textbooks, and advice from colleagues supplement the provider's expertise.13 The NP should educate patients regarding the medication regimen and potential adverse reactions.
Because medication adherence is a significant challenge among chronically ill adolescents, the NP should explore potential barriers to adherence as a means of increasing the likelihood that the adolescent patient will comply with the treatment regimen.14 One recommendation to improve adherence is to encourage the patient use a phone app such as MyMedSchedule Plus or websites such as www.carespeak.com/corp and https://medactionplan.com.
The NP should facilitate a smooth transition of management from a pediatric provider to an adult provider. It is also essential for NPs to consider that patients may experience psychosocial impact of having a chronic illness, especially GPA, given the differences in body images as compared with their healthy peers.15 Adolescents with chronic diseases are more likely to be at risk for comorbid symptoms of depression and anxiety and are also more likely to have lower self-esteem.16 The risk of mental health issues increases in correlation with disease severity.17
Additionally, pediatric chronic illnesses impact family functioning.18 Taken together, this suggests that the NP may want to screen for psychosocial problems. The pediatric NP develops a treatment plan with the patient and his or her family using a family-centered approach, shared decision-making, and if appropriate, makes referrals for mental health issues.
GPA is a small-vessel vasculitis that is most prevalent in middle-aged White individuals. It can present with constitutional symptoms such as fever, myalgia, and weight loss. Clinical features include eyes, ear, nose, and throat involvement, as well as pulmonary, kidney, and cutaneous manifestations.
The presence of leg ulcers should prompt immediate investigations into an underlying cause of the unhealed wound. It is imperative to recognize and to diagnose GPA as early as possible to prevent extensive perpetual damage and reduce mortality. Diagnosis includes nonspecific diagnostic labs as well as a chest X-ray, biopsy, and ANCA testing to determine GPA specifically. Management includes referral to rheumatology, ENT, pulmonology, and patient psychosocial screening and support, if warranted. The pediatric NP can also help manage follow-up appointments with the multiple specialties and educate regarding medication and disease manifestations.
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