Anti-neutrophil cytoplasmic antibodies-associated vasculitis: a guide and case study

Vasculitis

The term vasculitis refers to a relatively rare and poorly understood set of conditions, causing inflammation of the blood vessels, and AAV is a sub-group within this collection (Ball et al, 2014). According to guidance from the National Institute for Health and Care Excellence (NICE) (2014), the majority of AAV affects small- and medium-sized blood vessels, commonly in the respiratory system or, as in the case of the patient described in this article, the renal system.

Prevalence

The large number of AAV classifications limits epidemiological studies; however, a recurrent theme in the literature is that cases are becoming more common (Pearce et al, 2016). Pearce et al (2016) conducted a 5-year retrospective study from 2007 to 2013 in the Derby and Nottingham area, ascertaining an AAV incidence of 23.1 per million, and found a similar incidence reported in other epidemiological studies. They revealed no statistically significant difference between the ethnic groups in the 107 cases they examined. However, an epidemiological study in Norwich reported an incidence of 18.1 per million with evidence controversially suggesting occurrence varies in frequency in diverse ethnic groups (Ball et al, 2014). A study conducted by Lane et al (2005) found that vasculitides—a heterogeneous group of autoimmune diseases, all characterised by inflammation of blood vessels (vasculitis)—are more common in the white population. These studies provide contradictory and unclear evidence to support ethnic heritage or socio-economic trends.

On reviewing epidemiological evidence of GPA, a study in the late 1980s revealed an incidence of 2.8 per million (Andrews et al, 1990), while in 2010 a further 12-year study disclosed an increase of 11.3 per million (Watts et al, 2012), with more recent UK studies indicating an incidence upwards of 22.6 per million (Naz et al, 2019), all supporting a significant chronological increase in this sub-type. These rises in prevalence could be accredited to earlier diagnosis coupled with improved treatments and outcomes for these patients (Hilhorst et al, 2013; Ball et al, 2014). Improved recording systems and population increase have also been recognised as contributing factors (Berti et al, 2017).

Cost to society

The cost of vasculitis to society is unclear because of its rarity, and its many classifications make establishing accurate figures difficult (Watts et al, 2014). Evidence suggests that the financial burden to health care is underestimated and, as the chronic, relapsing condition progresses, so does the likelihood of developing an acute kidney injury (AKI) and renal failure (Watts et al, 2014; Spearpoint et al, 2019). It is of concern that renal failure often occurs before the kidney involvement is detected, leading to high mortality rates (Berden et al, 2012).

Mortality

Untreated AAV is fatal, and as risk escalates with age, coupled with a decline in renal function that often occurs in older people, these are the principal predictors of poor outcome (NICE, 2013). As many of the vasculitides are potentially lethal, they require prompt, high doses of immunosuppressive drugs, and, if left untreated, the prognosis declines substantially, with a 5-year survival rate of 10% (Watts et al, 2000). Untreated GPA has 90% mortality within 2 years of diagnosis (Biscettie et al, 2016).

Causes of vasculitis

The cause of vasculitis in many cases is unknown (Ball et al, 2014). It may be the primary disease, or develop as a consequence of drugs, malignancy or other diseases such as systemic lupus erythematosus (SLE) (John Hopkins Vasculitis Centre, 2019). Although none of these were demonstrated in the patient in this case study, a family history of Bright's disease, a condition today known as glomerulonephritis, proved relevant to the patient's case (Cameron, 1972). With many shared features, including necrotising vasculitis, Bright's disease will infrequently be hereditary (Cameron, 1972). Recording a thorough family history (Table 1) contributed significantly to this diagnosis, providing an additional tier of evidence to support the diagnosis.

Vasculitis criteria classification

In the 1990s there were significant developments in vasculitis criteria classification, with the American College of Rheumatology (ACR) (Hunder et al, 1990) and the international Chapel Hill Consensus Conference (CHCC) (Jennette et al, 1994), defining the most common forms of vasculitis. The CHCC grouping was widely adopted although, like the ACR classification, it had limitations. Therefore, in 2012, the CHCC formed another conference to re-examine the definitions, and include the AAV group that has since been recognised (Jennette et al, 2013; Seeliger et al, 2017). Despite these improvements, it is well documented that the current systems for identifying vasculitis types remain questionable, for both grouping and diagnostic purposes, with a multitude of investigations continuing to delay diagnosis in many cases (Havill et al, 2011; Mahr and de Menthon, 2015). Recognising these developments in diagnostic medicine, Luqmani et al (2011) set out to redefine and further develop these classifications, in a 6-year clinical trial involving 3500 patients, with diagnoses of primary vasculitis, or mimickers of the condition (University of Oxford, 2016). The results of this trial, due to be released, have great potential for earlier diagnosis.

GPA has features descr ibed as focal segmental glomerulonephritis (FSGS) and necrotising systemic vasculitis (Ball and Bridges, 2008). FSGS describes patches of scarring in the glomerulus, progressing to eventually cause renal failure (National Kidney Foundation, 2019) and necrotising vasculitis refers to the process of inflammatory changes, causing necrosis to the walls of the blood vessels (Ball and Bridges, 2008). Affecting arteries rather than veins, damage caused by AAV leads to tissue ischaemia and aneurysms (John Hopkins Vasculitis Centre, 2019). Smaller damaged vessels are more superficial to the skin, rendering these changes more visible. The damaged vessel appears as a palpable purpura, comparable to the findings in this case study (Table 1). Findings from the patient's initial assessment are set out in Table 2.

Complement system

Raised serum proteins, known as complement, are common in vasculitis (Rang et al, 2015). Detected in blood tests and on kidney biopsy, complement activates inflammation, destroys cells (a process known as cell lysis), and participates in opsonisation, meaning to enhance phagocytosis (Rang et al, 2015). When several differentials of vasculitides are listed, a renal biopsy supports classification, activity and damage caused by scarring; however, GPA is described as pauci-immune, therefore shows little evidence of complement deposits on the glomerular lesion (Table 3) (Jennette, 2012). Consequently this case required a multifaceted approach, involving blood and tissue analysis, coupled with clinical presentation, and a somewhat empirical attitude to diagnosis, further supporting the value of seeking early, specialised input for these patients (John Hopkins Vasculitis Centre, 2019).

Some vasculitides are well recognised; however, many of the AAV are not, and require a multitude of investigations. Vasculitis should therefore be considered in patients presenting with multisystem disease, with laboratory testing directed at the activity of the disease and affected organs (Watts et al, 2000). Specialised care of the condition should be sought early in suspected vasculitis, in an attempt to avoid subjecting patients to multiple investigations providing vague results (Suresh, 2006). The case offered several differentials requiring further investigation; however, following a number of tests, the detection of cytoplasmic-ANCA (C-ANCA) was a strong indicator of AAV, ruling out the remaining differentials. C-ANCA is a hostile auto-antibody produced to act against one of the body's own proteins (Wiik, 2000) and its presence is a characteristic result of small vessel vasculitides (Hamour et al, 2010). This auto-antibody is the main cause of GPA and, as it remains present in the system, relapses in GPA are common, with each episode accompanied by a considerable risk of morbidity (Specks, 2015).

Glomerulonephritis and necrotising glomerulonephritis

The process of glomerulonephritis and necrotising glomerulonephritis, commonly found in AAV, causes inflammation and damage to blood vessels in the kidneys. This disrupts the glomerular filtration barrier, and allows red cells and protein to pass through, resulting in haematuria, proteinuria and renal insufficiency in varying degrees (Hebert et al, 2013). Urinalysis is an economical, uncomplicated test forming part of the AKI bundle at a local level (University Hospitals of Derby and Burton, 2019). These features of glomerulonephritis are commonly identified by nurses, who predominantly perform the investigation, giving weight to the value of education at this level. Both proteinuria and haematuria were identified in the patient in this case study (Table 3), a combination demonstrating a significant marker of an inflammatory kidney process (John Hopkins Vasculitis Centre, 2019).

Rhee et al (2018) and De Joode et al (2016) found that the persistent presence of haematuria in AAV patients experiencing remission was a powerful indicator of relapse. Lv et al (2017) disagreed, indicating that haematuria bore no relationship to relapse but signified chronic renal damage or low-grade active renal disease in AAV. By utilising specific monitoring tools available for these patients, discussed later in the case study, clinicians are able to modify treatments, without relying on the contradictory evidence available.

Clinical symptoms

According to Watts et al (2000), history and clinical features play an important role in diagnosis, with a high significance placed on malaise, pyrexia, myalgia, arthralgia and complete, but not necessarily permanent, loss of hearing, all featured in this case (Table 1). Vasculitis is often mimicked by several conditions, the most common of these is infection, and less commonly, thrombotic thrombocytopenic purpura (TTP) and sickle cell disease (SCD) (Suresh, 2006). These mimickers require very different management, and as the treatment for vasculitis often carries significant risk, clinicians are inclined to postpone these therapies while establishing a firm diagnosis, often with a renal biopsy (John Hopkins Vasculitis Centre, 2019).

Although vasculitis frequently demonstrates the classic triad of vascular epithelioid granuloma, geographical necrosis and vasculitis in the vessel walls (Ball et al, 2014), the patient in this case experienced renal and auditory involvement alongside skin manifestations (Table 1). According to Suresh (2006), these features also commonly present as there are many other features of AAV, ranging from isolated cutaneous to multisystem involvement. The pathophysiology processes of this disease are unclear, but there is believed to be an element of molecular mimicry initiating the autoimmune responses mounted by the body, involving an attack on the blood vessels as opposed to the offending antigen (Guillevin and Dörner, 2007; Xiao et al, 2016). Vital roles for nurses caring for vasculitis patients lie in managing inflammation and pain, as these often distressing symptoms are prevalent in the disease (Pullen, 2007).

Inflammatory response

In the circulation, neutrophils are primed to migrate to tissue, assisting the inflammatory response. In AAV, antibodies bind to these neutrophils and trigger a premature activation, causing the neutrophils to release reactive oxygen species and further pro-inflammatory cytokines and chemokines, attracting more neutrophils (Szekanecz and Koch, 2001). Antibody immune complexes initiate a reaction from the circulating complement proteins awaiting activation, resulting in further promotion of the inflammatory response, and so the cycle continues, mounting response after response, the hyperactivity leading to tissue damage (Mortaz et al, 2018). Additionally, damaged vessels in AAV release debris and cytokines, heightening the inflammatory response further (van Paassen et al, 2007).

Haemostasis process

The haemostasis process is activated in an attempt to repair vessels using platelets and coagulation; however, these vessels will never return to an original state (Martinez Valenzuela et al, 2019). Loss of elasticity and stenosis due to fibrin deposited during the healing process leads to lumen narrowing and areas of aneurysm (Martinez Valenzuela et al, 2019). This reduced blood flow, aneurysms and stenosis leads to organ dysfunction (Mortaz et al, 2018).

Renal involvement

Renal involvement has a significant impact on prognosis and is often one of the major manifestations of the disease, particularly the AAV, affecting up to 80% of patients (Watts et al, 2000). As demonstrated in this case, the restricted blood flow to the glomeruli causes a reduction in urine production, an increase in blood pressure as the damaged kidney loses the ability to regulate blood volume, and kidney death (Ball et al, 2014). A kidney biopsy remains the most specific investigation in AAV (Jayne, 2017). The biopsy in this case revealed damage caused by GPA, as necrotising extra-capillary pauci-immune glomerulonephritis (Table 3) (Mumal, 2019).

Venous thromboembolism risk

AAV increases the risk of venous thromboembolism (VTE), and although the cause of this is unknown, there is speculation that the inflammatory process during active disease is influential (Stassen et al, 2007), with a risk of 7% in active disease compared with 0.2% of the general population (Monach, 2013).

Ocular involvement

Although not currently applicable to the patient in this case study, considering ocular involvement is pertinent as it is extremely common in GPA, with data suggesting that around 50% of newly diagnosed GPA patients develop ocular symptoms before attending the initial follow-up appointment (Garrity, 2012). As the eyeball and surrounding compositions are abundantly vascular and supplied by vessels from the internal and external carotids, vasculitis can cause damage to these vessels, threatening eyesight (Ball et al, 2014).

Hearing loss

Hearing loss is becoming an increasingly common complaint with AAV and, as with the patient in this case study, it is often an early sign and may prompt the initial presentation. Approximately 90% of GPA patients experience otitis media with effusion, the number reducing by 50% in the other ANCA-associated vasculitides (Berden et al, 2012; Kobari and Nagasawa, 2017). The disease creates granulomatous formation and effusions in the middle ear, leading to irreversible auditory damage, causing complete deafness with delayed treatment (Yoshida and Lino, 2014). It is also another AAV red flag for clinicians to consider when these patients present.

Patient education

Patient education on this subject is essential as GPA significantly increases the risk of developing visual difficulties. The eye is the solitary site where vasculature can be visualised, therefore ophthalmology input is invaluable in preserving vision, supporting the clinical diagnosis and defining the specific sub-type (Garrity, 2012; Ball et al, 2014). The patient in this case review was advised to seek an ophthalmology assessment to evaluate ocular damage and provide a baseline. Mooney et al (2014) identified that treatment-related information ranked as a high priority for these patients. As nurses are well placed to deliver information, value lies in their role in reducing the negative impacts of treatment regimens and compliance that accompany poor insight. This evidence supports a collaborative approach to AAV and patient education, illustrating the benefits to patient outcomes. Moreover, a major component of nurses' work is the delivery of empathy, emotional care and support to patients and their families diagnosed with ocular-related GPA.

Birmingham Vasculitis Activity Score

The Birmingham Vasculitis Activity Score (BVAS) (https://studyres.com/doc/14864837/birmingham-vasculitis-activity-score--version-3-) is a tool used to assess activity and damage caused by vasculitis (Kermani et al, 2016). Establishing a baseline by assessing nine body systems, the clinician can monitor disease progression (Ball et al, 2014). Used internationally, the BVAS is acknowledged as a validated tool and essential in clinical trials (Steddon et al, 2014). Studies have shown the BVAS is a reliable indicator of disease activity (Ramírez-Assad et al, 2013). In this case the patient scored 18 points out of a maximum 64, indicating a good prognosis. Ball et al (2014) reported that the value of this tool lies only with GPA, rendering it ineffectual to the entirety of the vasculitides, whereas Mukhtyar and Luqmani (2008) found a BVAS greater than 10 was 90% sensitive and 87% specific for a diagnosis of vasculitis, representing it as a highly effective screening tool. For nurses with an awareness of different classifications, and who understand the full systemic involvement of vasculitis, the BVAS allows them to assist specialists in monitoring disease activity. Interestingly, Biscetti et al (2016) found a higher BVAS score was significantly linked with increased intensive care unit (ICU) mortality, regardless of the patient's Acute Physiology and Chronic Health Evaluation (APACHE II) score (https://www.mdcalc.com/apache-ii-score) (Sean and Kane, 2019), further substantiating the gravity of vasculitis.

Treatment therapies

With limited therapies available for AAV, treatment goals lie in reaching and maintaining remission, using high-dose glucocorticoids to inhibit the immune response, chosen for their rapid action and relative safety (Ball and Bridges, 2008). Alongside this, cytotoxic immunosuppressants such as cyclophosphamide, as prescribed in this case (Table 4), or rituximab are introduced for 2–3 months to induce remission, before tapering the steroids over 12 months, with subsequent management based on changes in ANCA titres to prevent relapses (Rang et al, 2015).

Originally developed to treat some cancers, both rituximab and cyclophosphamide have shown similar results in inducing remission in AAV, with comparable adverse events (Steddon et al, 2014). Rituximab has also shown more success in refractory AAV, and coupled with a safer profile, this drug could be considered the new standard treatment for the condition. Unfortunately, rituximab's considerably greater annual cost compared with cyclophosphamide (around £4500 and £300 respectively) may impede this (Hamour et al, 2010). However, this increased expenditure may be offset by better control of the disease, as the cost associated with renal failure is estimated at almost £24 000 per patient per year (Watts et al 2017).

The introduction of cytotoxic therapy for AAV was a huge development in its management, with significant improvements to the prognosis, changing from a typically terminal illness to a manageable chronic illness (Geetha et al, 2015). However, these drugs are not curative and carry substantial threats for patients, including increased risk of infection (Selamet et al, 2007) and cancer, linked to cumulative doses of cyclophosphamide, which is particularly concerning for GPA as the relapse rate is much higher than with the other vasculitides (Calatroni et al, 2015; Rang et al, 2015; Brown, 2017). In order to care for these patients safely and effectively, it is essential to provide nurses with in-depth knowledge on these medications and their side effects (Pullen, 2007). With limited medicines available for vasculitis, further studies are required to understand the pathogenesis of the disease to enable the development of more effective treatments.

Importance of clinical assessment and surveillance

Clinical assessment plays a huge part in observing these patients (Table 5). The clinician can monitor progression of disease using the BVAS, studying the patient for new features of vasculitis and recurrence of pre-existing ones (Steddon et al, 2014). Regular urinalysis, blood testing and educating patients to avoid people with active infections or illnesses due to their immunosuppression, are vital to maintain the optimum health of these patients (Ball et al, 2014). Assessing a patient's understanding of self-care, particularly regarding infection risks, puts health professionals, especially nurses caring for these patients, in a position to influence the incidence of infection secondary to immunosuppressive therapy (Pullen, 2007). Developing further specialist nurse roles in delivering this information can help to maximise resources and positively affect patients' prognoses. Mooney et al (2014) stated that informed patients have higher rates of compliance and experience improved outcomes, but found that most patients preferred face-to-face instruction by a consultant nephrologist, limiting the opportunities for this education.

The patient in this case study was discharged home after 4 weeks, on a tapering dose of steroids, with regular specialist nephrologist follow-up appointments to monitor the activity of the vasculitis.

Summary

It has been well established that the criteria used for classifying vasculitides are inadequate, negatively impacting the time to diagnosis (Ball et al, 2014), with clinicians often relying on previous experience and definitions of disease when forming diagnoses, influencing a huge variance in detection time (University of Oxford, 2016). Early identification significantly impacts the patient's prognosis, but due to the multitude of guises in which it presents, vasculitis relies on a team of specialists for rapid identification, as many patients endure numerous investigations, systemic assessments and hospitalisation before a diagnosis is confidently reached (John Hopkins Vasculitis Centre, 2019). Increased education is required for clinicians on the value of simple blood testing, eye examinations and urinalysis to guide further investigations and earlier diagnoses; coupled with increased patient education, this would greatly benefit patient outcomes (Mooney et al, 2014). However, more work is required to facilitate these improvements.

Numerous epidemiological studies have been undertaken over many decades; however, the task of gathering this information on the multitude of subtypes has been difficult, and has resulted in sparse levels of data on individual conditions (Scott and Watts, 2000). Since the development of the ACR criteria (Hunder et al, 1990), vasculitis has clearer standards, assisting clinicians with the diagnosis. However, a considerable amount of work is still necessary, as research suggests that incidence is rapidly increasing and the multiplicity and vagueness of symptoms still presents a real diagnostic problem (Miller et al, 2010). Watts et al (2000) noted that major advances in diagnostics and treatment have improved survival; however, mortality and morbidity from disease and treatment remain high.

Further work on the study of medications is necessary in developing more effective, lower risk therapies (Selamet et al, 2007). Evidence suggests low-risk treatments appear to be limited to rituximab, but its significant cost, coupled with the rarity of AAV, restricts the platform for using it to develop evidence-based practice. Larger studies and trials are necessary to establish further epidemiology data and manifestations of the differing classifications, and to provide better treatments for this disease.

Nurses play a vital role in nursing vasculitis patients and managing inflammation and pain, as these distressing symptoms, are prevalent. Because of the multiple complications that can occur with vasculitis, treatment-related information is a high priority for these patients. As patient advocate, nurses require an in-depth knowledge of the treatment regimens, side-effects, and complications of the disease process. Nurses are therefore best placed to deliver information and to try to reduce the negative impacts on treatment regimens by offering empathy, emotional care and support to patients and their families.

KEY POINTS

CPD reflective questions