Continuing Education Activity

Microscopic polyangiitis is a small vessel necrotizing vasculitis, a part of a large spectrum of disorders termed as anti-neutrophil-cytoplasmic-antibody (ANCA)-associated vasculitides (AAV). This umbrella term includes granulomatosis with polyangiitis, microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss disease), and renal limited vasculitis (RLV). This activity reviews the evaluation and management of microscopic polyangiitis and highlights the role of the interprofessional team in the recognition and management of this condition.

Objectives:

• Describe the recommended management of microscopic polyangiitis.
• Outline the typical presentation for a patient with microscopic polyangiitis.
• Review the pathophysiology of microscopic polyangiitis.
• Explain the interprofessional team strategies for improving care coordination and communication regarding managing patients with microscopic polyangiitis.

Introduction

Microscopic polyangiitis is a small vessel necrotizing vasculitis, a part of a large spectrum of disorders termed as anti-neutrophil-cytoplasmic-antibody (ANCA)-associated vasculitides (AAV). This umbrella term includes granulomatosis with polyangiitis, microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss disease), and renal limited vasculitis (RLV). This classification of vasculitides based on the type of vessels involved and the underlying etiology was first laid down by the International Chapel Hill Convention Conference on the Nomenclature of Vasculitides (CHCC 2012).[1]

The term microscopic polyarteritis was introduced in the literature by Davson in 1948 to describe the pattern of glomerulonephritis seen in patients of polyarteritis nodosa.[2] It was later described as a pattern of necrotizing vasculitis, without immune complex deposition, affecting small vessels such as the capillaries, venules, and arterioles. The disease commonly involves glomerulonephritis, pulmonary capillaritis, and other systemic capillary beds. It shows considerable overlap with granulomatosis with polyangiitis. The absence of granulomatous inflammation involving the upper respiratory tract and the presence of pulmonary capillaritis is said to differentiate MPA from GPA. MPA is also included in a group of disorders termed pulmonary-renal syndrome, which includes MPA, GPA, Goodpasture disease, and systemic lupus erythematosus (SLE).[3]

Etiology

The etiopathogenesis of MPA and other related vasculitides has largely been attributed to anti-neutrophil-cytoplasmic antibodies or ANCA. These are host-derived auto-antibodies against shielded neutrophilic antigens. These antibodies react against primary granules present in neutrophils and monocytes. The formation of these antibodies has been hypothesized to be a 2-step process.[4] The first step involves exposure of neutrophils to inflammatory cytokines leading to surface exposure of cryptogenic antigens like myeloperoxidase or MPO. Next, predisposing genetic, environmental, and other factors result in the production of MPO-ANCA. In the second step, these MPO-ANCA cause damage to the host vasculature by reacting and crosslinking neutrophils to the endothelial receptors.[5]

Only 70% of cases of MPA have ANCA at the time of diagnosis, and most of the cases of limited MPA do not have ANCA at all. This has lead to the understanding that other factors may also be playing a role in its etiopathogenesis. These include, but are not limited to:

• Infectious causes: There is considerable overlap in the clinical presentation of various infectious processes and MPAN leading to this implication. A possible role of chronic nasal carriage of Staphylococcus aureus has been suggested in relapsing GPA as well.[6]
• Drugs: Various drugs like hydralazine, thionamides, sulfasalazine, and minocycline, among others, have been observed to be associated with the incidence of ANCA-associated vasculitis.[7]
• Genetic factors: More recently, A genome-wide study conducted in Europe has implicated genes like HLA-DP, HLA-DR3, and alpha-1 antitrypsin in the pathogenesis of ANCA-associated vasculitides.[8]

Epidemiology

Due to the recent differentiation of MPA from other AAV, widespread data regarding its demographic factors in the American population is not available yet. One study conducted in Rochester, Minnesota, over a period of 20 years estimated the annual incidence of AAV to be 3.3 per 100,000 with a prevalence of 42.1 per 100,000. The incidence of GPA and MPA were approximately 1.5 per 100,000.[9] Studies from European countries have revealed a comparatively higher incidence and prevalence of AAV, with the highest incidence rates seen in Spain and the United Kingdom, 11.6 and 5.8 cases per million population, respectively.[10] The disease is more prevalent among males, with a peak incidence around the age of 40.

Pathophysiology

As explained above, the clinical manifestations of MPA stem from activation of primed neutrophils and MPO-ANCA with receptors present on the endothelial surface. These lead to a variety of manifestations affecting the renal, pulmonary, and other capillary beds. Individuals may present with an insidious onset of systemic signs like fever, malaise, or weight loss, but more commonly, the onset is acute in patients complaining of arthralgia and flu-like symptoms.[11]

Renal manifestations are most common, and up to 80% to 100% of individuals have some form of glomerulonephritis at onset or with disease progression.[11] The most common manifestation is a "pauci-immune" form of rapidly progressive glomerulonephritis (RPGN). Clinical presentation may vary from asymptomatic hematuria, sub-nephrotic proteinuria, a rise in serum creatinine, or overt renal failure.[12] Pulmonary manifestations may be in the form of alveolar hemorrhage, which is sometimes the first presenting symptom of the disease. Cutaneous manifestations include leukocytoclastic-vasculitis, palpable purpura, or nodular and ulcerative lesions that commonly involve the lower extremities. Occasionally ocular manifestations (conjunctivitis, episcleritis, optic neuropathy) and neurological manifestations (mononeuritis multiplex, cranial neuropathy, among others) may also be seen.

Histopathology

Histopathological evidence of vasculitis is the gold standard for confirmation of the diagnosis of MPA and other AAV. The most commonly sampled tissues are renal, skin, and lung tissue. Pulmonary findings in MPA is most commonly a form of diffuse capillaritis (distinguishing it from GPA that characteristically shows granulomatous lesions). Skin biopsy yields acute or chronic leukocytoclastic vasculitis with neutrophilic infiltrate in the narrow caliber vessels of the superficial dermis. Renal biopsy most commonly varies from mild focal or segmental to a diffuse necrotizing and sclerosing glomerulonephritis that shows minimal to no immune complex deposits on light and immunofluorescent microscopy ("pauci-immune"). The importance of renal biopsy lies in the fact that the severity of renal involvement on histopathological evaluation correlates clinically with disease activity.[13] It thus plays an important role in guiding patient management and tapering immunosuppressive therapy. Although this is the mainstay, it has been shown that many patients may have diffuse interstitial nephritis without involving the glomeruli, which may pose a difficulty in diagnosis. Moreover, a few may have immune complex deposits in the glomeruli and experience more severe systemic signs and symptoms.[14]

History and Physical

Patients may present with insidious onset fever, arthralgia, weight loss, urinary abnormalities, cough with or without hemoptysis, skin findings consistent with palpable purpura, or non-specific neurological complaints. Some patients may present with acute onset of fulminant disease with frank hemoptysis, hematuria, or even renal failure. Physical examination may show ulceronodular skin lesions of the extremities, fever, tachypnea, and even tachycardia. A pulmonary examination may be significant for rales or bronchial breath sounds in pulmonary capillaritis cases, and neurological examination may show motor or sensory deficits that are localized to a particular dermatome. Other physical findings will vary depending on the involved capillary bed.

Evaluation

Evaluation of a patient suspected of AAV involves a thorough clinical, radiological, histopathological, and lab evaluation:

• A detailed clinical evaluation to elicit the site and extent of involvement of the different organ systems is the first step in the evaluation.
• Radiological evaluation involves a chest X-ray and a CT-scan of the chest to look for pulmonary lesions in the case of patients presenting with hemoptysis. It also helps differentiate between GPA and MPA with the former cavitary and nodular lesions on radiological evaluation.
• Histopathological evaluation should be done when possible (skin, renal. and lung biopsy) to look for evidence of vasculitis and immune deposits. The extent of inflammation seen on renal biopsy may be used to measure disease activity and help guide treatment.
• Lab evaluation involves routine complete blood count (CBC), electrolytes, and measurement of serum titers of MPO and PR3 antibodies, which may be seen in most cases. However, low serum levels cannot be used to rule out AAV reliably.

Treatment / Management

Treatment of MPA involves extensive use of immunosuppressive agents in different combinations. The aim of treatment has been defined in 2 parts: induction and subsequently maintenance o disease remission. It is important to know that remission does not imply the complete absence of symptoms; rather, it is used to convey the absence of symptoms attributable to active vasculitis.[15] The commonly used immunosuppressive agents in MPA management include cyclophosphamide, rituximab, methotrexate, glucocorticoids, azathioprine, and a few other biological agents.

• Induction of remission for individuals with non-severe disease is generally achieved using a combination of glucocorticoids and methotrexate or rituximab alone. For individuals with severe disease, induction using cyclophosphamide with glucocorticoids may be needed. The Rituximab versus Cyclophosphamide for Induction of Remission in AAV trial (RAVE trial) established that comparable results could be achieved using rituximab, especially in individuals experiencing side effects of cyclophosphamide therapy.[16] Typically remission is achieved in most individuals over a period of 2 to 6 months.
• Maintenance therapy is started after induction of remission and typically involves the use of azathioprine compared to cyclophosphamide, as demonstrated by the Cyclophosphamide versus Azathioprine for Early Remission Phase of Vasculitis trial (CYCAZAREM trial).[17]

Differential Diagnosis

Many conditions may mimic AAV/MPG and have to be excluded before a diagnosis can be established. These include:

Infectious Etiologies

• Infective endocarditis
• Disseminated Gonococcosis
• Rocky Mountain Spotted Fever (RMSF) and other tick-born vasculitides
• Disseminated fungal infections

Malignancies

• Atrial myxomas
• Lymphomas
• Carcinomatosis

Drug Toxicities

• Cocaine
• Amphetamines
• Ergot alkaloids
• Levamisole

Other Autoimmune Conditions

• Amyloidosis
• Goodpasture disease
• Sarcoidosis

Toxicity and Side Effect Management

The immunosuppressive agents used in the management of AAV have serious side effects, which may be more debilitating than the manifestations of the disease. These include:

Glucocorticoids

• Osteoporosis
• Cataract
• Glaucoma
• Diabetes mellitus
• Electrolyte abnormalities
• Avascular necrosis of bone

Cyclophosphamide

• Bone marrow suppression
• Hemorrhagic cystitis
• Bladder carcinoma
• myelodysplasia

Methotrexate

• Hepatotoxicity
• Pneumonitis
• Bone marrow suppression

Azathioprine

• Hepatotoxicity
• Bone marrow suppression

Rituximab

• Progressive multifocal leukoencephalopathy
• Opportunistic infections

Prognosis

When treated appropriately, about 90% of all MPA patients show improvement, and roughly 75% achieve full remission. The condition has a 5-year survival rate of 75%. MPA has a poorer survival rate than CHurgg-Strauss syndrome or granulomatosis with polyangiitis, likely resulting from renal impairment present at the onset of the disease.[18]

Complications

Left untreated, MPA can result in permanent damage to the organs. Kidney failure is the most common complication. MPA complications will depend on the particular organ system involved. Research has shown that older age, diastolic hypertension, and positive PR3-ANCA status correlate with cardiovascular events.[19]

The medications that treat MPA can also carry adverse complications. Cyclophosphamide has a relatively strong correlation with bladder cancer in those treated with the drug. Steroids are known to cause bone loss, hyperglycemia, muscle weakness, and skin problems.

Deterrence and Patient Education

Patients must be made to understand the seriousness of their condition and that they may not return to full pre-disease function and strength. Medication and therapy adherence is crucial, as are frequent follow-ups. 

Enhancing Healthcare Team Outcomes

Microscopic polyangiitis is a difficult condition to manage by the physician because of the heterogeneity in its clinical presentation and the patient-specific treatment that it demands. Good communication and interplay among the physicians, nurses, radiologists, pathologists, and pharmacists may help ease this hurdle. The nurses play an important role in monitoring and charting vitals, especially urine output, which has a crucial role in helping the physician decide the treatment. The radiologists play an important role in assisting image-guided tissue biopsy, which the pathologist then studies to confirm the presence of disease. Proper dosing and dispensing of the immunosuppressive agents by the pharmacists can help in the induction and maintenance of remission, whereas failure to do so can lead to severe systemic side-effects of these drugs. To ease the process of deciding the appropriate treatment, researchers at Johns Hopkins University have teamed up to provide the revised Birmingham score, which can be used to classify the disease state of the patient clinically.[20]