Defining disease activity and damage in patients with small-vessel vasculitis

Small-vessel vasculitides are complex diseases with highly variable clinical features and are associated with considerable morbidity and mortality. These systemic, multisystem, multiorgan diseases often threaten vital organs with manifestations that include upper airway disease, pulmonary disease, glomerulonephritis, neuropathy, arthritis/arthralgias, malaise/fatigue, eye disease, skin/mucosa irregularities, vascular disease, cardiac disease, and gastrointestinal disease.

Accurate assessment of the patient with vasculitis is a challenge for the clinician and is critical for managing therapeutic interventions throughout the course of the disease. Effective management includes repeated evaluations of the activity and severity of the disease as well as the damage it has caused. These distinct yet overlapping concepts must be measured separately but evaluated as a whole. Additional categorizations of disease course, such as whether it is active (new-onset, persistent, or flare) or in remission, further define the disease and are routinely employed in guiding treatment choices.

The importance of accurately assessing a patient’s clinical status is clear, but it is also important to standardize and quantify vasculitis assessment tools for use in clinical trials. Standardized assessments are needed to:

• Guide clinical trial enrollment criteria
• Describe and compare study populations
• Quantify and measure treatment effectiveness
• Describe long-term outcomes
• Translate standardized assessment tools into clinical practice.

Over the past few decades, improvements in clinical research have resulted in increasingly accurate data obtained from well-designed randomized controlled trials, all of which are based on better clinical assessments. Improving the quality of the assessment tools has improved both the interpretation of trial results and translation of findings into clinical practice.

DISEASE ASSESSMENT

When assessing patients with vasculitis, whether clinically or in the context of a clinical trial, it is essential to differentiate among disease activity, damage, and severity:

Disease activity, such as active bleeding or mucosal inflammation, is treatable and potentially responsive to therapy.

Disease damage is generally irreversible and not improved by treating vasculitis. Damage may be caused by the disease itself, its treatment, or a comorbid condition. In general, once damage is identified, it is considered permanent if it remains unchanged for more than 6 months. In the Wegener’s Granulomatosis Etanercept Trial,¹ damage that occurred in more than 10% of the cohort included hearing loss; proteinuria (≥ 0.5 g/24 hours); nasal blockage, chronic discharge, or crusting; nasal bridge collapse or septal perforation; glomerular filtration rate at least 50% lower than premorbid baseline; subglottic stenosis; and chronic sinusitis or radiologic damage. Disease-related damage can be addressed; a saddle-nose deformity can respond to plastic surgery, for example, but treating vasculitis will have no effect on the underlying established anatomic defect.

Disease severity assesses the intensity of the disease and guides the clinician in gauging how aggressive the therapy should be.

Vasculitis has two primary disease states: remission and active disease. In remission, there is no evidence of active disease. This is often qualified by describing the remission as either complete or partial; it is further defined by introducing an element of time, such as a “sustained” remission of more than 6 months. Active disease is the presence of any ongoing expression of vasculitis that is not caused by disease damage, comorbidity, or treatment. Active disease can be graded as low, medium, or high; if active disease lasts longer than 6 months, it is described as persistent or sustained. Flare, a manifestation of active disease, describes the transition from remission to active disease and is characterized by worsening of disease activity. Flares are graded as nonsevere or severe.

These descriptions of disease status can be further broken down into whether they are occurring “on” or “off” treatment. All of these elements are important and the subtleties and differences are critical in interpreting data for use in the clinical setting or in clinical trials.

CLINICAL ASSESSMENT

Assessing the status of disease for a patient with granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis [WG]) or microscopic polyangiitis (MPA) begins with a detailed medical history and physical examination every time the patient is seen. Appropriate laboratory assessments include a complete blood count, tests of renal function, acute phase reactants (possibly as disease markers, but not necessarily to guide therapy), and other laboratory tests as needed. Controversy exists regarding the role of antineutrophil cytoplasmic antibody (ANCA) testing in assessment of disease activity.

Urinalyses are key for assessing activity; if a urine dipstick result is positive, a subsequent microscopic examination should be conducted. Microscopic review may demonstrate red cell casts that a routine laboratory check may not reveal. In addition to spotting de novo hematuria, looking for a change in dipstick results may prove valuable, since hematuria may increase in patients in whom persistent hematuria has already been noted. The change may be due to renal disease from the vasculitis, cyclophosphamide-induced bladder toxicity, a kidney stone, menses, or a variety of other causes, but if the hematuria is not monitored, a key assessment will be missed.

Disease staging through diagnostic imaging of the sinuses, neck, and chest should be performed on a regular basis as appropriate, beginning at the patient’s initial visit. Restaging, in much the same way as an oncologist restages cancer, should take place regularly, because this informs whether to make a major change in therapy (eg, from cyclophosphamide, azathioprine, or rituximab). Restaging will also allow benchmarking of old, new, and changed damage so that when the disease recurs, the existing damage can be differentiated from new lesions. Once the disease has stabilized, imaging can be discontinued.

Consultations with otolaryngologists, ophthalmologists, cardiologists, and other specialists should be sought as needed. Serial audiograms, laryngoscopy, echocardiograms, and other appropriate tests should be performed as required. Biopsies are useful for assessment of patients, particularly at diagnosis, but also when it becomes necessary to reassess the progress of a patient’s disease or to identify a potential infection versus a possible malignancy. Biopsy is particularly helpful for kidney disease. If of active disease, then repeat biopsy is appropriate to determine whether the deterioration is associated with persistent active disease, the natural history of declining kidney function, or another cause. Patients with vasculitis may develop new comorbidities, particularly infections, so vigilance is always required. Importantly, documentation and awareness of disease-related damage are crucial in order to avoid overtreatment; damage should not be treated if therapy will not improve it.