A male patient was diagnosed at 48 years of age with Wegener’s granulomatosis (WG) involving the sinuses, nose, and lungs. He was treated with daily cyclophosphamide and prednisolone for 1 year, after which the medication was tapered and discontinued. After being in remission for 48 months, he had a relapse involving the sinuses and the kidneys with a crescentic glomerulonephritis with a peak creatinine at 270 µg/L. He was once again treated with oral cyclophosphamide and prednisolone, and his creatinine normalized. After 5 months of treatment, he developed hematuria and elevated liver enzymes. Cystoscopy revealed cyclophosphamide-induced bladder injury. He was switched to azathioprine and did well for 2 years. He then had a relapse in the sinuses and lungs; azathioprine was discontinued, and he was treated with prednisolone and methotrexate (MTX). Subsequently, he has been on and off MTX for 6 years combined with low-dose prednisolone. He had some relapses in the sinuses, but reintroduction of MTX has always led to remission. He has residual sinus symptoms and a slighty elevated creatinine (150 µg/L) and his life has been complicated by diabetes mellitus and hypertension, but he is feeling generally well and is working full time.
Comments: This case illustrates the problems in treating patients with WG. The major problem is often not getting the patient into remission but to prevent relapse and organ damage without causing permanent adverse effects by the immunosuppressive treatment.
A woman born in 1967 with insulin-treated diabetes mellitus since 2000 was first admitted to a rheumatology unit in 1990 because of arthralgia and fatigue. She had a moderately elevated erythrocyte sedimentation rate (ESR), proteinuria 0.4 g/day, and antinuclear antibody (ANA) titer 1/100, and she was antineutrophil cytoplasmic antibody (ANCA) negative. On examination, she had no arthritis and no other pathologic findings. Her fatigue and arthralgia resolved spontaneously; she received no treatment and was followed by her family doctor. In 2006, she got increasingly tired, experienced a fever for 4 weeks, and was admitted. The laboratory studies included hemoglobulin, 94 g/L; ESR, 105 mm/h; creatinine, 158 µg/L. The examination also indicated that she had proteinuria and pulmonary infiltrate in the right underlobe. Her preliminary diagnosis was pneumonia, and she was treated with antibiotics.
However, her condition deteriorated with hemoptysis, increasing fever, and several additional pulmonary infiltrates. Repeat hemoglobulin was 75 g/L, ESR 110 mm/h, serum creatinine 400 µg/L. The preliminary differential diagnosis included pneumonia, malignancy, and tuberculosis. Both a rheumatologist and a nephrologist were consulted, and further investigations were recommended including acute testing for ANCA, and antibodies against glomerular basal membrane (anti-GBM), and an acute kidney biopsy. She was positive for myeloperoxidase (MPO)-ANCA, and anti-GBM negative. Kidney biopsy showed a crescentic glomerulonephritis ( Fig. 16-1 ). The diagnosis was microscopic polyangiitis (MPA).
She was treated with 10 pulses of cyclophosphamide 15 mg/kg IV plus prednisolone. She was in remission after 3 months of treatment, and after 6 months, the cyclophosphamide was discontinued and she was put on azathioprine as a remission maintenance therapy. After 2 years, she is doing well and still in remission. She has a stable serum creatinine at 150 µg/L and low-grade proteinuria, probably due to her diabetes.
Comments: This case illustrates the often difficult challenge of differentiating acute ANCA-associated vasculitis (AAV) from infection. In this case, the patient’s acute condition was first diagnosed as pneumonia. However, resistance to antibiotic therapy, hemoptysis, and rising creatinine pointed to the diagnosis of MPA. Her positive MPO-ANCA and negative anti-GBM helped distinguish her condition from Goodpasture’s syndrome.
INTRODUCTION
Vasculitis is defined as inflammation of the vessel walls. Vasculitis develops either primarily or secondarily to certain background conditions, such as malignancy, infections, and systemic rheumatic diseases. The primary systemic vasculitides cause inflammation of blood vessels resulting in occlusive, stenotic, or aneurismal change, leading to ischemic or hemorrhagic events. They are classified as small, medium, or large vessel vasculitis depending on the caliber of the vessels involved. This chapter addresses the management of the adult spectrum of medium and small vessel vasculitides, which includes WG, MPA, Churg-Strauss syndrome (CSS), essential cryoglobulinemic vasculitis, polyarteritis nodosa (PAN) and Henoch-Schönlein purpura ( Table 16-1 ).
| Condition | Signs and Symptoms |
|---|---|
| Medium-Sized Vessel Vasculitides | |
| Polyarteritis nodosa | Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries and venules. |
| Kawasaki disease |
|
| Small Vessel Vasculitides | |
| Wegener’s granulomatosis |
|
| Churg-Strauss syndrome |
|
| Microscopic polyangiitis |
|
| Henoch-Schönlein purpura |
|
| Cryoglobulin-associated vasculitis |
|
| Cutaneous leukocytoclastic angiitis | Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis. |
Among the small vessel vasculitides, WG, MPA, and CSS are distinct from classic PAN and have common characteristics: the affected vessels are arterioles, capillaries, and venules; the most common organs affected are the kidney and lungs; and they involve ANCAs as the common pathogenesis. Therefore, MPA, WG, and CSS are called ANCA-associated vasculitides. The frequency of ANCA positivity differs from one vasculitis to another: ANCAs are present in more than 80% of WG patients, around 75% of patients with MPA, and only 40% of those with CSS.
OVERALL ASPECTS ON THE MANAGEMENT OF MEDIUM AND SMALL VESSEL VASCULITIS, INCLUDING THE DISEASES ASSOCIATED WITH ANTINUCLEAR ANTIBODIES
A primary vasculitis may be life-threatening, and therefore, rapid and correct management is mandatory for the survival of the patient. Therefore, patients with primary small and medium vessel vasculitides should be managed at centers of expertise. The rarity of primary systemic vasculitis makes it hard to maintain expertise in their management. Expert guidance is needed to differentiate damage from disease activity and to consider differential diagnoses. Patients with vasculitis may require interventions by specialists with a deep knowledge of vasculitis, such as specialized radiography, renal transplantation, or therapeutic injection of a subglottic stenosis. Vasculitis may relapse years after remission, even in previously unaffected organ systems. Patients may also develop complications from the treatment many years after discontinuation.
ANCA testing should be performed by indirect immunofluorescence to detect the characteristic labeling: cytoplasmic or perinuclear. All serum samples positive for ANCA by immunofluorescence should be tested for reactivity to proteinase 3 (PR3) and MPO. A positive test for cytoplasmic ANCA targeted to PR3, or perinuclear ANCA against MPO has a high sensitivity and specificity for the diagnosis of ANCA-associated vasculitis. PR3-ANCA occur in 75% to 90% of patients with WG, whereas 5% to 20% of patients with WG have MPO-ANCA. MPO-ANCAs are seen in 50% to 80% of patients with MPA, with 10% to 20% having PR3-ANCA. ANCA is also found in up to 40% of patients with CSS when anti-MPO ANCA are seen predominantly. Patients with isolated granulomatous disease of the upper or lower respiratory tract may not have a positive ANCA. Therefore, the absence of a positive test does not rule out a diagnosis.
The initial observation that ANCA levels were higher in those with active disease gave rise to hope that ANCA could be a biomarker for disease activity. However, in a prospective study of 156 patients, only a weak association with disease activity was demonstrated; decreases in PR3-ANCA during remission induction treatment were not associated with a shorter time to sustained remission; and increases in PR3-ANCA levels were not associated with relapse in the following year. Therefore, serial ANCA levels should not be used to monitor disease activity or guide decisions concerning immunosuppressive treatment in ANCA-associated vasculitis.
Biopsy is highly recommended because it can strongly support a diagnosis of vasculitis. Histopathologic evidence of vessel wall inflammation is the gold standard for the diagnosis of vasculitis. The diagnostic yield of biopsies showing either vasculitis (glomerulonephritis in a kidney biopsy) or granuloma is more than 90%, but the yield of the biopsy may vary due to the organ sampled, the skill of the operator, and the sampling method used. A biopsy may be especially helpful in patients with negative ANCA test. Biopsies are also important to rule out other diagnoses. The site of the biopsy must be determined by individual assessment. In renal involvement, repeated biopsies may be of value to follow up treatment results, disease relapse, and chronic damage.
CLINICAL ASSESSMENT AND EVALUATION OF VASCULITIS AND DISEASE SCORING
In several complex rheumatic diseases, measurement of disease activity is becoming increasingly important. Patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and vasculitis are expected to live for many years, having frequent episodes of relapse, accumulation of damage, and drug toxicity. In this context, indices of clinical disease assessment have become necessary because of the failure of serologic markers to provide accurate information for selecting appropriate treatments. Multiorgan involvement is very common in primary systemic vasculitis. Therefore, it is important to have a structured clinical assessment conducted in all patients with a suspicion of vasculitis. In vasculitis, the Birmingham Vasculitis Activity Score (BVAS) ( Tables 16-2 and 16-3 ) has been adopted to assess disease activity, whereas the Vasculitis Damage Index (VDI) ( Table 16-4 ) provides information on disease damage. BVAS and VDI have become internationally recognized assessment tools, allowing comparison of studies from different continents and effective collaboration in multicenter studies. Clinical trials using these tools have provided a firm evidence base for treatment decisions in vasculitis. The first version of the BVAS was published in 1994. Since then, the list of clinical features has been revised by the European Vasculitis Study Group (EUVAS). The BVAS is divided into nine organ-based systems, with each section including symptoms and signs that are typical of that particular organ involvement in systemic vasculitis. Altogether, 66 clinical features are included. The clinician only scores features believed to be due to active vasculitis. Each item is given a numeric value according to its clinical relevance. The different organ systems are also weighted according to clinical relevance by applying maximal scores for each system. For example, ear-nose-throat (ENT) has a maximal score of 6, whereas the renal system has 12. The latest version of BVAS is called BVAS 2003. A glossary of terms was also developed for the BVAS and published along with the new version of the assessment tool (see Table 16-3 ), emphasizing the importance of scoring an item only if it is due to active vasculitis, based on clinical judgment.
| Glossary and scoring for BVAS 2003. GENERAL RULE: disease features are scored only when they are due to active vasculitis, after excluding other causes (e.g., infection, hypertension, etc.). If the feature is due to active disease, it is scored in the boxes. It is essential to apply these principles to each item below. Scores have been weighted according to the severity which each symptom or sign is thought to represent. Tick “Persistent Disease” box if all the abnormalities are due to active (but not new or worse) vasculitis. If any of the abnormalities are due to new/worse disease, DO NOT tick the “Persistent Disease” box. For some features, further information (from specialist opinion on further tests) is required if abnormality is newly present or worse. Remember that in most instances, you will be able to complete the whole record when you see the patient. However, you may need further information before entering some items. Please leave these items blank, until the information is available, and then fill them in. For example, If the patient has new onset of stridor, you would usually ask an ENT colleague to investigate this further to determine whether or not it is due to active Wegener’s granulomatosis. | BVAS persistent | BVAS new/worse | |
|---|---|---|---|
| 1. General | Maximum scores | 2 | 3 |
| Myalgia | Pain in the muscles | 1 | 1 |
| Arthralgia or arthritis | Pain in the joints or joint inflammation | 1 | 1 |
| Fever at 38.0 °C | Documented oral/axillary temperature elevation. Rectal temps are 0.5 °C higher | 2 | 2 |
| Weight loss | At least 2 kg loss of body weight (not fluid) having occurred since last assessment or in the 4 weeks not as a consequence of dieting | 2 | 2 |
| 2. Cutaneous | Maximum scores | 3 | 6 |
| Infarct | Area of tissue necrosis or splinter hemorrhages | 1 | 2 |
| Purpura | Petechiae (small red spots), palpable purpura, or ecchymoses (large plaques) in skin or oozing (in the absence of trauma) in the mucous membranes. | 1 | 2 |
| Ulcer | Open sore in a skin surface. | 1 | 4 |
| Gangrene | Extensive tissue necrosis (e.g., digit) | 2 | 6 |
| Other skin vasculitis | Livedo reticularis, subcutaneous nodules, erythema nodosum, etc. | 1 | 2 |
| 3. Mucous membranes/eyes | Maximum scores | 3 | 6 |
| Mouth ulcers/granulomata | Aphthous stomalitis, deep ulcers and/or “Strawberry” gingival hyperplasia, excluding lupus erythematosus, and infection | 1 | 2 |
| Genital ulcers | Ulcers localized in the genitalia or perineum, excluding infections. | 1 | 1 |
| Adnexal inflammation | Salivary (diffuse, tender swelling unrelated to meals) or lacrimal gland inflammation. Exclude other causes (infection). Specialist opinion preferably required. | 2 | 4 |
| Significant proptosis | Protrusion of the eyeball due to significant amounts of inflammation in the orbit; if unilateral, there should be a difference of 2 mm between one eye and the other. This may be associated with diplopia due to infiltration of extra-ocular muscles. Developing myopia (measured on best visual acuity, see later) can also be a manifestation of proptosis | 2 | 4 |
| Red eye (Epi)scleritis | Inflammation of the scierae (specialist opinion usually required). Can be heralded by photophobia. | 1 | 2 |
| Red eye conjunctivitis | Inflammation of the conjuctivae (exclude infectious causes and excluding uveitis as cause of red eye, also exclude conjunctivitis sicca which should not be scored as this is not a feature of active vasculitis): (specialist opinion not usually required). | 1 | 1 |
| Blepharitis | Inflammation of eyelids. Exclude other causes (trauma, infection). Usually no specialist opinion is required | ||
| Keratitis | Inflammation of central or peripheral cornea as evaluated by specialist | ||
| Blurred vision | Altered measurement of best visual acuity from previous or baseline, requiring specialist opinion for further evaluation. | 2 | 3 |
| Sudden visual loss | Sudden loss of vision requiring ophthalmological assessment. | 6 | |
| Uveitis | Inflammation of the uvea (iris, ciliary body, choroid) confirmed by ophthalmologist. | 2 | 6 |
| Retinal vasculitis | Retinal vessel sheathing on examination by specialist or confirmed by retinal fluoroscein angiography | 2 | 6 |
| Retinal vessel thrombosis | Arterial or venous retinal blood vessel occlusion | ||
| Retinal exudates | Any area of soft retinal exudates (exclude hard exudates) seen on ophthalmoscopic examination. | ||
| Retinal hemorrhages | Any area retinal hemorrhage seen on ophthalmoscopic examination. | ||
| 4. ENT | Maximum scores | 3 | 6 |
| Bloody nasal discharge/nasal crusts/ulcers and/or granulomata | Bloody, mucopurulent, nasal secretion, light or dark brown crusts frequently obstructing the nose, nasal ulcers and/or granulomatous lesions observed by rhinoscopy | 3 | 6 |
| Paranasal sinus involvement | Tenderness or pain over paranasal sinuses usually with pathologic imaging (CT, MR, x-ray, ultrasound) | 1 | 2 |
| Subglottic stenosis | Stridor and hoarseness due to inflammation and narrowing of the subglottic area observed by laryngoscopy | 3 | 6 |
| Conductive hearing loss | Hearing loss due to middle ear involvement confirmed by otoscopy and/or tuning fork examination and/or audiometry | 1 | 3 |
| Sensorineural hearing loss | Hearing loss due to auditory nerve or cochlear damage confirmed by audiometry | 2 | 6 |
| 5. Chest | Maximum scores | 3 | 6 |
| Wheeze | Wheeze on clinical examination | 1 | 2 |
| Nodules or cavities | New lesions, detected by CXR | 3 | |
| Pleural effusion/pleurisy | Pleural pain and/or friction rub on clinical assessment or new onset of radiologically confirmed pleural effusion. Other causes (e.g., infection, malignancy) should be excluded | 2 | 4 |
| Infiltrate | Detected by CXR or CT scan. Other causes (infection) should be excluded | 2 | 4 |
| Endobronchial involvement | Endobronchial pseudotumor or ulcerative lesions. Other causes such as infection or malignancy should be excluded. NB: smooth stenotic lesions to be included in VDI; subglottic lesions to be recorded in the ENT section. | 2 | 4 |
| Massive hemoptysis/alveolar hemorrhage | Major pulmonary bleeding, with shifting pulmonary infiltrates; other causes of bleeding should be excluded if possible | 4 | 6 |
| Respiratory failure | Dyspnea which is sufficiently severe as to require artificial verification | 4 | 6 |
| 6. Cardiovascular | Maximum scores | 3 | 6 |
| Loss of pulses | Loss of pulses in any vessel detected clinically; this may include loss of pulses leading to threatened loss of limb | 1 | 4 |
| Valvular heart disease | Significant valve abnormalities in the aortic mitral or pulmonary valves detected clinically or echocardiographically. | 2 | 4 |
| Pericarditis | Pericardial pain and/or friction rub on clinical assessment. | 1 | 3 |
| Ischemic cardiac pain | Typical clinical history of cardiac pain leading to myocardial infarction or angina. Consider the possibility of more common causes (e.g., atherosclerosis) | 2 | 4 |
| Cardiomyopathy | Significant impairment of cardiac function due to poor ventricular wall motion confirmed on echocardiography | 3 | 6 |
| 7. Abdominal | Maximum scores | 4 | 9 |
| Peritonism | Acute abdominal pain with peritonism/peritonitis due to perforation/infarction of small bowel, appendix or gallbladder, etc., or acute pancreatitis confirmed by radiology/surgery/elevated amylase | 3 | 9 |
| Bloody diarrhea | Of recent onset; inflammatory bowel disease and infectious causes excluded. | 3 | 9 |
| Ischemic abdominal pain | Severe abdominal pain with typical features of ischemia confirmed by imaging or at surgery, with typical appearances of aneursyms or abnormal vasculature characteristic of vasculitis. | 2 | 6 |
| 8. Renal | Maximum scores | 6 | 12 |
| Hypertension | Diastolic BP>95, accelerated or not, with or without retinal changes. | 1 | 4 |
| Proteinuria | >1+ on urinalysis; >0.2 g/24 hours infection should be excluded. | 2 | 4 |
| Hematuria | 10 or more RBC per hpf (high power field), excluding urinary infection and urinary uthlasis (stone) | 3 | 6 |
| Creatinine 125-249 | Serum creatinine values 125-249 µmol/l at first assessment only. | 2 | 4 |
| Creatinine 250-499 | Serum creatinine values 250-499 µmol/l at first assessment only. | 3 | 6 |
| Creatinine ≥ 500 | Serum creatinine values 500 µmol/l or greater at first assessment only. | 4 | 8 |
| Rise in creatinine > 30% or creatinine clearance fall > 25% | Significant deterioration in renal function attributable to active vasculitis. | 6 | |
| 9. Nervous system | Maximum scores | 6 | 9 |
| Headache | New, unaccustomed & persistent headache | 1 | 1 |
| Meningitis | Severe headache with neck stiffness ascribed to inflammatory meningitis after excluding infection/bleeding | 1 | 3 |
| Organic confusion | Impaired orientation, memory or other intellectual function in the absence of metabolic, psychiatric, pharmacological or toxic causes. | 1 | 3 |
| Seizures (not hypertensive) | Paroxysmal electrical discharges in the brain & producing characteristic physical changes including tonic & clonic movements & certain behavioral changes. | 3 | 9 |
| Stroke | Cerebrovascular accident resulting in focal neurological signs such as paresis, wetness, etc. A stroke due to other causes (e.g., atherosclerosis) should be considered & appropriate neurological advice is recommended | 3 | 9 |
| Cord lesion | Transverse myelitis with lower extremity wetness or sensory loss (usually with a detectable sensory level) with loss of sphincter control (rectal & urinary bladder). | 3 | 9 |
| Cranial nerve palsy | Facial nerve palsy, recurrent nerve palsy, oculomotor nerve palsy, etc. excluding sensorineural hearing loss and ophthalmic symptoms due to inflammation | 3 | 6 |
| Sensory peripheral neuropathy | Sensory neuropathy resulting in glove and/or stocking distribution of sensory loss. Other causes should be excluded (e.g., idiopathic, metabolic, vitamin deficiencies, infectious, toxic, hereditary). | 3 | 6 |
| Motor mononeuritis multiplex | Simultaneous neuritis of single or many peripheral nerves, only scored if motor involvement. Other causes should be excluded (diabetes, sarcoidosis, carcinoma, amyloidosis). | 3 | 9 |
| 10. Other | Other feature of active vasculitis-please describe | ||
Damage caused by vasculitis or its treatment may prove more troublesome to the patient than disease activity and is highly unlikely to respond to immunosuppressive treatment. In a longitudinal WG cohort from the National Institutes of Health, 86% of patients had permanent damage as a consequence of the disease itself and 42% had treatment-related morbidity. This damage included, for example, end-stage renal disease, chronic pulmonary dysfunction, saddle-nose deformities, blindness, and death. VDI is composed of 64 items of damage grouped into 11 organ systems and records items of change, due to vasculitis, treatment, or unrelated, that have occurred since the onset of vasculitis. Completion of the form provides a numeric score. The VDI was first published in 1997 and is constructed to be a cumulative index; therefore, the VDI score can never decrease over time. A comprehensive overview of the clinical evaluation of vasculitis and the development of the BVAS 2003 and the VDI was published in 2007.
Training is an essential part of these assessment tools. Because of this, a training manual is provided by the EUVA, along with a practical guide.
A helpful tool for evaluating prognosis is the five-factor score (FFS). It is a prognostic score developed by the French vasculitis study group and has been proven accurately to predict survival for patients with PAN, MPA, and CSS. The FFS is based on five clinical items, with the presence of each accorded one point for a maximum score of 5: renal insufficiency, proteinuria, central nervous system involvement, cardiomyopathy, and severe gastrointestinal involvement. For PAN, MPA, and CSS, 5-year survival rates were 88% when FFS was 0; 74% when FFS equaled 1; and 54% when FFS 2 or more.
It is very important during treatment of vasculitis to critically assess the effect of given therapy, disease activity, disease progress and to notice adverse events (for example, infections due to immunomodulation, drug-induced pneumonitis, or bladder toxicity). Urinalysis should be performed on each patient at each visit to screen for renal relapse or response, infection, and bladder toxicity in patients treated with cyclophosphamide. It is important to monitor a full blood count and liver enzymes at regular intervals to screen for drug toxicity, along with inflammatory markers and renal function parameters at 1- to 3-month intervals in order to monitor disease evaluation and treatment response. A declining renal function may necessitate drug alteration or dose adjustment of the immunosuppressive agent. A drastic fall in white cell count or a slowly progressive leukopenia may require discontinuation or reduction of the immunomodulation.
It is important to categorize the ANCA-associated vasculitides by different levels of severity to arrive at treatment decisions. Treating physicians need to be aware of the fact that patients with different levels of disease severity respond to different treatment strategies, which has been demonstrated by clinical trials conducted by the EUVAS. It may be appropriate to treat a patient with early systemic or local AAV with methotrexate, but the same patient will need cyclophosphamide if he or she develops a more generalized disease or a life-threatening disease manifestation. The EUVAS disease categorization of AAV is shown in Table 16-5 .
| Category | Definition |
|---|---|
| Localized | Upper or lower respiratory tract disease without any other systemic involvement or constitutional symptoms |
| Early systemic | Any, without organ-threatening or life-threatening disease |
| Generalized | Renal or other organ-threatening disease, serum creatinine < 500 μmol/L (5.6 mg/dL) |
| Severe | Renal or other vital organ failure, serum creatinine > 500 μmol/L (5.6 mg/dL) |
| Refractory | Progressive disease unresponsive to glucocorticoids and cyclophosphamide |
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