|For a clinician, the |
systemic necrotizing vasculitides are a heterogeneous group of disorders that share clinical, morphological and occasionally, serologic features. They are uncommon and are thus not often considered in the
differential diagnosis of perplexing patients. They are also potentially lethal and their prompt recognition and treatment often produces a gratifying result. Hence the importance of their consideration, diagnosis and treatment cannot be over emphasized.
Classifying these conditions has been a vexed issue for decades and it is perhaps prudent to start from the beginning. Even though Henoch Schonlein Purpura had been described earlier, Polyarteritis Nodosa(1)was a broad term that encompassed all the necrotizing vasculitides that we know today till well into the 20th century. Variants, however began to be identified in the first half.
In the 1930's, first Klinger(2), and then Wegener(3), described a clinically and morphologically distinct disorder characterized by recurrent, unresponsive, sinus and upper airways inflammation for variable duration followed by the development of lung and renal involvement as predominant features of a rapidly progressive, highly fatal, multisystem disorder. A Norwegian later named it Wegener's granulomatosis (WG)(4). The first use of this term in English was by Godman and Churg(5) who also set down the first set of criteria for a diagnosis in 1954.
In 1948, Davson and colleagues had identified a disorder like Polyarteritis but lacking in aneurysm formation and predominantly affecting small vessels along with glomerulonephritis(6). They called it Microscopic Polyarteritis. It was later named microscopic polyangiitis.
Churg and colleagues, had, in the early 1950's, defined the asthma, granulomatous inflammation and eosinophilia related vasculitis. This condition came to be known as the Churg Strauss Syndrome(7). For many years the vasculitides lacked a diagnostic serologic abnormality or test. However, with the discovery of ANCA in the 1980's, this void was also filled(8). Several studies have testified to the c-ANCA pattern at indirect immunofluorescence as being characteristic of WG9. In contrast, most patients with MPA show the p-ANCA pattern.
The vasculitides are as much clinical entities as they are pathological ones. A proper understanding of their diverse manifestations can only be reached if one takes into account both the clinical manifestations and the histological findings. Several attempts at classifying the vasculitides have been made since Zeek's pioneering work in the 1950s(10). That so many schemes of classification have emerged in the last 50 years is testimony to both the unsatisfactory nature of these classifications as well as the remarkable progress in the understanding of these uncommon and often devastating conditions(11).
Zeek (Table.1) recognized a broad category of conditions that were grouped together as hypersensitivity angiitis. She used this term probably because WG had not been reported in the English literature till that time and rheumatic arteritis, probably to represent on vasculitis of connective tissue diseases. She recognized the Churg Strauss syndrome, Classic PAN and temporal arteritis. Alarcon Segovia and Brown, in 1964 included WG, considered vasculitis secondary to rheumatic diseases as a separate entity and included HSP. de Shazo (1975) and Gilliam and Smiley (1976) made small changes. Takayasu's arteritis and the vasculitis of hepatitis B virus infection were recognized by the later.
Fauci (1978) while recognizing Kawasaki's disease for the first time classified the conditions into groups of disorders. McCluskey and Fienberg (1983) first classified the conditions into primary and secondary. The Chapel Hill consensus conference in 1993 was a bold initiative that attempted to define disorders exactly and to classify them according to the size of vessel predominantly involved (Table 2)(12). While this effort was based on a pathologic spectrum, it has resulted in diagnostic confusion because using its strict definition, it has become difficult to sustain a diagnosis of PAN in most instances. Lie summarized the problems with the classification and introduced one of his own in 1994 (Table 3)(11). He differentiated between primary and secondary forms, delineated the causes of the later and with his extensive experience with the pathology of these conditions made the Chapel Hill classification more flexible. He mentioned drug related vasculitis and we know today that several drugs can produce these problems (Table 4). Later workers have recognized the importance of vessel size but have been more flexible in defining it as the dominant involved vessel size. Both Savage(13) (Table 5), and Jennette and Falk(14), simplified the classification by incorporating another histopathologic element, that of granulomatous inflammation. Along with the use of ANCA serology these changes have led to a far clearer understanding(15).
clinical features of the vasculitis are diverse, multisystemic and protean. A detailed description is beyond the scope of this article however the common presentations will be outlined below.
Giant cell arteritis (GCA) is a disease of older adults and is infrequently seen in this country. It is often accompanied by symptoms of polymyalgia rheumatica, body pain, tender muscles, a high ESR, jaw claudication and headaches. One of the most sinister complications is blindness due to retinal vascular insult. Of all the symptoms, jaw claudication is the most noteworthy. Very often a thickened cord like prominent temporal artery is found on examination. Takayasu's arteritis is another large vessel vasculitis affecting a far younger population than GCA. In its classic form, it is characterized by absent pulses and hypertension both of which are a consequence of clinically silent arterial inflammation. Sometimes an episode of fever, arthralgia and myalgia may be remembered but the initial manifestations are usually not. Patients manifest with ischemia of the limbs, head and neck, heart, abdominal viscera and lungs depending on the territory most severely affected. Isolated angiitis of the CNS is an uncommon condition characterized by focal neurological deficits of vascular origin and can be diagnosed on brain biopsy.
Classic polyarteritis nodosa (PAN) is characterized by fever, weight loss, myalgia, arthralgia, hypertension, testicular infarction, bowel ischemia, mononeuritis multiplex, cutaneous lesions, hepatitis B positivity pan arteritis of predominantly medium sized arteries and aneurysms at angiography. Pulmonary involvement is rare and it is usually a "one shot" illness. Churg Strauss syndrome comprises many features of PAN but is dominated by asthma, eosinophilia and extravascular eosinophilic granulomatous vasculitis. It cannot be diagnosed in the absence of asthma and eosinophilia. Neurologic, skin and cardiac involvement are common. Wegener's granulomatosis (WG) is characterized by predominant involvement of the upper airways, lungs and kidneys by a granulomatous necrotizing small vessel vasculitis. No organ is spared and it can involve the GI tract, brain, heart, skin and other organs. In several instances the disease has an indolent granulomatous phase characterized by recurrent severe sinus inflammation, otitis media or scleritis for several months before a rapidly progressive vasculitic phase supervenes and this is usually rapidly fatal if not treated early. Microscopic polyangiitis is a disease that resembles the vasculitic phase of WG in terms of renal involvement and pulmonary hemorrhage. Granulomatous inflammation is usually not seen. Henoch Schonlein purpura is characterized by purpura, joint pain and vasculitis involving the bowel. It is related to IgA and in children is usually a mild illness. In adults it can be severe and life threatening.
Berger's disease is a disease of adults and is associated with smoking. It results in an ischemic painful limb and is progressive. Occasionally it may progress to visceral involvement. Cogan's syndrome is characterized by large vessel vasculitis and interstitial keratitis while Kawasaki's disease is characterized by skin changes and coronary arteritis.
It is important to ask oneself the question "Could this patient have a vasculitis? In the face of perplexing clinical problems that suggest common ailments but do not go away with adequate appropriate therapy. The common conditions are fever of unexplained origin, myalgia, arthralgia, night sweats and unexplained weight loss. Broadly these are termed as constitutional symptoms. Those with polymyalgia rheumatica, non destructive oligoarticular arthritis, unexplained stubborn elevation of the ESR, unexplained anemia and raised platelet counts should be investigated. The "red flag" signs that suggest an underlying vasculitis very strongly are skin abnormalities like palpable purpura, livedo reticularis, skin infarction, skin necrosis, non-healing ulcers, mononeuritis multiplex, claudication of the jaw and abnormal urinary sediment. All of these warrant a search for a vasculitic etiology because if it is found and treated, the results can be excellent. If missed they are usually fatal.
Table 1. Classification of the Vasculitides. (Zeek 1952) 10
Allergic granulomatous angiitis
Table 2. Chapel Hill consensus conference classification (1993) 12
Large vessel vasculitis
Giant cell arteritis, Takayasu disease
Medium vessel vasculitis
Polyarteritis nodosa, Kawasaki disease
Small vessel vasculitis
Microscopic polyangiitis, WG, CSS, HSP, EMC, cutaneous vasculitis
Table 3. Classification of vasculitis (Lie 1994) 11
Large, medium and small vessels
Giant cell arteritis, Takayasu dis.
Isolated angiitis of CNS
Medium and small vessels
PAN, CSS, WG
Microscopic polyangiitis, HSP
Cutaneous leukocytoclastic vasculitis
Buerger's, Cogan's, Kawasaki's
Connective tissue diseases
Post organ transplant
Table 4. Drugs causing Vasculitis
Antibiotics (Macrolides, Aminoglycosides, Quinolones, Sulphonamides, Tetracyclines, Penicillins, INH, Rifampicin)
Anticonvulsants (Phenytoin, Carbamazepine, Valproate)
Antihypertensives (Hydralazine, Methyldopa, HCT, Nifedipine, Atenolol, Captopril, Diltiazem, Frusemide)
Antiarrhythmics (Quinidine, Procainamide)
Anticoagulants (Heparin, Warfarin, Streptokinase)
Vaccines (Hepatitis A, B, Influenza, Rubella, Smallpox)
Interferons (Alpha, beta, gamma)
Growth factors (G-CSF, GM-CSF)
Antimetabolites (Allopurinol, Colchicine, Retinoids,
Alkylating agents, Methotrexate, Cytosine arabinoside)
Psychoactive (Antidepressants, Cocaine, Ecstasy).
Dominant Vessel size
Non granulomatous pathology
Temporal arteritis Takayasu's
Classic PAN, Kawasaki's disease
Wegener's Churg Strauss
Microscopic polyangiitis, HSP, EMC.