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physicians have been continuously trying to find a way to better classify vasculitides in order to facilitate a fast and accurate diagnosis .
proper diagnosis is extremely important , as some diseases only require supportive treatment while others need prompt and aggressive therapy if significant morbidity and mortality is to be avoided .
the difficulty comes when physicians encounter complex cases that do not follow any current classification .  
vasculitis of the temporal artery was observed in the biopsy specimen of a patient with clinical symptoms   suggestive of temporal arteritis .
86-year - old white man was referred to our rheumatology clinic on july 23rd , 2008 .
he was complaining of persistent fatigue , low grade fever , proximal arthralgias , and myalgias , especially in his hips .
mg / l , wbc 12600/cumm , hb 10.6  g / dl , ht 32.3% , ferritin 2217  ng / ml , albumin 2.6  g / dl , bun 18  mg / dl , and cr 0.87  mg / dl .
a diagnosis of polymyalgia rheumatica and giant cell arteritis was suspected and treatment with prednisone 60  mg daily was started .
the patient had dramatic improvement of his symptoms and rapid decline of the inflammatory markers . on august 15th ,
3 weeks after initiating steroid therapy , his esr decreased to 39  mm / h and crp to 21.7  mg / dl . over the next three weeks the steroid dose
however , he did not tolerate further taper due to recurrence of polymyalgia - like symptoms .   despite overall clinical improvement and continuous treatment with prednisone ( 2030  mg daily ) , renal dysfunction ensued over the three months since the onset of the patient 's illness . in september
, 2008 patient 's bun rose to 77  mg / dl and cr to 3.33  mg / dl .
urinalysis revealed 2 + proteins , few rbcs , no rbc casts , and no wbc . at that point a vasculitic process in the kidneys was considered , prompting further workup .
the following serologies were negative or normal : anca , c3 , c4 , ch50 , ana , anti - dsdna , anti - gbm , anticardiolipin antibodies , and cryoglobulins .
magnetic resonance angiography was negative for renal artery stenosis .                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            in september , 2008 , the kidney biopsy was performed , showing acute and chronic granulomatous necrotising vasculitis of medium - sized ( renal ) arteries and crescent formation .
the immunofluorescence report was negative for igg , igm , iga , c3 , c1 , fibrinogen , albumin , or light chains   ( figures 1(a ) , 1(b ) , and 1(c ) ) .  
based on the clinical and pathological findings , we concluded that our patient had anca - negative granulomatous necrotizing vasculitis involving the small- , medium- and large - size vessels . in october , 2008 , cyclophosphamide was added to prednisone .
the regimen of cyclophosphamide 50  mg daily alternating with 75  mg daily and prednisone 15  mg daily was continued for four months . of note ,
this regimen achieved stabilization of the renal function to a creatinine of 2.32.5  mg / dl and normalization of the inflammatory markers , while no other symptoms were present . in february , 2009 , cyclophosphamide was discontinued due to the concern for potential side effects and toxicity of cyclophosphamide .
patient was administered a course of rituximab , 1000  mg 2 doses 2 weeks apart with intention to prevent the disease flare upon stopping cyclophosphomide . patient continued to taper the dose of prednisone gradually and discontinued it completely in june , 2009 .
as of march of 2010 , he feels very well without any polymyalgia or cranial symptoms , resumed his regular tennis playing and other activities .
his renal function has been stable with bun of 35  mg / dl and creatinine of 1.64  mg / dl .
classifying a vasculitis can be a real challenge and most likely the final word in the classification has not yet been said .
the current approach using the vessel size ( small , medium , and large ) is useful in suggesting clinical features associated with a particular disease . it is important to realize that there are unclassified vasculitic processes when clinical judgement and case particularities are guiding the best therapeutic approach .
vessels are very complex and not enough studied organs as determinants of a vasculitic pattern .
more research is being oriented toward establishing the basis for this selective vulnerability beyond vessel size .
it has been hypothesized that several factors , including embryogenesis , age - related changes , immunologic susceptibility , and injury - repair process might be involved in the etiology and pathogenesis of vasculitis .  
temporal artery biopsy is a simple tool for diagnosis of vasculitis , but vasculitis of the temporal artery is not limited to giant cell arteritis .
other systemic vasculitides ( e.g. , polyarteritis nodosa , wegener 's granulomatosis , microscopic polyangiitis , churg - strauss syndrome , systemic lupus erythematosus ) may show inflammatory changes on the temporal artery biopsy [ 48 ] .
there have been case reports of systemic vasculitis ( e.g.,wegener granulomatosis ) , found to have biopsy - proven vasculitis of the temporal artery . in 2003 , hamidou et al . reported seven cases of systemic necrotizing vasculitis with histologically proven temporal artery involvement . in 1998 , lenz et al . described a patient with cranial symptoms suggestive of temporal arteritis who was also diagnosed with anca - negative pauci - immune glomerulonephritis .
fibrinoid necrosis is atypical for giant cell arteritis and its presence should raise doubts about such a diagnosis .  
our patient 's kidney biopsy was consistent with pauci - immune anca - negative granulomatous necrotizing glomerulonephritis .  
the rare finding of granuloma in the kidney biopsy , mandated the exclusion of other potential culprits beside the vasculitic etiology ( most commonly wegener 's granulomatosis ) .
the differential diagnosis of granulomatous renal disease is broad , including tuberculosis as a classic cause of noncaseating granuloma .
our patient had no risk factors for tuberculosis , negative ppd test , and no pulmonary symptoms whatsoever .
we excluded also other potential infectious causes ( e.g. , fungal infections like histoplasmosis and cryptococcosis , chronic pyelonephritis , cat - scratch fever ) .
chaveau et al . showed that renal involvement occurs in 75% of the patients with systemic necrotizing small - vessel vasculitis .
the absence or paucity of vascular immune deposits distinguishes microscopic polyangiitis , wegener 's granulomatosis ( wg ) and churg - strauss syndrome from the variety of necrotizing vasculitides .
the classic triad of respiratory tract granulomatous inflammation , systemic small - vessel vasculitis and necrotizing glomerulonephritis suggests the diagnosis of wg , but a lot of patients do not present with the classic findings .
antineutrophilic cytoplasmic antibody testing ( anca ) is a very important diagnostic aid , with 70% of the wg 's having antibodies towards proteinase 3(pr3-anca ) , 20% against myeloperoxidase , while 10% may be anca negative .  
the glomerulonephritis is characterized by focal necrosis , crescent formation , and the absence or paucity of immunoglobulin deposits .
a similar pauci - immune , crescentic , necrotizing glomerulonephritis is found in patients with microscopic polyangiitis and churg - strauss syndrome .
the latter is characterized by a triad of asthma , eosinophilia and necrotizing granulomatous vasculitis .
p - anca(or anti - mpo ) is positive in 35%75% of patients and up to 10% can have a positive c - anca .
microscopic polyangiitis is differentiated by the absence of asthma and development of rapidly progressive glomerulonephritis ( rpgn ) without granulomata . over 80% of patients
our case though , does not fit into any of the classic granulomatous necrotizing vasculitis .
when facing a systemic vasculitis it is extremely important to make an accurate diagnosis . as of yet
a clinician has to take into consideration both the clinical manifestations and the histological findings , in his endeavors to understand these rare and devastating conditions .  
aggressive , early , and appropriate treatment minimizes disease - related mortality and irreversible damage . whereas steroid treatment is usually sufficient for giant cell arteritis , renal involvement in the form of glomerulonephritis , traditionally requires addition of immunopsupressive drugs . before the institution of immunosuppressive therapy , the mortality rate of patients with systemic vasculitis ( such as wg or polyarteritis nodosa ) was 75% at 5 months .
when cyclophosphamide was administered along with corticosteroids , the 5-year mortality rate lowered to 12% .
the risks and benefits of aggressive immunosuppression must be assessed in each patient and treatment established accordingly .
our case does not fall into any classifiable vasculitic profile . to our best knowledge , this is the only reported case of anca - negative systemic granulomatous necrotizing vasculitis involving small- , medium- , and large - size vessels in a patient facing the diagnosis of a systemic , yet unclassified vasculitis .
we describe the case of an 86-year - old man presenting with clinical symptoms   suggestive of temporal arteritis . 
 the evolution of the case prompted extensive work - up , including temporal artery and kidney biopsy . 
 based on the clinical and pathological findings , a diagnosis of anca - negative granulomatous necrotizing vasculitis involving the small- , medium- , and large - size vessels was made . 
 the patient was treated with prednisone and cyclophosphamide , which was later switched to rituximab . 
 the patient remained asymptomatic under this regimen and stabilization of his kidney function was achieved .