Evaluation and treatment of vasculitis in the critically ill patient

Crit Care Clin 18 (2002) 321 – 344

Evaluation and treatment of vasculitis in the critically ill patient Peter A. Merkel, MD, MPH a,*, Hyon K. Choi, MD, MPH b, John L. Niles, MD c a Rheumatology Section, Boston Medical Center, Arthritis Center, Boston University School of Medicine, 730 Albany Street, Boston, MA 02118, USA b Rheumatology Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02117, USA c Renal Unit and Pathology Department, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA

The inflammatory vasculitides are a group of multisystem diseases that can result in rapid clinical deterioration and admission to an intensive care unit (ICU). Vasculitis is usually idiopathic and often difficult to diagnosis quickly making the approach to these patients especially challenging in an ICU. Critical illness may be the initial presentation of an inflammatory vasculitis, it may be the result of progressive primary or recurrent disease or it may be due to complications of treatment, such as sepsis. This article focuses on critical care aspects of patients with vasculitis with a focus on the approach to diagnosis and treatment in the ICU. A particular emphasis is placed on the renal manifestations of the diseases. The most difficult aspect of diagnosing a case of vasculitis is often simply considering it in patients with severe multisystem disease. It must be emphasized that vasculitides are rare diseases and often mimic other diseases, such as infections and malignancies. Furthermore, because treatment for severe vasculitis almost always involves high-dose glucocorticoids and immunosuppressive agents, infections must be carefully ruled out even in patients who clearly have vasculitis. Patients who already carry an established diagnosis of vasculitis can present to an ICU with an exacerbation of their underlying inflammatory process, an infectious complication of therapy, or both problems. In can often be difficult to determine whether patients with a history of vasculitis have active disease. Currently, there are no fully reliable measures of disease activity for vasculitis * Corresponding author. E-mail address: [email protected] (P.A. Merkel). 0749-0704/02/$ - see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 7 0 4 ( 0 1 ) 0 0 0 0 6 - 9

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and it is often necessary to embark upon an extensive evaluation in such patients to determine disease activity.

The approach to the diagnosis of vasculitis The diagnostic evaluation of patients with suspected vasculitis involves clinical history taking, physical examination, common laboratory studies, autoimmune serologies, various diagnostic imaging modalities, and often tissue biopsy. Because of toxicity of therapy and the need for long-term treatment, it is important to pursue a firm diagnosis of vasculitis. However, it is recognized that with critically ill patients, empiric therapy for vasculitis may need to be initiated prior to establishing a firm diagnosis. The gold standard for diagnosis of vasculitis has been the demonstration, in biopsy specimens, of vascular inflammation, with or without vessel wall destruction. Almost any organ can be involved in various vasculitides but the clinician needs to understand that the yield of certain tissue specimens varies greatly among the different diseases. For example, sinus biopsies from patients with Wegener’s granulomatosis (WG), while easy and safe to obtain, often demonstrate non-specific inflammation [39]. However, renal biopsies in patients with WG or microscopic polyangiitis are almost always diagnostic. There are frequently histologic changes other than vascular inflammation that may also indicate one of the vasculitic syndromes. For example, diagnostic specimens from patients with Wegener’s granulomatosis often reveal extravascular histiocytic infiltrates, granulomatous inflammation, and piecemeal necrosis [28, 39]. In many cases, tissue biopsy is either not practical to obtain or the findings are non-diagnostic. Alternatively, other findings may be sufficient to establish a diagnosis. Examples of this include the angiographic changes seen in Takayasu’s arteritis or polyarteritis nodosa. Furthermore, there are several practical considerations for obtaining biopsies in patients with suspected vasculitis who are in the ICU. Critically ill patients may not be suitable operative candidates for biopsies. This is especially true for lung biopsies in patients with respiratory failure. While transbronchial biopsies are easily performed in the ICU, they are both of much lower diagnostic yield and carry risk of causing pneumothorax and lung hemorrhage [80,85]. Renal biopsies are also often diagnostic in patients with renal vasculitis, although sampling error can occur [69]. However, critically ill patients may have bleeding diatheses making renal biopsies more dangerous. Skin is excellent tissue for biopsy to establish a diagnosis of vasculitis in patients with suspicious cutaneous findings. Not all ‘‘purpuric’’ lesions are vasculitis and not all skin vasculitis is purpuric. Biopsies should be sought from ‘‘fresh’’ lesions when possible. Skin biopsy carries low risk, even among patients in an ICU. However, a finding of vasculitis in a skin biopsy does not usually allow for differentiation among the different types of small to medium vessel vasculitides. Diagnostic considerations for specific vasculitides are outlined in each section below.

Table 1 Inflammatory vasculitides presenting with critical illness Vessel size

Pulmonary

Renal

Skin

Other manifestations

Useful serologies

Wegener’s granulomatosis

Small-medium

+++ RPGN

ANCA

Small-medium

+++ RPGN

+ Purpura, gangrene + Purpura, gangrene

ENT, arthritis, mononeuritis, optho

Microscopic polyangiitis Churg-Strauss syndrome

Small

+++ Hemorrhage, infiltrates, lesions +++ Hemorrhage, infiltrates, lesions +++ Infiltrates

Systemic lupus erythematosus

Small

Goodpasture’s syndrome Cryoglobulinemic vasculitis

Small Small

+ Hemorrhage, infiltrates +++ Hemorrhage +

++ GN, nephrotic syndrome +++ RPGN ++

Polyarteritis nodosa

Medium

+

Drug-induced vasculitis Behcßet’s disease

Small-medium Medium-large

+ +

++ Renal artery, not GN +

Giant-cell arteritis Takayasu’s arteritis

Large Large

+

++ Renal artery

++ Malar rash, photosensitivity ++ Purpura

+++ Purpura ++

ANCA Mononeuritis, ENT, eosinophilia Arthritis, CNS

Liver disease, arthritis, GI GI

ANCA ANA and many other antibodies Anti-GBM antibodies Cryoglobulins, hepatitis C Hepatitis B

Eosinophilia, arthritis Phlebitis, CNS, ophtho, thrombosis CNS, ophtho, aorta Claudication, aorta

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Vasculitis type

RPGN = rapidly progressive glomerulonephritis; ENT = ear, nose, and throat; ANCA = antineutrophil cytoplasmic antibodies; ANA = antinuclear antibodies; GN = glomerulonephritis; CNS = central nervous system; GBM = glomerular basement membrane; GI = gastrointestinal; Ophtho = ophthomalogic; + = less common; + + = common; ++ + = more common.

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Clinical manifestations and treatment of specific vasculitides There are many types of vasculitis and almost any type can present with critical illness. Additionally, many clinical manifestations are common among the different vasculitides. However, the vasculitides do differ in several important ways and some have unique and unusual clinical problems. An understanding of the basic classification of vasculitides is helpful for clinicians considering this diagnosis [7,46]. Similarly, making a diagnosis of a specific type of vasculitis can help clinicians anticipate potential complications. Table 1 briefly outlines many of the more common vasculitides likely to be seen by critical care physicians and Table 2 outlines treatment of vasculitis. The pulmonary-renal syndromes are of particular interest to critical care clinicians [62]. Among the pulmonary-renal syndromes to consider are the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (Wegener’s granulomatosis, microscopic polyangiitis, and the Churg-Strauss syndrome), Goodpasture’s syndrome (anti-glomerular basement membrane disease), and systemic lupus erythematosus. Details of these disorders will be provided below. While this categorization is useful for clinicians it is important to recognize that these diseases may present in other ways and that either pulmonary or renal involvement may not be present at the time of diagnosis. Furthermore, other vasculitides such as cryoglobulinemia may present with pulmonary and renal disease but are not traditionally considered in this category.

ANCA-associated vasculitis The vasculitic syndromes of Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), the Churg Straus syndrome (CSS) and renal-limited variants are linked by the presence of overlapping clinical and histologic features and the presence, in the majority of cases, of a specific type of autoantibody called antineutrophil cytoplasmic antibodies (ANCA) [25,30,32,33,39,68,77]. Hence, these syndromes are best grouped together as one category or spectrum of disease that is now commonly called ANCA-associated vasculitis. Patients with one of these syndromes may develop features of one of the other syndromes in this spectrum. While some patients with ANCA-associated vasculitis may have slowly progressive symptoms and findings, most will progress to have life-threatening disease with destruction of the lungs, kidneys and other organs if untreated [39,87]. Some patients may present with explosive disease from the outset. It is important to understand that not all patients with ANCA-associated vasculitis test positive for ANCA [12,28,34]. While the majority of patients with WG and MPA will be ANCA-positive, especially if renal disease is present [14,71], some will be ANCA-negative at presentation. Some patients become ANCA-positive only later in the course of their disease. The rate of ANCA positivity in CSS is below that of WG or MPA [15,16,33]. Nevertheless, all patients with Wegener’s granulomatosis, microscopic polyangiitis, pauci-immune glomerulonephritis, and the Churg Straus syndrome are considered to have

Vasculitis type

Glucocorticoids

Cyclophosphamide

Wegener’s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Systemic lupus erythematosus Goodpasture’s syndrome Cryoglobulinemic vasculitis Polyarteritis nodosa Drug-induced vasculitis Behcßet’s disease Giant-cell arteritis Takayasu’s arteritis

++ + + ++ + + ++ + + ++ + + +++ ++ ++ + + ++ +++ ++ + + ++ + +

++ + + ++ + + ++ +++ +++ ++ ++ + ++ + +

Methotrexate or azathioprine +++ ++ ++ +++

Plasmapheresis

Interferon-a

+ +

Other treatments IVIg, mycophenolate IVIg, mycophenolate

+ IVIg, mycophenolate ++ + + +++

++++ (Hepatitis C+)

+ + +++ +/? ++

+ = prescribed infrequently; ++ = regularly prescribed; +++ = often prescribed; ++++ = almost always prescribed; ? = controversial. IVIg = intravenous immunoglobulin.

Drug withdrawal Chlorambucil, cyclosporin

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Table 2 Treatment of various vasculitic conditions

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ANCA-associated vasculitis since the approach to diagnosis and treatment is similar among the syndromes. CSS has its own unique features and is discussed separately as well. Clinical features of ANCA-associated vasculitis ANCA-associated vasculitis has a predilection for the upper airways, lungs and kidneys, but can affect almost any organ [25,39]. The most characteristic manifestations are listed in Table 3. However, patients often initially present with very non-specific symptoms, such as joint and muscle pains or unexplained fever. Among patients who develop the most severe disease and who may require an ICU for management, the most devastating findings are usually alveolar hemorrhage and rapidly progressive glomerulonephritis. Unfortunately, there may not be many clues to lead one to suspect vasculitis before these devastating sequelae develop. Prior to hospital admission, many patients have been treated as an outpatient with more than one course of antibiotics without resolution of their symptoms. Once the patient comes back after failing antibiotics, he/she deserves closer evaluation. When the patient has hemoptysis, unexplained pulmonary infiltrates and/or hematuria it becomes easier to suspect a vasculitis syndrome, but it also becomes a medical emergency. Table 3 Major clinical features of the antineutropil cytoplasmic antibody-associated vasculitides Organ system

Clinical features

Upper respiratory tract

Bloody or crusting nasal or sinus secretions Destructive rhinitis and sinusitis Subglottic tracheal stenosis Bronchitis Pulmonary nodules Pulmonary infiltrates Alveolar hemorrhage Hematuria Proteinuria Renal failure Arthralgias and arthritis Purpura Nonhealing ulcers Scleritis, episcleritis, conjunctivitis, and iritis Retro-orbital pseudotumor Otitis Mastoiditis Mononeuritis multiplex Cranial neuropathies Hearing loss (sensorineural or conductive) Meningeal involvement with mass effects Anemia Eosinophilia Fever Weight loss

Lower respiratory tract

Kidneys

Joints Skin Eyes Ears Central nervous system

Miscellaneous

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Pulmonary manifestations may fall into one or more categories [28,85]. The most lethal aspect of the ANCA-associated vasculitides is diffuse alveolar hemorrhage, which may be explosive and require admission to an ICU. Alveolar hemorrhage occurs in patients with either WG or MPA and is due to alveolar capillaritis where alveoli may rapidly fill with blood causing massive hemoptysis and acute respiratory failure. Finally, some patients who do survive the acute hemorrhage may develop pulmonary fibrosis or the adult respiratory distress syndrome and fail to wean from the ventilator. Bleeding in the lungs may also occur subacutely with minimal early symptoms, but with the development of hemosiderin-laden macrophages that may be found in the sputum, or in bronchoscopy or biopsy specimens. Another pulmonary manifestation is the formation of granulomatous lesions which are the hallmark of WG, but may also be seen in CSS. Granulomas may develop slowly, become localized nodules, and may cavitate. In other patients the disease may present as bronchitis which may progress to bronchiectasis. While pulmonary fibrosis may develop as a sequelae to many of these lung injuries, it also may be the presenting finding. Among patients with CSS, asthma and eosinophilic infiltrates may be the main manifestations. In all these cases, superimposed infection is a major concern. Patients with WG may have varying degrees of subglottic and tracheal stenosis that must be considered in the airway management [53]. This is a lifethreatening complication that both patient and treating physicians may be unaware of until the narrowing is quite severe. The treatment of this problem is local glucocorticoid injection and tracheal dilation. Some patients require tracheostomy for management. Patients with WG entering the ICU should be questioned for signs and symptoms of subglottic/tracheal stenosis. Renal manifestations of ANCA-associated vasculitis also fall into several categories. The most pathognomonic lesion is pauci-immune focal, segmental, necrotizing glomerulonephritis [47,70]. This lesion is usually accompanied by crescent formation. When severe it causes subacute or acute renal failure. Interstitial nephritis commonly accompanies the glomerular lesions or can occur alone. Sometimes the main lesion may be in the medulla giving ‘‘medullary capillaritis.’’ Necrotizing arteritis may be found, but granulomatous lesions are rare in the kidney. Diagnosis of ANCA-associated vasculitis While various combinations of clinical findings raise suspicion of ANCAassociated vasculitis, clinical findings alone are rarely specific enough to secure a diagnosis and additional testing is needed. Routine laboratory tests can be quite helpful. Hematuria is relatively sensitive but not specific for vasculitis. The presence of red blood cell casts is a much more specific finding, but these are usually missed on routine laboratory urinalyses even if they are present. Erythrocyte sedimentation rates are very high in most patients, but a low or normal result does not exclude any form of vasculitis. Complement levels should be normal in the

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ANCA-associated vasculitidies, but are low in cryoglobulinemia, lupus-related vasculitis and post infectious forms of glomerulonephritis. ANCA There are two specific types of ANCA that have been associated with the spectrum of vasculitis described above: one directed against a neutrophil cytoplasmic serine proteinase called proteinase 3 (PR3) and the other directed against myeloperoxidase (MPO), another component of neutrophil granules [12,34,71]. Patients have one or the other of these two types of ANCA and virtually never both. There are two basic techniques for detecting these antibodies, indirect immunofluorescence and antigen-specific ELISA. By indirect immunofluorescence, antibodies to PR3 produce a cytoplasmic pattern of staining of neutrophils, while antibodies to MPO produce a perinuclear or nuclear pattern of staining. The difference in staining pattern is due to an artifact of fixation [24]. Unfortunately, other autoantibodies can also produce these patterns of staining and hence the specificity of immunofluorescence tests for vasculitis is poor [65]. Antigen specific ELISAs for detection of anti-PR3 and anti-MPO antibodies have a much higher specificity for this disease spectrum than does indirect immunofluorescence. However, the diagnostic specificity is even higher when indirect immunofluorescence tests are combined with antigen specific ELISAs. A recently completed meta-analysis of the sensitivity and specificity of tests for ANCA found the sensitivity of combined testing for C-ANCA with anti-PR3 antibodies or P-ANCA with anti-MPO antibodies to be 85.5% with a specificity of 98.6% for the presence of the disease spectrum described above [12]. In another recent study of patients with multiorgan system disease in ICUs, ANCA testing was extremely specific for the diagnosis of vasculitis [86]. Thus, if clinical findings are typical and a test for anti-PR3 ANCA together with C-ANCA or antiMPO antibodies together with P-ANCA is unequivocally positive, the findings are essentially diagnostic and may preclude the need for tissue biopsy [69]. However, if the clinical findings are atypical or the ANCA tests are equivocal, additional diagnostic studies may be needed. Bronchoscopy in the evaluation of ANCA-associated vasculitis The differential diagnosis for patchy or diffuse pulmonary infiltrates includes: alveolar hemorrhage, acute respiratory distress syndrome, widespread pneumonia, pulmonary edema, aspiration pneumonitis and others processes. However, the findings of bronchoscopy with bronchoalveolar lavage are distinctive in alveolar hemorrhage. When serial aspirations of lavage fluid become increasingly bloody, it indicates the alveoli as the source of the hemorrhage. Alternatively, hemosiderin-laden macrophages may be found in alveolar lavage specimens, suggesting more chronic hemorrhage [31]. Thus, bronchoscopy with alveolar lavage may support a diagnosis of alveolar hemorrhage and simultaneously help rule out other causes for pulmonary infiltrates, particularly infections. It is

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important to recognize that there are causes of lung hemorrhage other than vasculitis, such as pulmonary edema and thromboembolism, and there are types of vasculitis other than ANCA-associated vasculitis, such as anti-GBM disease and systemic lupus erythematosus, that can also cause alveolar hemorrhage.

Biopsies for the diagnosis of ANCA-associated vasculitis Compared to bronchoscopy, lung biopsy is more likely to help determine the etiology of alveolar hemorrhage [80,85]. Furthermore, biopsy may also show granulomatous changes by demonstrating the presence of giant cells and areas of necrosis bordered by palisading histiocytes, the pathognomonic features of WG. Transbronchial biopsies are of limited sensitivity and while open lung biopsies or video-assisted thoracoscopic biopsies have a higher sensitivity, they are also associated with a higher morbidity. Renal biopsies are highly sensitive for the lesion of pauci-immune focal and segemental necrotizing and crescentic glomerulonephritis when there is appreciable renal failure, but because the lesions are focal, the sensitivity is lower when renal function is normal. When the classic lesions are found, they can secure the diagnosis, but sometimes the interpretation of renal biopsies is difficult and pathognomonic lesions may not be present [71]. A critical situation where renal biopsy is needed is in the setting of rapidly progressive glomerulonephritis when ANCA-associated vasculitis and anti-glomerular basement membrane disease are possibilities and serologic assays for ANCA and anti-glomerular basement membrane antibodies are not rapidly available. Biopsies of other organs, including skin, nose, sinuses, nerves and meninges, may be helpful if discrete lesions are identified.

Treatment of ANCA-associated vasculitis The treatment for all of the ANCA-associated vasculitides is immunosuppression [30,39]. The major factor for successful treatment of ANCA-associated vasculitis is to start treatment early, before the development of respiratory failure from alveolar hemorrhage and before the development of renal failure from rapidly progressive glomerulonephritis. Thus, for a patient in the ICU with active vasculitis treatment cannot wait for serologies or biopsies and needs to be started immediately. If the diagnosis is not confirmed or if another explanation for the findings becomes apparent, the treatment can be stopped. High-dose glucocorticoids remain the cornerstone of immunosuppression for critically ill patients with vasculitis. Most centers will start treatment with daily intravenous pulses of 500 – 1000 mg of methylprednisolone for 3– 5 days. As the life threatening features subside, treatment is reduced to approximately 1 mg/kg of prednisone (or equivalent) daily. Most pulmonary hemorrhage stops within 3 –7 days of initiation of glucocorticoids, but on rare occasions, it may continue for up to 10 –14 days.

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Glucocorticoid therapy alone is not sufficient to properly treat and control ANCA-associated vasculitis [26]. The early use of a cytotoxic agent allows for more rapid tapering of glucocorticoids. While different agents are used for these diseases, cyclophosphamide is the one that has had the most widely demonstrable success for controlling this disease and is the currently established choice for use in patients with life-threatening disease. Most regimens call for using a relatively high dose initially to get the disease under control, followed by a lower dose to maintain the remission. For patients with completely normal renal function, we recommend using cyclophosphamide at a dose of 1 gm/m2 administered intravenously, either as a pulse or in divided doses over the first week of treatment. It is important to adjust doses of cyclophosphamide for renal failure. If the estimated creatinine clearance is less than 15% of normal, we use one-half the full dose; for 15– 40% of normal renal function, we use two-thirds of the full dose; and for 40– 70% of normal renal function, we use three-fourths the full dose. For patients receiving pulse intravenous cyclophosphamide, some centers administer mesna for prophylaxis against bladder toxicity. Mesna is given in a total dose equal to the cyclophosphamide dose, starting with the initiation of cylcophosphamide and continued in divided doses over the next 12 – 24 hours. After the first week, cyclophosphamide is continued at a dose designed to approximate the eventual maintenance dose. The standard dose is 2 mg/kg/d for patients with normal renal function and reduced doses based on the scale given above for those with impaired renal function. Because ANCA-associated vasculitides are associated with high relapse rates, immunosuppression must be continued for prolonged periods of time with careful follow up to titrate the immunosuppression so as to avoid toxicities of the treatment, such as neutropenia, as well as to ward off recurrent disease. We urge treatment for patients who appear to have end-stage renal disease with minimal extrarenal findings at presentation. The utility of treating patients whose kidney function appears permanently lost at presentation is frequently questioned. However, renal function often improves dramatically with treatment in the ANCA-associated vasculitides, so in the acute setting it is premature to forgo hope for renal recovery. Secondly, such patients remain at high risk for other manifestations of ANCA-associated vasculitis, including life-threatening alveolar hemorrhage that can be prevented by starting treatment. During the maintenance phase several other medications may be used as alternatives to cyclophosphamide. Azathioprine has been shown to be effective in maintaining remission in one large randomized trial [61] and several case series [1,17,43,45]. Methotrexate can be effective in many patients and may be used as initial therapy among patients without organ-threatening disease at presentation or for more limited disease flares [18,40,54,81,82]. Recent anecdotes and small case series suggest that mycophenolate mofetil may also be a useful agent [72]. The potential benefit of plasma exchange (plasmapheresis) for patients with life or organ threatening ANCA-positive vasculitis remains undefined. Because evidence of active disease usually stops completely within 7 –14 days with the glucocorticoid and cyclophosphamide induction regimen outlined above without

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plasma exchange, any potential benefit from plasma exchange would have to occur within the first few days. Plasma exchange has some theoretical benefit in that it can remove inflammatory mediators and ANCA, each of which might play a direct pathogenic role in the disease. Aggressive use of plasma exchange may make sense during the first few days of a patient’s treatment in the ICU [75]. This treatment is used extensively in some centers and not at all in others. A prospective randomized trial of the use of plasma exchange is needed to better define its optimum role. However, at the initiation of treatment, plasma exchange also needs to be a standard part of the therapy until anti-GBM disease is ruled out. Anti-GBM disease may be easily confused with ANCA-associated vasculitis and the two diseases may occur together. High dose intravenous immunoglobin (IVIG) (2 g/kg administered monthly) has been shown to have some beneficial effects among patients with ANCAassociated vasculitis. A sustained effect appears to be dependent on sustained usage [44,60,79]. Another adjunct to treatment that has been proposed is the use of inhibitors to tumor necrosis factor [83]. A large randomized controlled trial is currently under way to evaluate the efficacy of etanercept for the treatment of WG [84]. One of the early life-threatening complications of alveolar hemorrhage is superimposed pneumonia. We advocate the use of daily surveillance sputum cultures for all patients with alveolar hemorrhage in the ICU. Early antibiotic treatment of superimposed infectious processes in imperative. We use trimethoprim-sulfamethoxazole (or an appropriate alternative) for prophylaxis against Pneumocystis pneumonia (PCP) in all patients treated with immunosuppressive agents, especially in combination with glucocorticoids. PCP prophylaxis should be begun within 2 weeks of initiating immunosuppressive therapy. Anti-glomerular basement membrane antibody disease: Goodpasture’s syndrome Anti-glomerular basement membrane (anti-GBM) antibodies cause injury to the basement membranes in glomeruli and alveoli resulting in rapidly progressive glomerulonephritis and alveolar hemorrhage [55]. In approximately half of cases, there is renal involvement alone and in the other half, renal involvement occurs together with alveolar hemorrhage. In rare cases there may be prominent alveolar hemorrhage without appreciable renal injury. By the most widely used definition, the term ‘‘Goodpasture’s syndrome’’ is reserved for anti-GBM disease with both rapidly progressive glomerulonephritis and pulmonary hemorrhage. The incidence of alveolar hemorrhage appears to be much higher among patients who smoke as opposed to non-smokers [20]. Diagnosis of anti-GBM disease is dependent on the recognition of rapidly progressive glomerulonephritis, with or without pulmonary hemorrhage, together with appropriate tests for anti-GBM antibodies. Unfortunately, most patients with anti-GBM disease present with or progress to end-stage renal disease [56]. Among patients without pulmonary findings, the initial symptoms

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may be those of uremia from the renal failure. A high early suspicion of this very rare disease is necessary in order to improve the prognosis. If glomerulonephritis or pulmonary-renal syndrome is suspected, the finding of red cell casts in the urine greatly increases the probability of anti-GBM disease or ANCA-associated vasculitis. The antigen recognized by anti-GBM antibodies is the non-collagenous domain of the alpha 3 chain of type IV collagen [42,89]. With identification of this specific protein as the target antigen, highly specific assays have been developed for the detection of the antibodies. The most specific tests are Western blots using collagenase digests of glomerular basement membrane and antigen specific ELISAs using purified antigen [37,78]. Less specific tests such as indirect immunofluorescence looking for staining of the GBM, and assays using crude preparations of glomerular basement membrane should no longer be considered adequate for patient care. When specific tests for anti-GBM antibodies are not rapidly available, renal biopsy may be the only method for rapid diagnosis. The finding of deposition of immunoglobulin along the basement membrane by direct fluorescence examination of kidney sections, together with crescentic glomerulonephritis is the histologic standard for diagnosis. Treatment of anti-GBM disease consists of two parts: suppression of the production of the pathogenic antibodies and removal of the existing antibodies from the circulation. We initiate immunosuppression in the same manner for antiGBM disease as we do for ANCA-associated vasculitis. However, when antiGBM antibodies are present, their removal from the circulation is urgent. Therefore, we also start with daily plasma exchange when anti-GBM disease is suspected. If tests for anti-GBM antibodies come back negative, the plasma exchange is discontinued. However, if the antibodies are confirmed, we continue daily exchange until the antibody titer is brought down to the normal range as detected by available semiquantitative ELISAs. Typically, about 14 treatments of plasma exchange may be needed. Antibody levels must be monitored for the first several months, because there may be early rebounds in antibody titers. However, in contrast to ANCA-associated vasculitis, after 6 months there is almost never a rebound in anti-GBM disease and long-term immunosuppression is not needed. Combined ANCA and anti-GBM disease As mentioned earlier, ANCA disease may occur together with anti-GBM disease. Approximately 30 –40% of cases with anti-GBM antibodies also will have ANCA [37] A much smaller percentage of patients with ANCA-associated vasculitis will also have anti-GBM antibodies. Over two thirds of cases with antiGBM and ANCA will have anti-MPO antibodies while less than one third will have anti-PR3 antibodies. Because patients with pulmonary-renal syndrome may have either ANCA-associated vasculitis, anti-GBM disease or both, all such patients should be tested for both types of antibodies. Patients with both types of

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antibodies may have distinct features of both types of disease. The very high rate of ESRD found among patients with anti-GBM disease is also found in patients with both antibodies and relapses of vasculitis with recurrent rises in ANCA titer also occur. Treatment for combined anti-GBM/ANCA disease incorporates the therapy for both individual entities: aggressive plasma exchange, pulse glucocorticoids and cyclophosphamide, and long-term immunosuppression. Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is the autoimmune disease with perhaps the most varied clinical manifestations, including some that come to the attention of critical care physicians. Vasculitis in lupus is not uncommon and can result in a wide variety of clinical problems ranging from isolated skin lesions to severe multisystemic disease. The most acutely devastating problems in patients with SLE are pulmonary hemorrhage [10,22,63,66], nephritis [9], central nervous system (CNS) disease [27,49,88], and gastrointestinal ischemia [91]. Pulmonary hemorrhage in lupus may be the result of pulmonary emboli, triggered either by antiphospholipid antibodies or the nephrotic syndrome, or from pulmonary capillaritis with alveolar hemorrhage [22,66]. Alveolar hemorrhage from pulmonary capillaritis is rare, but can occur at any time in the course of the disease, often with rapid progression, and is associated with a high mortality rate, even if treated quickly. Alveolar hemorrhage usually occurs in association with other features of active lupus, in particular, active renal disease with rapidly progressive glomerulonephritis. The most serious form of lupus nephritis is that of diffuse proliferative glomerulonephritis, which is a form of rapidly progressive glomerulonephritis and can lead to acute and chronic renal failure [9] The typical clinical features of diffuse proliferative lupus nephritis are those of hypertension, edema, high grade proteinuria, microscopic hematuria and red cell casts with a rising creatinine. Most patients will already have other features of lupus and will carry a diagnosis of SLE. Virtually all patients will have positive tests for antinuclear antibodies (ANA) and most will have antibodies to anti-double stranded DNA and be hypocomplementemic. In patients on minimal or no immunosuppression, the renal findings may be explosive and aggressive treatment is required. CNS disease is one of the most feared and lethal complications of lupus and can result in rapid clinical decline and admission to an ICU [27,49,88]. Cognitive deterioration, psychosis, delirium, seizures, sensory and motor deficits, and coma with death are possible manifestations of CNS lupus. However, it is important to realize that SLE is associated with several different types of CNS disease, each with different pathophysiologies requiring different treatment approaches. It is not always possible to determine the exact cause of acute CNS deterioration in patients with lupus and infection must always be considered. ‘‘Lupus cerebritis’’ stems from perivascular inflammatory disease. The diagnosis is often one of exclusion. Transverse myelitis and aseptic meningitis are also seen in SLE. True CNS vasculitis in lupus is rare but can result in either focal or global impairment

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and requires angiography or biopsy for confirmation. Involvement of both small and medium cerebral vessels can be involved and may not be detectable by standard angiography. Patients with lupus are at risk for mesenteric ischemia and vasculitis with subsequent intestinal, splenic, or hepatic infarction [91]. Intestinal vasculitis in lupus can be an insidious problem with early symptoms of dyspepsia or mild abdominal pains often ignored by patient and clinician alike. Furthermore, GI vasculitis is extremely difficult to diagnosis in its early stages. By the time changes in bowel wall or mucosa are present, infarction may have already occurred. Angiography is almost always non-diagnostic because of the small size of the vessels involved. Mortality from intestinal vasculitis in lupus is extremely high due to intestinal infarction, viscous rupture, peritonitis and subsequent sepsis. Surgery is often necessary and the excised tissue may provide the first evidence of vasculitis. The incidence of antiphospholipid antibody syndrome (APS) is significantly increased among patients with lupus [36,59,73]. APS can cause venous or arterial thromboses and result in significant pulmonary, central nervous system, or other complications. The ‘‘catastrophic antiphospholipid syndrome’’ refers to a rare presentation of multisystem microthrombi that can include acute renal failure, stroke, or mesenteric ischemia [4,5]. Microthrombotic renal disease is an increasingly recognized complication of SLE and it may be necessary to perform a renal biopsy to differentiate it from glomerulonephritis. Immunosuppressive therapy is commonly associated with serious infections among patients with SLE and can lead to admission to an ICU. Differentiating active SLE from infection can be extremely difficult and the two conditions often coexist. Many patients with SLE are already taking glucocorticoids that may mask fever or other signs of infection. Thus, in patients with lupus and critical illness, infection must be searched for thoroughly. In settings where an underlying diagnosis of SLE has yet to be established, serologies are useful in helping to determine a diagnosis. Assays for ANA are extremely useful screening tests for the diagnosis of SLE. The sensitivity of ANA in SLE in greater than 95% and it is highly unlikely that a patient would have SLE with vasculitic complications and be ANA-negative. However, the specificity of ANA positivity for SLE is not high. Many drugs are associated with positive ANA in the absence of drug-induced lupus syndrome. Furthermore, the rate of false positive ANA in the general population is high enough to warrant skepticism when interpreting results. Nevertheless, the presence of a positive ANA in the right clinical setting can be very helpful in establishing a new diagnosis of SLE. Furthermore, the higher the titer, the more likely the ANA is a true-positive for an autoimmune disease. Similarly, in the correct clinical setting, patients with positive tests for anti-Smith or antibodies to double-stranded DNA (anti-dsDNA), two highly specific (but not sensitive) tests for SLE, mostly likely have lupus. Hypocomplementemia is common in SLE, especially in patients with active glomerulonephritis, but is also only supporting evidence and not diagnostic its their own.

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Treatment of severe pathology in SLE is based on high doses of glucocorticoids often in combination with other immunosuppressive drugs, especially cyclophosphamide. As with other forms of vasculitis, the rapid introduction of glucocorticoids is imperative for short-term stabilization and improvement in the ICU. Cytotoxic agents must be started early because their effect is delayed by several weeks. Pulse doses of cyclophosphamide together with glucocorticoids are the mainstay of therapy for lupus nephritis [6]. Newer regimens with less toxic therapies have been proposed including a recent trial of mycophenolate mofetil [11].

Cryoglobulinemic vasculitis The prevalence of cryoglobulinemic vasculitis (CV) is rapidly increasing in association with the spread of hepatitis C viral infection throughout the world [2,52]. Critical care physicians need to be aware of CV as either a primary cause of admission to an ICU or a secondary problem for critically ill patients. The majority of cases of CV are now known to be caused by hepatitis C virus infection (previously referred to as essential mixed cryoglobulinemia). CV can also occur in association with myeloproliferative diseases, connective tissue diseases, and other infections including human immunodeficiency virus. There are still some cases with an unknown etiology. This section will focus on hepatitis C virus-related CV. CV is an immune complex-mediated vasculitis that preferentially affects small vessels. CV is characterized by the presence of cryoglobulins, which are coldprecipitable monoclonal or polyclonal immunoglobulins. Common clinical features of CV are purpura, arthritis/arthralgia, weakness, peripheral neuropathy, and renal disease. Renal manifestations from CV range from nephrotic syndrome with preserved renal function to smouldering hematuria to rapidly progressive glomerulonephritis. Other less common presentations include Raynaud’s phenomenon, Sjogren’s syndrome, CNS involvement, gastrointestinal manifestations, pulmonary lesions [21], and even pulmonary renal syndrome [52]. When CV is suspected, serum should be tested for the presence of cryoglobulins. In searching for cryoglobulins, it is critical to draw the blood and immediately transport the specimen at 37C to the laboratory where the sample is allowed to clot for 2 hours at 37C. The serum is then incubated at 4C for several days and a quantitative measure of the cryoprecipitate is determined (‘‘cryocrit’’) [52]. Any deviation from this strict protocol will invalidate the test as it can lead to false-negative results because of trapping of cryoglobulins in the clot. Other laboratory clues for CV include elevated serum gammaglobulins, positive rheumatoid factor, and severe hypocomplementemia (especially C4). However, none of these latter tests replace proper testing for cryoglobulins. As the diagnosis of CV is established, analysis of the cryoglobulin components helps elucidate the underlying etiology. Virtually all patients with CV should be screened for hepatitis C infection, even those with normal liver

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enzymes [19]. Evaluation for an underlying connective tissue disorder, malignancy, or other infection will depend on the clinical presentation and type of cryoglobulins identified. There is no consensus on how to treat either acute or chronic CV with few clinical trials to guide decisions. Many centers utilize a combination of high-dose glucocorticoids, immunosuppressive agents (especially cyclophosphamide) and plasmapheresis to treat an acute flare of disease. The chronic treatment of CV increasingly involves treatment of hepatitis C infection, even if liver disease is absent. The rare cases of CV not associated with hepatitis C virus may require different therapies. Large-vessel vasculitis Large-vessel vasculitis refers to the vasculitis of aorta and its major branches. Vessel narrowing or aneurysm formation may cause ischemic end-organ damage, aortic regurgitation, arterial dissection, rupture, and death. Giant cell arteritis (GCA) [23,57,58] and Takayasu’s arteritis [51] are most common forms of largevessel vasculitis. The aorta is rarely involved in other vasculitides. Clinical manifestations of large-vessel vasculitis GCA almost exclusively affects individuals over 50 years of age, while Takayasu’s seldom starts after the age of 40 years. However, there is often a long delay in diagnosing Takayasu’s and thus these age criteria refer to the age at disease onset. GCA is most commonly recognized when the classic cranial presentation of headaches, jaw claudication, scalp tenderness, or visual impairment occurs in a patient with an elevated erythrocyte sedimentation rate (ESR). Irreversible monocular blindness is the most feared complication of GCA. Many patients also have polymyalgia rheumatica, constitutional symptoms, and anemia. However, so-called ‘‘large-vessel GCA’’ involves the aorta and its branches with vascular insufficiency findings or limb claudication, arterial bruits, decreased or absent pulses and blood pressure [8]. Diagnosis is confirmed by temporal artery biopsy with findings of intraarterial inflammation, necrosis and sometimes giant cells. Bilateral biopsies increase the diagnostic yield. The sensitivity of temporal artery biopsy is lower in those presenting with large-vessel GCA alone than those with classic cranial GCA [8]. Aortitis and its complications can also occur without known systemic diseases and may be an unexpected finding in pathology specimens from patients undergoing repairs of aortic aneurysms or dissections [76]. Takayasu’s arteritis primarily affects large-vessels causing limb claudication and cerebral ischemia. Potential critical care issues in patients with TA include dissecting aortic aneurysm; malignant hypertension due to renal artery stenosis; visual disturbance, transient ischemic attacks, and cerebrovascular accidents due to carotid or vertebral artery involvement; and critical limb ischemia [51]. Coronary artery disease and aortic regurgitation resulting from a dilated aortic root are

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the most common cardiac findings. Death may occur from cardiac failure, myocardial infarction, stroke, aneurysmal rupture, and renal failure. Because biopsy of the aorta and large arteries is dangerous, diagnosis of Takayasu’s is usually confirmed by angiography. Acute phase reactants (ESR, C-reactive protein and others) are not always reliable indicators of disease activity, especially in Takayasu’s arteritis. Angiography for diagnosis of large-vessel vasculitis In the evaluation of patients with medium to large-vessel vasculitis, angiography can provide confirmation of the suspected diagnosis as well as determination of the distribution and severity of disease process. When a tissue biopsy of involved vessels is not available or not possible with an acceptable safely level, angiographic findings often must substitute for a histologic diagnosis. This is particularly true for Takayasu’s arteritis as well as mesenteric and renal vasculitis in polyarteritis nodosa. In contrast, angiography is not usually useful in the evaluation for small-vessel vasculitis as the level of resolution of the study does not include smaller arteries. A negative angiogram may be misleading in the evaluation of small-vessel disease. Angiographic findings often are not specific for vasculitis. Individual arterial lesions of luminal irregularity, stenosis, occlusion, and aneurysm are often found with disease processes that involve arteries, including atherosclerotic lesions or vasospasm. Therefore, evaluation of the specific characteristics of these lesions, their locations, and distribution forms a constellation of angiographic findings that in the correct clinical context leads to the diagnosis of vasculitis. Because critically ill patients commonly have renal insufficiency, the increased risk of angiographic contrast dye should be considered in making the decision to pursue angiography. Selective angiography for specific target organs should be utilized whenever possible to minimize dye load. Magnetic resonance imaging for large-vessel vasculitis Recently, noninvasive magnetic resonance imaging (MRI) methods, such as magnetic resonance angiography (MRA), have become increasingly useful for evaluation of medium to large vessel vasculitis [3,35,48,67,90]. Advantages of MRI /MRA over conventional angiography include lack of invasive procedures, avoidance of nephrotoxic contrast dye load, and absence of ionizing radiation. MRI /MRA provides detailed information for detecting arterial stenoses, occlusions, dilatations, and aneurysms [74,90]. Increasingly, MR imaging is being used to detect mural edema (inflammation) for vasculitis disease activity assessment in Takayasu’s arteritis [29] and other large-vessel arteritides. MRI /MRI may be a useful method of following patients serially to detect new lesions and monitor response to treatment. It is important to recognize that using MRI / MRA for diagnosing and managing patients with vasculitis is a new and evolving clinical practice. This

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technology is certainly not perfected for use in vasculitis and it has not replaced conventional angiography as the gold standard for vascular imaging. Furthermore, the technology is evolving rapidly and many medical centers do have MRI machines capable of the more advanced techniques described. Treatment of large-vessel vasculitis Treatment of large-vessel vasculitis almost always involves high-dose glucocorticoids. For GCA, glucocorticoid therapy alone is usually sufficient. The use of adjunctive immunosuppressive agents has yielded conflicting results. GCA responds extremely well to glucocorticoids, thus the major challenge facing clinicians is management of complications of therapy. Monocular blindness, the most feared complication of GCA is rarely reversible. Treatment of Takayasu’s also centers on glucocorticoids but early institution of cytotoxic drugs including methotrexate or cyclophosphamide are increasingly advocated [38,41,50]. Arterial monitoring and procedures Patients with large-vessel vasculitis can pose challenges in the ICU when procedures involving arterial catheters are necessary. Invasive arterial blood pressure monitoring can be complicated by limb ischemia in patients with large-vessel vasculitis. Blood pressure readings obtained either by cuff methods or intra-arterially may be falsely low in a patient with a severe arterial stenosis. Similarly, intraarterial procedures, including diagnostic angiography, cardiac catheterization, and intraaortic balloon pumps may also all be complicated by stenoses associated with large-vessel vasculitis.

Churg-Strauss syndrome Churg-Strauss syndrome (CSS), also known as allergic granulomatosis and angiitis is usually categorized as a variant of the ANCA-associated vasculitides [33]. It involves the combination of asthma and eosinophilia ( >1500/mm3) together with small or medium vessel vasculitis. Most patients with CSS have history of asthma and then months to years later develop signs and symptoms of the full syndrome including hypereosinophilia, and some combination of pulmonary infiltrates, sinusitis, purpura, mononeuritis multiplex, carditis, gastrointestinal ischemia, and systemic symptoms. Compared to patients with WG or MPA fewer patients with CSS will be positive for ANCA. Treatment of CSS is based on the use of glucocorticoids. Additional immunosuppressive agents reserved for patients with multiple serious manifestations or inability to be tapered off of glucocorticoids. It is, however, important to avoid over-treatment of the bronchospastic disease of CSS and not treat all asthma flares as recurrences of the vasculitis itself. Similarly, while the total blood eosinophil count is a useful marker of disease activity in many patients, this lab result itself should not be the main focus of treatment.

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Drug-induced vasculitis Drug-induced vasculitis (DIV) is likely the most common of the vasculitides seen in patients in ICUs. The list of agents that are suspected to cause vasculitis is extensive and reviewed elsewhere [64]. While skin vasculitis with purpura is the most common manifestation of DIV, virtually any organ can be involved. Patients in ICUs are often exposed to multiple different pharmaceutical agents making identification of a causative agent difficult. There is also a growing understanding and appreciation that some cases of ANCA-associated vasculitis may be druginduced [13]. DIV must be considered in all cases of suspected or proven vasculitis, especially since withdrawal of a causative agent is central to therapy. It is imperative that clinicians determine what drugs patients have been exposed to including prescription, illegal, over the counter, herbal, or ‘‘alternative’’ agents. It is necessary to seek drug information going back at least 6 months from clinical presentation in patients with suspected vasculitis. It is essential that even if drug exposure is thought the likely cause of vasculitis, clinicians continue to survey their patients for signs and symptoms of another definable vasculitis syndrome.

Other vasculitides There are several other types of vasculitis that may involve manifestations requiring admission to an intensive care unit. These other vasculitides are even more rare than those described above and will not be detailed in this article. These entities include polyarteritis nodosa, Behcet’s disease, rheumatoid vasculitis, relapsing polychondritis, Cogan’s syndrome, moyamoya, isolated vasculitis of the CNS, and others. These disorders can be devastating and lifethreatening and have many manifestations similar to those described for the more common vasculitides.

Mimickers of vasculitis in the ICU Many medical conditions have clinical manifestations that mimic systemic inflammatory vasculitis. These mimickers will not be discussed here in detail but must be considered in all potential cases of vasculitis as these entities are more common than idiopathic inflammatory vasculitides and the treatments for them are markedly different than for vasculitis. Thromboses of vessels of any size, especially arterial thromboses, are common mimickers of vasculitis. Embolic disease of any sort can mimic vasculitis as the embolic material disperses diffusely into small vessels. Cholesterol emboli syndrome, especially following arterial catheterization, commonly presents with cutaneous lesions and renal disease. Similarly, fat emboli or tumor emboli may mimic vasculitis. A variety of other non-vasculitic disorders or clinical states may also mimic the pulmonary-renal syndromes such as lung infections with acute tubular necrosis, congestive heart failure with renal hypoperfusion, or volume overload with renal

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failure. Malignancies may also mimic vasculitis, especially primary skin tumors (e.g., Kaposi’s sarcoma) and hematologic malignancies. Many infections initially present with skin lesions and systemic symptoms suggestive of vasculitis. Infections commonly presenting in this manner include chronic bacteremia, Neisserial infections, and various viral entities. It is imperative that these and other non-vasculitis disorders always be considered and screened for in any patient for whom vasculitis is a diagnostic possibility.

Summary The systemic vasculitides, if left untreated, often lead to major organ damage and death. When a patient presents with features that may be consistent with vasculitis, especially with pulmonary and renal findings, it is important to make a specific diagnosis as quickly as possible so that specific therapy can be started. Diagnosis is dependent on familiarity with the myriad of typical and unusual clinical features of the various vasculitides together with performance of supportive tests including serologies, angiograms, and biopsies. When evaluating a potential case of vasculitis, clinicians must comprehensively search for other more common, non-vasculitic diseases. The diagnosis may be even more difficult in patients with established diagnoses of vasculitis on immunosuppressive treatment who develop new clinical findings. Rapid initiation of immunosuppressive therapy for critically ill patients with vasculitis is crucial and may be life-saving. References [1] Adu D, Pall A, Luqmani RA, Richards NT, Howie AJ, Emery P, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM 1997;90:401 – 9. [2] Agnello V, Romain PL. Mixed cryoglobulinemia secondary to hepatitis C virus infection. Rheum Dis Clin North Am 1996;22:1 – 21. [3] Anders HJ, Sigl T, Sander A, Coppenrath E, Pfluger T, Kellner H. Gadolinium contrast magnetic resonance imaging of the temporal artery in giant cell arteritis. J Rheumatol 1999;26: 2287 – 8. [4] Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992;19:508 – 12. [5] Asherson RA, Cervera R, Piette JC, Font J, Lie JT, Burcoglu A, et al. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998;77: 195 – 207. [6] Austin HA, Balow JE. Treatment of lupus nephritis. Semin Nephrol 2000;20:265 – 76. [7] Bloch DA, Michel BA, Hunder GG, McShane DJ, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Patients and methods. Arthritis Rheum 1990;33:1068 – 73. [8] Brack A, Martinez-Taboada V, Stanson A, Goronzy JJ, Weyand CM. Disease pattern in cranial and large-vessel giant cell arteritis. Arthritis Rheum 1999;42:311 – 7. [9] Cameron JS. Lupus nephritis: an historical perspective 1968 – 1998. J Nephrol 1999;12 (Suppl 2): S29 – 41. [10] Carette S. Cardiopulmonary manifestations of systemic lupus erythematous. Rheum Dis Clin North Am 1988;14:135 – 47. [11] Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil

P.A. Merkel et al. / Crit Care Clin 18 (2002) 321–344

[12]

[13]

[14]

[15] [16] [17]

[18]

[19] [20] [21] [22] [23] [24]

[25] [26] [27]

[28]

[29] [30]

[31] [32] [33]

341

in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343:1156 – 62. Choi HK, Liu S, Merkel PA, Colditz GA, Niles JL. Diagnostic performance of antineutrophil cytoplasmic antibody tests for idiopathic vasculitides: metaanalysis with a focus on antimyeloperoxidase antibodies. J Rheumatol 2001;28:1584 – 90. Choi HK, Merkel PA, Walker AM, Niles JL. Drug-associated ANCA-positive vasculitis: Prevalence among patients with high titers of anti-myeloperoxidase antibodies. Arthritis Rheum 2000;43:405 – 13. Cohen Tervaert JW, Goldschmeding R, Elema JD, van der Giessen M, Huitema MG, van der Hem GK, The TH, von dem Borne AE, Kallenberg CG. Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int 1990;37:799 – 806. Cohen Tervaert JW, Goldschmeding R, Elema JD, von dem Borne AE, Kallenberg CG. Antimyeloperoxidase antibodies in the Churg-Strauss syndrome. Thorax 1991;46:70 – 1. Cohen Tervaert JW, Kallenberg CG. Anti-myeloperoxidase antibodies in Churg-Strauss syndrome. [letter; comment] J Neurol 1993;240:449 – 50. Cole E, Cattran D, Magil A, Greenwood C, Churchill D, Sutton D, et al. A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis 1992;20:261 – 9. de Groot K, Reinhold-Keller E, Tatsis E, Paulsen J, Heller M, Nolle B, et al. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’s granulomatosis. Methotrexate versus trimethoprim /sulfamethoxazole. Arthritis Rheum 1996;39:2052 – 61. Di Bisceglie AM. Hepatitis C. Lancet 1998;351:351 – 5. Donaghy M, Rees AJ. Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet 1983;2:1390 – 3. Dweik RA, Arroliga AC, Cash JM. Alveolar hemorrhage in patients with rheumatic disease. Rheum Dis Clin North Am 1997;23:395 – 401. Eagen JW, Memoli VA, Roberts JL, Matthew GR, Schwartz MM, Lewis EJ. Pulmonary hemorrhage in systemic lupus erythematosus. Medicine (Baltimore) 1978;57:545 – 60. Evans JM, Hunder GG. Polymyalgia rheumatica and giant cell arteritis. Rheum Dis Clin North Am 2000;26:493 – 515. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988;318:1651 – 7. Falk RJ, Jennette JC. ANCA small-vessel vasculitis. J Am Soc Nephrol 1997;8:314 – 22. Fauci AS, Haynes B, Katz P. The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic considerations. Ann Intern Med 1978;89:660 – 76. Feinglass EJ, Arnett FC, Dorsch CA, Zizic TM, Stevens MB. Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine (Baltimore) 1976;55:323 – 39. Fienberg R, Mark EJ, Goodman M, McCluskey RT, Niles JL. Correlation of anti-neutrophil cytoplasmic antibodies with the extra-renal histopathology of Wegener’s (pathergic) granulomatosis and related forms of vasculitis. Hum Pathol 1993;24:160 – 8. Flamm SD, White RD, Hoffman GS. The clinical application of ‘‘edema-weighted’’ magnetic resonance imaging in the assessment of Takayasu’s arteritis. Int J Cardiol 1998;66:S151 – 9. Gayraud M, Guillevin L, le Toumelin P, Cohen P, Lhote F, Casassus P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001;44:666 – 75. Green RJ, Ruoss SJ, Kraft SA, Berry GJ, Raffin TA. Pulmonary capillaritis and alveolar hemorrhage: update on diagnosis and management. Chest 1996;110:1305 – 16. Gross WL. Antineutrophil cytoplasmic autoantibody testing in vasculitis. Rheum Dis Clin North Am 1995;21:987 – 1011. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 1999;78:26 – 37.

342

P.A. Merkel et al. / Crit Care Clin 18 (2002) 321–344

[34] Hagen EC, Daha MR, Hermans J, Andrassy K, Csernok E, Gaskin G, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization. [see comments] Kidney Int 1998;53: 743 – 53. [35] Harada S, Mitsunobu F, Kodama F, Hosaki Y, Mifune T, Tsugeno H, et al. Giant cell arteritis associated with rheumatoid arthritis monitored by magnetic resonance angiography. Intern Med 1999;38:675 – 8. [36] Harris EN. The antiphospholipid syndrome. Diagnosis, management, and pathogenesis. [Review] Clin Rev Allergy Immunol 1995;13:39 – 48. [37] Hellmark T, Niles JL, Collins AB, McCluskey RT, Brunmark C. Comparison of anti-GBM antibodies in sera with or without ANCA. J Am Soc Nephrol 1997;8:376 – 85. [38] Hoffman G, Cid M, Hellmann D, Merkel P, Guillevin L, Dickler H, et al. A multicenter placebocontrolled study of methotrexate (MTX) in giant cell artertitis (GCA) [abstract]. Arthritis and Rheumatism 2000;43. [39] Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488 – 98. [40] Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatment of Wegener’s granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322 – 9. [41] Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994;37: 578 – 82. [42] Hudson BG, Wieslander J, Wisdom Jr BJ, Noelken ME. Goodpasture syndrome: molecular architecture and function of basement membrane antigen. Lab Invest 1989;61:256 – 69. [43] Jayne D. Update on the European Vasculitis Study Group trials. Curr Opin Rheumatol 2001;13:48 – 55. [44] Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000;93: 433 – 9. [45] Jayne DR, Gaskin G, Pusey CD, Lockwood CM. ANCA and predicting relapse in systemic vasculitis. QJM 1995;88:127 – 33. [46] Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitis, proposal of an international conference. Arthritis Rheum 1994;37:187 – 92. [47] Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol 1989;135:921 – 30. [48] Joelson E, Ruthrauff B, Ali F, Lindeman N, Sharp FR. Multifocal dural enhancement associated with temporal arteritis. Arch Neurol 2000;57:119 – 22. [49] Johnson RT, Richardson EP. The neurological manifestations of systemic lupus erythematosus. Medicine (Baltimore) 1968;47:337 – 69. [50] Jover JA, Hernandez-Garcia C, Morado IC, Vargas E, Banares A, Fernandez-Gutierrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134:106 – 14. [51] Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al. Takayasu arteritis. Ann Intern Med 1994;120:919 – 29. [52] Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum 1999;42: 2507 – 16. [53] Langford CA, Sneller MC, Hallahan CW, Hoffman GS, Kammerer WA, Talar-Williams C, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum 1996;39:1754 – 60. [54] Langford CA, Sneller MC, Hoffman GS. Methotrexate use in systemic vasculitis. Rheum Dis Clin North Am 1997;23:841 – 53. [55] Lerner RA, Glassock RJ, Dixon FJ. The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 1967;126:989 – 1004. [56] Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement

P.A. Merkel et al. / Crit Care Clin 18 (2002) 321–344

[57]

[58] [59] [60] [61]

[62] [63]

[64] [65]

[66]

[67] [68] [69] [70]

[71]

[72]

[73]

[74] [75] [76] [77]

343

membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033 – 42. Lie JT. Illustrated histopathologic classification criteria for selected vasculitis syndromes. American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum 1990;33:1074 – 87. Lie JT. Aortic and extracranial large vessel giant cell arteritis: a review of 72 cases with histopathologic documentation. Semin Arthritis Rheum 1995;24:422 – 31. Lockshin MD. Antiphospholipid antibody syndrome. Rheum Dis Clin North Am 1994;20: 45 – 59. Lockwood CM. New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy. Clin Exp Immunol 1996;104:77 – 82. Luqmani R, Jayne D. Group. EVS: a multi-centre randmised trial of cyclophosphamide versus azathioprine during remission in ANCA-associated systemic vasculitis (CYCAZEREM). [abstract] Arthritis Rheum 1999;42:S225. Matthay RA, Bromberg SI, Putman CE. Pulmonary renal syndromes — a review. Yale J Biol Med 1980;53:497 – 523. Matthay RA, Schwarz MI, Petty TL, Stanford RE, Gupta RC, Sahn SA, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore) 1975;54:397 – 409. Merkel PA. Drug-induced vasculitis. Rheumatic disease clinics of North America, 2001;27: 849 – 62. Merkel PA, Polisson RP, Chang Y, Skates SJ, Niles JL. Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med 1997;126:866 – 73. Mintz G, Galindo LF, Fernandez-Diez J, Jimenez FJ, Robles-Saavedra E, Enriquez-Casillas RD. Acute massive pulmonary hemorrhage in systemic lupus erythematosus. J Rheumatol 1978;5: 39 – 50. Mitomo T, Funyu T, Takahashi Y, Murakami K, Koyama K, Kamio K. Giant cell arteritis and magnetic resonance angiography. Arthritis Rheum 1998;41:1702. Niles JL. Antineutrophil cytoplasmic autoantibodies in the classification of vasculitis. Ann Rev Med 1996;47:303 – 13. Niles JL. A renal biopsy is essential for the management of ANCA-positive patients with glomerulonephritis: the contra-view. Sarcoidosis 1996;13:232 – 34. Niles JL, Pan G, Collins AB, Shannon T, Skates S, Fienberg R, et al. Value of antigen-specific radioimmunoassays for measuring anti-neutrophil cytoplasmic antibodies (ANCA) in the differential diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 1991;2:27 – 36. Niles JL, Pan GL, Collins AB, Shannon T, Skates S, Fienberg R, et al. Antigen-specific radioimmunoassays for anti-neutrophil cytoplasmic antibodies in the diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol 1991;2:27 – 36. Nowack R, Gobel U, Klooker P, Hergesell O, Andrassy K, van der Woude FJ. Mycophenolate mofetil for maintenance therapy of Wegener’s granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol 1999;10:1965 – 71. Petri M, Rheinschmidt M, Whiting OKQ, Hellmann D, Corash L. The frequency of lupus anticoagulant in systemic lupus erythematosus. A study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987;106:524 – 31. Prince MR. Gadolinium-enhanced MR aortography. Radiology 1994;191:155 – 64. Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CM. Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int 1991;40:757 – 63. Rojo-Leyva F, Ratliff NB, Cosgrove DM, Hoffman GS. Study of 52 patients with idiopathic aortitis from a cohort of 1,204 surgical cases. Arthritis Rheum 2000;43:901 – 7. Savage CO, Harper L, Adu D. Primary systemic vasculitis. [see comments] Lancet 1997;349: 553 – 8.

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P.A. Merkel et al. / Crit Care Clin 18 (2002) 321–344

[78] Saxena R, Isaksson B, Bygren P, Wieslander J. A rapid assay for circulating anti-glomerular basement membrane antibodies in Goodpasture syndrome. J Immunol Methods 1989;118:73 – 8. [79] Schmitt WH, Gross WL. Vasculitis in the seriously ill patient: diagnostic approaches and therapeutic options in ANCA-associated vasculitis. Kidney Int Suppl 1998;64:S39 – 44. [80] Schnabel A, Holl-Ulrich K, Dalhoff K, Reuter M, Gross WL. Efficacy of transbronchial biopsy in pulmonary vaculitides. Eur Respir J 1997;10:2738 – 43. [81] Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, Hallahan CW, Fauci AS. An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995;38:608 – 13. [82] Stone JH, Tun W, Hellman DB. Treatment of non-life threatening Wegener’s granulomatosis with methotrexate and daily prednisone as the initial therapy of choice. J Rheumatol 1999;25: 1134 – 9. [83] Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs NM, Hoffman GS. Etanercept combined with conventional treatment in Wegener’s granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum 2001;44:1149 – 54. [84] The WGET Research Group. Design Of The Wegener’s Granulomatosis Etanercept Trial (WGET). Controlled Clinical Trials (in press). [85] Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci AS. Surgical pathology of the lung in Wegener’s granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol 1991;15:315 – 33. [86] Vassilopoulos D, Niles JL, Villa-Forte A, Arroliga AC, Sullivan EJ, Merkel PA, et al. Prevalence of antineutrophil cytoplasmic antibodies in patients with various pulmonary diseases or multiorgan dysfunction (submitted). [87] Walton EW. Giant-cell granuloma of the respiratory tract (Wegener’s granulomatosis). BMJ 1958; 2:265 – 70. [88] Warren RW, Kredich DW. Transverse myelitis and acute central nervous system manifestations of systemic lupus erythematosus. Arthritis Rheum 1984;27:1058 – 60. [89] Wieslander J, Barr JF, Butkowski RJ, Edwards SJ, Bygren P, Heinegard D, et al. Goodpasture antigen of the glomerular basement membrane: localization to noncollagenous regions of type IV collagen. Proc Natl Acad Sci USA 1984;81:3838 – 42. [90] Yamada I, Nakagawa T, Himeno Y, Kobayashi Y, Numano F, Shibuya H. Takayasu arteritis: diagnosis with breath-hold contrast-enhanced three-dimensional MR angiography. J Magn Reson Imaging 2000;11:481 – 7. [91] Zizic TM, Shulman LE, Stevens MB. Colonic perforations in systemic lupus erythematosus. Medicine (Baltimore) 1975;54:411 – 26.