Author's Accepted Manuscript
Polyarteritis Nodosa Travis Howard MD, Kinza Ahmad BS, Jerome (Allen) A. Swanson MD, Sanjay Misra MD
PII: DOI: Reference:
S1089-2516(14)00061-4 http://dx.doi.org/10.1053/j.tvir.2014.11.005 YTVIR429
To appear in: Tech Vasc Interventional Rad
Cite this article as: Travis Howard MD, Kinza Ahmad BS, Jerome (Allen) A. Swanson MD, Sanjay Misra MD, Polyarteritis Nodosa, Tech Vasc Interventional Rad , http://dx.doi.org/10.1053/j.tvir.2014.11.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Travis Howard, MD, Kinza Ahmad, BS, Jerome (Allen) A. Swanson, MD, Sanjay Misra MD
Correspondence: Sanjay Misra, MD, FSIR, FAHA Professor of Radiology Mayo Clinic Department of Radiology Rochester, MN 55905 Tel: 507-293-3793 Fax: 503 494 4324 Email: [email protected]
The first description of polyarteritis nodosa (PAN) was in 1852 by Karl Rokitansky, a Pathologist at the University of Vienna.(1) The initial report describes a 23 year-old man who had a five-day history of fever and diarrhea. Since then, the definition of PAN has evolved. The currently accepted definition of PAN comes from the 2012 Chapel Hill Conference which classified PAN as a necrotizing arteritis not associated with anti-neutrophil cytoplasmic antibodies (ANCAs) of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules.(2)
The requirement for negative ANCAs in PAN is a useful new change that allows for discrimination between PAN and ANCA-associated vasculitides which otherwise have similar presentations pathologically and clinically. PAN can solely involve a single organ or present systemically. It may affect any organ, but for unknown reasons it spares the pulmonary and glomerular arteries. PAN can be idiopathic, or it can be associated with an infectious etiology such as Hepatitis B virus (HBV). PAN has been associated with various infectious viruses including HBV and human immunodeficiency virus (HIV), and the prevalence of infectionassociated PAN is related to the prevalence of the infections themselves.(2) For example, with the development of a vaccine for HBV vaccine, the percentage of PAN patients with HBV has decreased from 36% to less than 5%.(3, 4) In European countries, the incidence of PAN ranges from 0 to 1.6 cases/million and the prevalence is about 31 cases/million.(5) The mean age of patients at diagnosis is 51 years and males are more frequently involved although people of any age, gender, and ethnicity can be affected. (5) Angiography remains the gold standard for imaging diagnosis.
Clinical evaluation of the patient - physical exam, history, labs, and treatment.
The typical presentation of PAN involves the skin or peripheral nerves.(5) The skin can be involved and exhibit a range of lesions including purpura, livedoid, subcutaneous nodules, and necrotic ulcers. The main neurological manifestation is mononeuritis multiplex, which can present with wrist or foot drop, etc. Subacute presentation consists of vague symptoms including
fever, weight loss, malaise, headache, and myalgia. The spectrum of disease ranges from involving a single organ to polyvisceral failure.
Patients with involvement of the kidneys typically present with hypertension, renal insufficiency, or renal failure. Renal hemorrhage may also present with spontaneous subcapsular and perirenal hemorrhage. With acute renal hemorrhage, patients may represent with Wunderlich syndrome: acute flank pain, flank mass, and hypovolemic shock.(6) Gastrointestinal symptoms consist of ischemia, infarction, abdominal pain, weight loss, bowel perforation, hemorrhage, pancreatitis, appendicitis, and cholecystitis. Brain, eyes, pancreas, lungs, testicles, ureters, breasts, and ovaries are rarely involved. Five year survival for untreated polyarteritis nodosa is 13 percent.(7, 8) The outcome of PAN has improved in patients receiving treatment; five-year survival is approximately 80 percent.(9) The survival rates for patients with hepatitis B virus (HBV)-associated PAN is lower than for patients with non-HBV-associated disease. With fulminant or polyvisceral disease 5-year survival rate is less than 15%. Relapse occurs in 40% of patients with a median survival of 33 months. Fifty percent of patients with abdominal involvement develop acute surgical abdomen with mortality rate of 12.5%.
The French Vasculitis Study Group (FVSG) has established a large, well-characterized longitudinal cohort of patients with PAN and reported a comprehensive series of studies on the natural history and treatment of this disorder. In 1996, using regression analytical techniques, this group derived the “Five Factor Score” (FFS) as a simple prognostic tool for clinicians to use when evaluating patients with various forms of vasculitis, including PAN.(10, 11) The FFS was revised in 2011 based upon additional data and for PAN now only includes four factors
associated with increased mortality: i) age >65 years, ii) cardiac symptoms, iii) gastrointestinal involvement, and iv) renal insufficiency (plasma creatinine >1.7 mg/dL [150 micromol/L]. The original FFS had included central nervous system disease (dropped from the score in 2011) but did not include age (included in 2011). The FFS has been used to stratify patients in treatment studies; this tool is helpful in both interpreting the data and formulating an approach to treatment of PAN. However, the FFS is based upon mortality and is not designed to predict either relapse or long-term morbidity, both of which are also important outcomes that influence treatment decisions in PAN. There is no diagnostic laboratory test for PAN. Laboratory tests can help determine the extent of organs affected and their degree of involvement. These include serum creatinine, muscle enzyme concentrations, liver function studies, HBV and hepatitis C virus (HCV) serologies, and urinalysis. Acute-phase proteins are typically elevated, as evidenced by increased erythrocyte sedimentation rate and C reactive protein concentrations, but are neither sensitive nor specific enough for the diagnosis of PAN to substantially impact diagnostic decision making.
Blood cultures should be obtained in all patients suspected of having a systemic vasculitis in order to exclude endovascular infection. Additional laboratory testing is valuable in narrowing the differential diagnosis. These include the following assays, depending upon the alternative diagnoses being considered based upon the patients signs and symptoms: ANCA, antinuclear antibody, C3 and C4, cryoglobulins, serum and urine immunofixation electrophoresis to test for monoclonal gammopathy, and testing for human immunodeficiency virus.
The American College of Rheumatology has established ten criteria for the classification of polyarteritis nodosa in a patient with a vasculitis.(12) The sensitivity and specificity for the diagnosis of polyarteritis is 82 and 87 percent, respectively in the patient with a documented vasculitis in whom at least three of the following criteria are present: otherwise unexplained weight loss greater than 4-kg, livedo reticularis, testicular pain or tenderness, myalgias (excluding that of the shoulder and hip girdle), weakness of muscles, tenderness of leg muscles, mononeuropathy or polyneuropathy, new-onset diastolic blood pressure greater than 90 mmHg, elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine (>1.5 mg/dL or 132 micromol/L), evidence of hepatitis B virus infection via serum antibody or antigen serology, characteristic arteriographic abnormalities not resulting from non-inflammatory disease processes, biopsy of small- or medium-sized artery containing polymorphonuclear cells. Glucocorticoids remain the first-line treatment with remission occurring in 50% of patients. With the addition of cyclophosphamides, remission or cure approaches 90% of the patients. HBVassociated PAN requires the addition of antivirals as well. Plasma exchange/plasmapheresis may have added benefit in refractory cases.
Imaging Arteriography and cross-sectional imaging can be used as alternatives to tissue biopsy for the diagnosis and are typically performed analyzing the mesenteric or renal circulation.(7) These studies can often be diagnostic, demonstrating multiple aneurysms and irregular constrictions in the larger vessels with occlusion of smaller penetrating arteries (see Figs. 1-2). Other findings can include multiple 1-5 mm peripheral aneurysms, occlusions, irregular stenoses, and/or diffuse
wall thickening of medium-sized arteries (see Figs. 1-4). For unknown reasons, PAN typically occurs at small and medium vessel bifurcations. Locations commonly involved include: kidneys (70-80%), GI tract, peripheral nerves, skin (50%), skeletal muscles and mesentery (30%), and central nervous system (10%). CT and MR are less invasive and provide evidence of end-organ damage, arterial wall thickening, and arterial occlusion.
Indications for the procedure – when or when not to perform the procedure
The diagnosis of PAN is made by tissue biopsy or in conjunction with angiography. Rapid diagnosis is necessary due to progression of life-threatening complications such as acute renal failure, renal/perirenal hematoma, gastrointestinal hemorrhage or perforation, liver infarct, and even cardiac failure. A patient with decreased renal function is a relative contraindication for contrast administration. In general, a glomerular filtration rate (GFR) above 60 should be considered safe. A GFR of 30-60 ml/min should warrant caution and a reduced contrast dose and post-procedure intravenous fluids might help reduce the renal toxic effects of contrast administration.
Patients with cutaneous-only PAN or other single-organ presentations of PAN must also be followed regularly for the possible development of disease in new organ systems. In addition to clinical examinations and appropriate follow-up of patient-reported symptoms, periodic testing by measuring serum creatinine and a urinalysis can help monitor for asymptomatic renal disease. ESR and C-reactive protein may correlate with disease activity. Follow-up angiography is not required unless there are signs or symptoms suggestive of new disease, concerns for
ischemia that may require intervention, or aneurysms that are at risk for expansion or rupture and may require intervention. Depending on the anatomic location and size of affected arteries, magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be substituted for catheter-based angiography. The choice of which imaging modality (MR, CT, or catheter-based) to use will depend upon the availability of equipment and expertise at a medical center and may be influenced by an interest in utilizing the same approach used for prior evaluations to allow for direct comparisons.
Tesar V, Kazderova M, Hlavackova L. Rokitansky and his first description of
polyarteritis nodosa. Journal of nephrology. 2004;17:172-174.
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised
International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis and rheumatism. 2013;65:1-11.
Patel N, Patel N, Khan T, Patel N, Espinoza LR. HIV infection and clinical spectrum of
associated vasculitides. Current rheumatology reports. 2011;13:506-512.
Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritis nodosa,
microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis and rheumatism. 2004;51:92-99.
Hernandez-Rodriguez J, Alba MA, Prieto-Gonzalez S, Cid MC. Diagnosis and
classification of polyarteritis nodosa. Journal of autoimmunity. 2014;48-49:84-89.
Katabathina VS, Katre R, Prasad SR, Surabhi VR, Shanbhogue AK, Sunnapwar A.
Wunderlich syndrome: cross-sectional imaging review. Journal of computer assisted tomography. 2011;35:425-433.
Balow JE. Renal vasculitis. Kidney international. 1985;27:954-964.
Frohnert PP, Sheps SG. Long-term follow-up study of periarteritis nodosa. The American
journal of medicine. 1967;43:8-14.
Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, et al. Clinical features
and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis and rheumatism. 2010;62:616-626.
Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P, et al. The Five-
Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine. 2011;90:19-27.
Bourgarit A, Le Toumelin P, Pagnoux C, Cohen P, Mahr A, Le Guern V, et al. Deaths
occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine. 2005;84:323-330.
Lightfoot RW, Jr., Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al.
The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis and rheumatism. 1990;33:1088-1093.
Figure 1: Twenty-seven year-old male who presented with headache, hypertension, and renal insufficiency. A left renal artery angiogram demonstrates multiple small aneurysms (red arrows) with segmental/sub-segmental irregular narrowing (yellow arrows).
Figure 2: 54 year-old woman with non-healing ulcerations on her legs and distal gangrene. A left renal artery angiogram demonstrates small aneurysms (red arrows).
Figure 3: 60 year old male who developed acute onset of burning paresthesias in his toes and feet followed by blistering ischemic lesions involving his toes with skin breakdown, splinter hemorrhages involving his fingers, and swelling involving his right third finger. ANCA serologies were negative. Angiogram of both hands demonstrates segmental narrowing and micro-aneurysms (red arrows).
Figure 4: Seventy-nine year-old female with dissection (red arrow) of her superior mesenteric artery on sagittal CT (A) and axial CT (B) with irregular narrowing (red arrow) of renal arteries (C).