1 Arthritis & Rheumatism (Arthritis Care & Research) Vol. 59, No. 9, September 15, 2008, pp DOI /art , American College of Rheumatology CLINICOPATHOLOGIC CONFERENCE A 36-Year-Old Man With Paresthesias and a Headache FLAVIA V. CASTELINO, JASON H. WASFY, AND DEBORAH COLLIER CASE PRESENTATION History of the present illness A 36-year-old man with a history of non-hodgkin s lymphoma was admitted to the hospital with paresthesias and a headache. His paresthesias began 5 months prior to admission, when he developed left leg numbness and pain, accompanied by an erythematous rash that he described as splotchy. The rash appeared initially on the patient s left leg, but then expanded to include his torso and upper extremities. The rash, numbness, and pain all resolved without intervention after 1 week. Three months prior to admission, he experienced recurrent numbness in the left leg that again resolved spontaneously after several days. Two months prior to admission, the patient s symptoms intensified. He developed bilateral numbness and tingling, first in both feet and then in both hands. He noted that grasping objects with his hands caused a burning sensation in his palms, and he experienced pain and swelling in his left foot and ankle. After these symptoms had been present for several weeks, the patient established care with a primary care physician. At his first appointment his erythrocyte sedimentation rate (ESR) was 42 mm/hour (normal range 1 20). An assay for antinuclear antibodies (ANA) was positive at a titer of 1:160 (speckled), but antibodies to double-stranded DNA and to extractable nuclear antigens (Ro, La, Sm, and RNP) were negative. The laboratory results are shown in Table 1. One month before admission, the patient developed unbearable pain in his feet and noted that his socks felt too tight. He reported tingling in his hands, nausea, and daily emesis. The patient was referred for nerve conduction velocity and electromyography of the lower and upper extremities. These investigations revealed a symmetric sensory polyneuropathy that predominantly involved the lower extremities. The patient was prescribed gabapentin Flavia V. Castelino, MD, Jason H. Wasfy, MD, Deborah Collier, MD: Massachusetts General Hospital, Boston. Address correspondence to Flavia V. Castelino, MD, Massachusetts General Hospital, Yawkey Center, Suite 2C-2100, 55 Fruit Street, Boston, MA partners.org. Submitted for publication January 25, 2008; accepted in revised form May 2, (200 mg 3 times daily), but his symptoms persisted. Three days prior to admission, the patient developed a severe occipital headache that did not remit despite use of ibuprofen (600 mg 3 times daily). On the morning of admission, the patient presented to his primary care doctor reporting a severe headache (rated as 10/10), profound fatigue, and numbness, pain, and weakness in both feet. His blood pressure was 168/119 mm Hg in the right arm and 175/123 mm Hg in the left arm. He was referred to the emergency department for hypertensive urgency. Past medical history The patient s non-hodgkin s lymphoma was diagnosed at age 16 years. He had been treated with a standard chemotherapy regimen for 6 cycles (CHOP: cyclophosphamide, hydroxydaunomycin [doxorubicin], vincristine, and prednisone). This treatment was presumed to have resulted in a cure. The patient was also diagnosed with iron deficiency anemia several years before admission. An esophagogastroduodenoscopy at that time was normal. Family and social history The patient s family history was remarkable for the fact that his father had multiple strokes before the age of 40 years. In addition, the patient reported many relatives on both parents sides with hypertension. The age of those individuals at the time of their hypertension onset was not known. The patient worked as a bartender and drank approximately 40 alcoholic beverages/week. He also smoked 1 pack of cigarettes/day and reported active cocaine use by nasal insufflation and occasionally by intravenous use. His most recent cocaine use had occurred 1 day prior to admission. Review of systems The patient reported a 20-pound weight loss over the 5 months prior to admission. He denied alopecia, oral ulcers, dry mouth, dry eyes, photosensitivity, pleuritic chest pain, and Raynaud s phenomenon. He also denied fevers, sweats, auditory or visual changes, and lower back pain. 1358
2 Clinicopathologic Conference 1359 Table 1. Laboratory results* Variable Normal value 6 weeks before admission Admission 3 months after admission White blood cell count, cells/mm 3 4,500 11,000 7,300 11,600 7,800 Differential cell count, % Neutrophils Lymphocytes Monocytes Eosinophils Hematocrit, % Platelets, cells/mm 3 150, , , , ,000 Mean corpuscular volume, fl Red blood cell distribution width, % International normalized ratio N/A 1.1 Partial thromboplastin time, seconds Prothrombin time, seconds Glucose, mg/dl Sodium, mmoles/liter Potassium, mmoles/liter Chloride, mmoles/liter Bicarbonate, mmoles/liter Urea nitrogen, mg/dl Creatinine, mg/dl Total bilirubin, mg/dl Direct bilirubin, mg/dl Albumin, gm/dl Calcium, mg/dl Alkaline phosphatase, units/liter Aspartate aminotransferase (SGOT), units/ liter Alanine aminotransferase (SGPT), units/liter Urinalysis Blood Negative Negative 1 Negative Protein Negative Negative 2 Trace Red blood cells, per hpf White blood cells, per hpf Bacteria Negative Negative Negative Rheumatoid factor, IU/ml ANA Negative at 1:40 and 1:160 Positive at 1:160 Positive at 1:40 and 1:160 C3, mg/dl C4, mg/dl ESR, mm/hour C-reactive protein, mg/dl ANCA Negative Cryoprotein None None None * N/A not applicable; SGOT serum glutamic oxaloacetic transaminase; SGPT serum glutamic pyruvic transaminase; hpf high-power field; ANA antinuclear antibodies; ESR erythrocyte sedimentation rate; ANCA antineutrophil cytoplasmic antibody. Physical examination In the emergency department, the patient s temperature was 97.9 F; his pulse and respiratory rate were 126 beats/minute and 18 breaths/minute, respectively; his blood pressure was 174/113 mm Hg in the left arm and 180/110 mm Hg in the right arm; and his oxygen saturation was 98% on room air. Examination of his head, eyes, ears, nose, and throat revealed no abnormalities. There was no cervical, supraclavicular, axillary, or femoral adenopathy. His skin was clear, with no signs of the previous rash. Cardiac auscultation revealed a tachycardia with regular rhythm and normal S 1 and S 2 without murmurs. The lung examination revealed normal breath sounds bilaterally, and his abdomen was benign. The patient s extremities had no clubbing, cyanosis, or edema, but there was tenderness along the anterior joint line of the left ankle. The neurologic examination was significant for decreased sensation bilaterally to light touch and pinprick to the mid-shins. The same sensory modalities were also decreased in the left arm, in the distribution of the superficial radial nerve. Motor strength was intact in both the upper and lower extremities. The deep tendon reflexes were 2 and symmetric, and the plantar responses were flexor.
3 1360 Castelino et al The patient was admitted for management of his hypertension and further evaluation. Figure 1. Computed tomography angiogram showing multiple hypoperfused areas of the kidneys bilaterally suggestive of multiple infarctions (original magnification mm, DPI). Laboratory and radiologic evaluation The complete blood count and serum chemistries on admission are shown in Table 1. The serum creatinine was 1.3 mg/dl (baseline 0.7 mg/dl, normal range ) and the blood urea nitrogen was 10 mg/dl (normal range 8 25). A urinalysis with microscopic examination of the sediment was notable for 2 protein on dipstick, but no white or red blood cells and no casts. A urine microalbumin: creatinine ratio was 93.5 mg per gram of creatinine (normal value 30). A chest radiograph revealed a normal cardiac:chest ratio and no infiltrates. A computed tomography (CT) scan of the head without intravenous contrast showed no evidence of midline shift or acute bleeding. Initial hospital course The patient s hypertensive urgency was treated with intravenous labetalol (20 mg once), followed by oral metoprolol (37.5 mg 4 times daily). By hospital day 2, his blood pressure had improved to 140/80 mm Hg and his headache had resolved. A CT angiogram of the chest, abdomen, and pelvis revealed multiple, bilateral areas of hypoperfusion in the kidneys (Figure 1). These findings suggested parenchymal infarctions or medium-vessel occlusive disease. There were no pulmonary infiltrates and no lymphadenopathy. A mesenteric and renal angiogram showed smallvessel occlusions of the arcuate and interlobular arteries of the kidneys bilaterally, but no microaneurysms, beading, or vascular malformations (Figure 2). Additional serologic evaluations were performed. The patient s ESR was 42 mm/hour (normal range 0 17 mm/ hour) and his C-reactive protein (CRP) level was 37.4 mg/dl (normal value 8). His plasma renin level was 5.1 ng/ml/hour (reference range 1.5), consistent with renovascular hypertension. An assay for ANA was positive at a titer of 1:40 and 1:60 in a speckled pattern, but antibodies to extractable nuclear antigens and to doublestranded DNA were again negative, as were assays for rheumatoid factor and antineutrophil cytoplasmic antibodies (ANCAs). The serum C3 and C4 levels were 94 mg/dl (normal range ) and 17 mg/dl (normal range 20 58), respectively. The CH50 was 144 units/ml (normal range ). A diagnostic procedure was performed. Figure 2. A, Renal angiogram showing diffuse nonspecific small-vessel occlusions involving the bilateral arcuate and interlobular renal arteries (original magnification mm, DPI). B, Mesenteric angiogram did not demonstrate any evidence of wall irregularity or aneurysm (original magnification mm, DPI).
4 Clinicopathologic Conference 1361 CASE SUMMARY Table 2. Differential diagnosis Recurrent lymphoma Effects of cocaine abuse Cocaine-associated vasculitis Effects of intravenous drug abuse Hepatitis B virus associated polyarteritis nodosa Hepatitis C virus associated cryoglobulinemia Human immunodeficiency virus neuropathy Primary systemic vasculitides Classic polyarteritis nodosa Antineutrophil cytoplasmic antibody associated Wegener s granulomatosis Microscopic polyangiitis Churg-Strauss vasculitis A 36-year-old man with a history of non-hodgkin s lymphoma and cocaine use presented with a stuttering but increasingly severe peripheral neuropathy, arthralgias, and new-onset hypertensive urgency associated with bilateral renal infarctions. DIFFERENTIAL DIAGNOSIS The principal components of the differential diagnosis in this case are a recurrence of the patient s remote lymphoma, the effects of active cocaine use, potential infectious complications of intravenous drug use, and systemic vasculitis (Table 2). Recurrent lymphoma Recurrence of the patient s malignant disease must be considered. Lymphoma can be associated with symptoms and signs that mimic systemic vasculitis, such as a multifocal neuropathy (1). In patients with non-hodgkin s lymphoma, malignant cells occasionally infiltrate nerves and cause axonal damage, which can resemble an asymmetric mononeuritis multiplex or a more diffuse peripheral neuropathy (2). Non-Hodgkin s lymphoma can also cause cutaneous vasculitis with palpable purpura and necrotizing leukocytoclastic vasculitis (3), and is sometimes associated with a positive ANA (4). However, in our patient, the absence of lymphadenopathy on both physical examination and radiographic studies suggested that a lymphoma recurrence was not likely. Cocaine abuse The patient s active substance abuse may have also contributed to his presentation. Cocaine can cause a number of clinical vascular events, many of which are mediated by vasoconstriction leading to ischemia and acute hypertension (5). Vascular events related to cocaine use include myocardial infarction, cerebral vasoconstriction syndromes, mesenteric ischemia, and (rarely) renal infarction (6). Cocaine-associated vasculitis is uncommon. Two case reports described in the literature are potentially relevant to our patient. In one report, a 35-year-old woman with a history of asthma and cocaine use presented with fatigue, palpable purpura of her lower and upper extremities, and arthritis of her knees and ankles. Her acute-phase reactants (ESR and CRP) were normal, and assays for autoantibodies, cryoglobulins, and complement levels were negative or normal. Skin biopsy samples revealed fibrin thrombi and mild leukocytoclasis, findings that were attributed to a cocaine-induced vasculopathy (7). In a second report, a 27-year-old cocaine addict presented with progressive pharyngitis, fatigue, and cutaneous lesions on her face, arms, legs, and back. She had an ANA at a titer of 1:640, an ESR of 150 mm/hour, and a positive assay for ANCAs by immunofluorescence (8). Serial skin biopsy samples were notable for extensive neutrophilic infiltrates and a few small blood vessels with inflammatory infiltrates. The final diagnosis was cocaineinduced vasculitis. Cocaine is known to have toxic effects on the kidneys, affecting vascular reactivity and renal hemodynamics (6). Therefore, it is conceivable that our patient s cocaine abuse led to his renal infarctions and hypertension. However, a peripheral neuropathy such as the one developed by our patient, a sensory mononeuritis multiplex, is unusual in the setting of cocaine use. In addition, despite being floridly abnormal, the vascular imaging studies in our patient were not specific for cocaine-induced vasculopathy or any other single form of vascular disease. Infectious complications of intravenous drug abuse Given the patient s history of intravenous drug use, certain parenteral infections must be considered. In particular, hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) infections must be excluded. HCV-related cryoglobulinemia, a vasculitis of both small- and medium-sized blood vessels, often involves the skin, peripheral nerves, kidneys, and other organs. Complications of medium-vessel disease (such as those apparent on our patient s angiogram) are unusual in HCV-related cryoglobulinemia in the absence of smallvessel vasculitis, particularly palpable purpura (9). The absence of clinical signs of a small-vessel vasculitis at presentation and the patient s negative rheumatoid factor argue against HCV-related cryoglobulinemia. HBV-associated polyarteritis nodosa (PAN) is a form of medium-vessel vasculitis that is also mediated by immune complex deposition. HBV-associated PAN occurs in the setting of active HBV infection, typically within 6 8 months of the acquisition of HBV. This disorder is characterized by fever, weight loss, and multisystem dysfunction, including but not limited to peripheral neuropathy, an array of cutaneous findings, renal insufficiency, and hypertension (10). Vasculitic neuropathy, often leading to a crippling motor mononeuritis multiplex or a painful sensory neuropathy, is common in PAN. The patient in this case developed a symmetric sensory polyneuropathy. Although the classic syndrome of vasculitis neuropathy is a mononeuritis multiplex, symmetric sensory polyneuropathy is also well described (11).
5 1362 Castelino et al Figure 3. A, Left sural nerve biopsy specimen demonstrates chronic inflammatory changes in a section of a longitudinal vessel supplying the epineurium (hematoxylin and eosin stained; original magnification mm, DPI). B, Cross-section of an arteriole from sural nerve biopsy sample demonstrating inflammatory change in the vessel wall (hematoxylin and eosin stained; original magnification mm, DPI). C, Section from sural nerve biopsy sample demonstrating fibrinoid necrosis with pleomorphic cell infiltration (hematoxylin and eosin stained; original magnification mm, DPI). D, Section from left quadriceps muscle biopsy sample demonstrating arteritis involving a muscular artery of the interfascicular fibrous septa (original magnification mm, DPI). HIV infection has been associated with a number of vasculitis syndromes, including disorders that bear a strong resemblance to PAN with involvement of the skin, peripheral nerves, and skeletal muscles (12). Peripheral neuropathy with distal, symmetric disease is the most common neurologic manifestation of HIV (13). Mononeuritis multiplex is a rare manifestation of HIV and usually indicates the presence of an underlying vasculitis (14). Primary systemic vasculitides This patient s multi-organ system presentation of peripheral neuropathy, renal infarctions, and joint inflammation occurring in the absence of pulmonary involvement are highly consistent with classic PAN, a necrotizing form of systemic vasculitis that involves medium-sized muscular arteries and arterioles. The other types of systemic vasculitis that are often associated with vasculitic neuropathy are those that are commonly associated with ANCAs: Wegener s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome (15). Among these 3 disorders, peripheral nerve involvement is more common in both Churg-Strauss syndrome and microscopic polyangiitis, but devastating peripheral neuropathy can occur in Wegener s granulomatosis as well. Our patient did not have ANCAs in his serum and had no indication of pulmonary disease, significantly reducing the likelihood of an ANCA-associated vasculitis. In summary, both classic (idiopathic) and HBV-related PAN appeared to be strong possibilities as the explanation for this patient s problems. A cocaine-associated vasculopathy could also have explained many of his clinical manifestations.
6 Clinicopathologic Conference 1363 ADDITIONAL EVALUATION Additional serologic evaluations after admission revealed that the patient was negative for antibodies to HCV and HIV. An assay for cryoglobulins was also negative. However, HBV serology revealed that the patient was positive for both the HBV surface antigen and e antigen and the IgM core antibody, but negative for antibodies to this virus. These findings were consistent with an acute HBV infection. The patient s HBV viral load was 121 million IU/ml. The patient s positive HBV serology offered a strong possible explanation for his presentation. However, the renal and mesenteric angiographic findings were not diagnostic of vascular injury associated with HBV-related PAN. Angiographic findings, including microaneurysms and occlusive disease, are present in a range of 40 90% of patients with PAN at the time of clinical presentation; however, the frequency of specific findings is limited by non-specificity and sampling bias (16). Since the patient did not have classic PAN findings, he underwent both a peripheral nerve and muscle biopsy. Biopsy findings of the left sural nerve showed chronic granulomatous inflammation in the vessels supplying the epineurium of the sural nerve (Figure 3A). A trichrome stain revealed moderate secondary loss of myelinated axons. The chronicity of the inflammation was consistent with PAN, as opposed to an acute vasculopathy or arteritis caused by cocaine. Left quadriceps muscle biopsy findings showed arteritis involving a muscular artery of the interfascicular fibrous septa (Figure 3D). As with the sural nerve biopsy results, the chronicity of the inflammation supported the diagnosis of PAN. In the setting of active HBV infection, these histopathologic findings confirmed the diagnosis of HBV-related PAN. DISCUSSION Active hepatitis B infection is strongly associated with PAN, and has been reported to occur in up to 36% of patients with PAN in France before 1995 (10). Although it is difficult to pinpoint the timing of the patient s infection precisely, we believe that he probably acquired his HBV infection approximately 5 months prior to admission through the intravenous use of cocaine. In this context, it is notable that the patient also had a positive IgM anti hepatitis B core antibody, which typically persists for at least 6 months following infection. Approximately 70% of patients with acute HBV infections have subclinical (anicteric) hepatitis, which is the likely explanation for his only mildly elevated serum aminotransferase levels at the time of presentation (17). His splotchy rash was consistent with a viral exanthem that is typical of acute HBV infections (18). Kussmaul and Maier first described PAN in 1866 (19). The disease typically occurs in middle-aged adults and is usually a multisystem disease process characterized by fatigue, weakness, hypertension, renal insufficiency, rash, and neuropathy. The American College of Rheumatology (ACR) has devised classification criteria for the inclusion of patients in studies of PAN (20). The presence of 3 or more ACR criteria is associated with a sensitivity of 82.2% and a specificity of 86.6%. Gocke et al (21) and Trepo and Thivolet (22) described the association between PAN and HBV in HBVassociated PAN is attributed to high viral replication leading to antigen excess and the formation of soluble immune complexes, which deposit in the arterial walls (23). ANCA serology is negative in these patients. The declining incidence of HBV-associated PAN since the late 1980s has been attributed to the introduction of the HBV vaccine and the consequent safety of blood products. The approach to treating HBV-associated PAN has evolved over the past decades and is changing more quickly now with the availability of effective antiviral therapies. The major components of treatment are now glucocorticoids, antiviral agents, and often plasma exchange. In contrast, from the 1950s through the 1970s, prolonged glucocorticoid use was deemed essential for the suppression of inflammation. Unfortunately, this led to further replication of the virus and frequent relapses (30% at 1 year and 42% at 5 years) (10). In 1988, Trepo et al reported a retrospective analysis of 7 patients with HBV-associated PAN treated between 1979 and 1985 with a therapeutic protocol of glucocorticoids for 2 weeks, followed by initiation of antiviral therapy with vidarabine, and plasma exchange (initially performed 3 times per week for the first 3 weeks, followed by 1 time per week, then weekly for 3 6 weeks) (24). The rationale for this therapeutic approach included glucocorticoids to control inflammation, plasma exchange to remove immune complexes and improve the capacity of the reticuloendothelial system to clear these complexes, and antiviral therapy to suppress HBV replication and facilitate immune complex clearance by decreasing viral load. Six of the 7 patients treated were clinically and virologically cured and did not relapse during a range of up to 7 years in followup. Guillevin et al performed a retrospective analysis of 115 patients with HBV-associated PAN (either biopsy proven or positive angiogram with clinical symptoms) (25). These investigators evaluated the frequency, clinical characteristics, and long-term outcome based on various treatment protocols from Most treatment protocols utilized an antiviral agent (more recent trials used lamivudine), glucocorticoids, and plasmapheresis. Seroconversion from hepatitis B e antigen to hepatitis B e antibody was the strongest indicator of survival, and all patients who seroconverted achieved clinical remission without relapse. Among those patients treated without an antiviral agent, the seroconversion rate of HBV was 15% compared with 49% among patients treated with the antiviral strategy. The role of plasma exchange in HBV-associated PAN has not been studied in randomized controlled trials. Guidelines published by the American Society for Apheresis classify vasculitis as a category III indication for plasmapheresis; i.e., the procedure is not clearly indicated based on insufficient evidence, conflicting results, or inability to document a favorable risk-to-benefit ratio (26,27). Guillevin et al showed that the combination of glucocorticoids and plasma exchange was of no further benefit in prevent-
7 1364 Castelino et al ing relapse and offered no survival benefit when compared with glucocorticoids alone in patients with systemic PAN (without HBV) or Churg-Strauss syndrome (28). Based on the absence of proof that plasma exchange is required to treat HBV-associated PAN effectively (29), we opted to treat our patient initially with glucocorticoids and antiviral therapy alone. THE PATIENT S COURSE Our patient s headache and hypertension resolved quickly with the addition of labetalol and amlodipine. His serum creatinine level normalized and he did not have any further evidence of organ-threatening disease. During his hospitalization, he was started on entecavir 5 mg by mouth daily and prednisone 60 mg daily. The prednisone was tapered off over 2 weeks. Although lamivudine and other earlier antiviral agents have proven effective for HBVassociated PAN, entecavir was used in this patient because it has exhibited antiviral efficacy superior to that of lamivudine in dose-finding studies (30). Entecavir can also be used with impaired renal function and is currently considered a standard treatment for hepatitis B infection (31). Three months after discharge, the patient s HBV viral load was below the detectable range and he had seroconverted from HBV e antigen positive to HBV e antibody positive. His neurologic condition had improved, with decreased pain in his feet. Some pain and numbness persisted in his left arm. The patient continued to drink alcohol daily but abstained from cocaine. FINAL DIAGNOSIS Hepatitis B virus associated polyarteritis nodosa. ACKNOWLEDGMENT We appreciate the thoughtful review of the manuscript by John Stone, MD. 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