Magnetic resonance imaging depicts mural ... - Wiley Online Library

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Dec 15, 2004 - First, all patients with acute HBV infection probably experience an .... primary systemic vasculitis from others (2), these tools ..... Philip Seo, MD.
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 51, No. 6, December 15, 2004, pp 1060 –1064 © 2004, American College of Rheumatology

LETTERS DOI 10.1002/art.20833

Treatment of polyarteritis nodosa: comment on the article by Guillevin et al To the Editor: I read with interest the recent article Guillevin et al (1). The authors are members of a cooperative study group in France that has reported (over the past 2 decades) several studies of systemic vasculitis syndromes, in particular evaluation of regimens that include antiviral drugs in the treatment of hepatitis B virus (HBV)–associated polyarteritis nodosa (PAN). As a preface to my comments, I submit the following points as background. First, all patients with acute HBV infection probably experience an early phase that is the equivalent of oneshot acute serum sickness. From the classic studies of Krugman et al (2), it is known that the first HBV reactant to appear in the circulation is HBV surface antigen (HBsAg), which percolates thoughout vascular and extravascular compartments for a period of weeks before the appearance of viral DNA or anti-HBV antibodies and before the onset of clinical illness. When the host immune complex is expressed, the distribution of HBsAg (as in acute serum sickness) determines organ system involvement; this may be subclinical, mild, moderately severe (arthritis/cutaneous vasculitis syndrome), or severe, including multisystemic patterns of involvement consistent with PAN. In addition to organ-directed inflammation, anti-HBsAg antibody, reacting with circulating antigen, can mediate diffuse vascular injury via immune complex deposition. The majority of patients with PAN (whether HbsAg positive or not) have an acute illness; if they escape irreversible injury to vital organ systems during that phase, they survive (with or without chronic residua) and infrequently manifest recurrent active vasculitis. The keys to success are diagnosis early in the course of the illness and prompt institution of treatment. Second, there are 2 objectives in the management of HBV-associated PAN: 1) the first priority is suppression of inflammation with corticosteroids, sometimes combined with cytotoxic drugs and plasma exchange (the efficacy of the latter is difficult to judge because, when used, it is almost always combined with other treatments), and 2) institution of antiviral therapy. Two agents (lamivudine and interferon-␣) have proven efficacy in the suppression of HBV viremia and promotion of seroconversion. Because

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of the relative rarity of HBV-associated vasculitis, there are no prospective controlled therapeutic trials. The tendency to standardize management by protocols, i.e.,“one plan fits all,” is not appropriate, considering the clinical and pathologic heterogeneity described above. Third, the American College of Rheumatology (ACR) criteria for classification of PAN were designed to assure some semblance of uniformity in reporting cases, but they are not accurate in either establishing or excluding diagnosis. Three of 10 criteria are required to meet the ACR classification for polyarteritis. The 10 criteria are as follows: 1) weight loss (at least 4 kg), 2) livedo reticularis, 3) testicular pain/tenderness, 4) myalgia, weakness, or tenderness, 5) mononeuropathy or polyneuropathy, 6) diastolic blood pressure ⬎90 mm Hg, 7) elevated serum blood urea nitrogen or creatinine, 8) hepatitis B infection, 9) abnormal arteriography, and 10) biopsy specimen showing a small or medium-sized artery containing granulocytes with/or without mononuclear leukocytes. There are endless scenarios illustrating how bedside application of these criteria for diagnosis would lead one astray. Finally, sometimes sequential observations of an individual patient over time can be particularly instructive; an example is the followup over more than 3 decades of the first patient in whom Koch’s postulates were fulfilled regarding HBV etiology of PAN. In this subject, patient # 5 in 2 publications (3,4), PAN developed 3 weeks after known infusion of a single unit of HbsAg-positive blood; more than a decade later she had seroconverted to all HBV reactants except HbsAg, and that antigen was (at least in part) in immune complex form. After another decade, the patient was still alive and fairly well. HbsAg antigen had disappeared, and anti-HBsAg antibodies were measurable. Beyond the first several months of her illness there were no clinical manifestations of active vasculitis. Reviewing the study of Guillevin et al and in light of comments above, I accept the fact that their patients did have HBV-associated syndromes, but I am not convinced that all 10 patients had PAN. Seven subjects had relatively mild disease (zero on the “5 factor score”), and 6 patients seroconverted between 0.5 and 6 months, periods not inconsistent with natural seroconversion following HBV infection. It is stated that 7 patients had “histologic proof of vasculitis,” and the site of biopsy in 5 subjects (see Table 3) was described as “neuromuscular.” Does that mean both nerve and muscle sites were positive? It would be useful to know if all of the “positive” biopsy specimens demonstrated leukocytes in artery walls (ACR classification cri-

Letters

teria) because perivascular leukocyte exudation can be a feature of almost any inflammatory process. Why am I raising these questions? I think there is a wide spectrum of HBV-associated vascular syndromes. All of them warrant prompt treatment, but there is a strong case for individualizing treatment regimens according to anatomic patterns and severity, adjusting the dose and duration of corticosteroid, and for patients with very severe disease, employment of cyclophosphamide (maybe even plasma exchange). I strongly suspect that patients with the relatively common HBV-associated arthritis and dermalvasculitis syndrome have vasculitis in other sites. However, in the absence of evidence of visceral involvement and considering the overall benign character of that problem, aggressive management is not warranted. Finally, I believe the authors have made a good case for antiviral therapy of patients with HBV-associated PAN, given the relative safety of lamivudine therapy and the high frequency of persistent HBsAg antigenemia in such subjects. Charles L. Christian, MD University of Florida, Jacksonville 1. Guillevin L, Mahr A, Cohen P, Larroche C, Queyrel V, Loustaud-Ratti V, et al. Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus–related polyarteritis nodosa. Arthritis Rheum 2004;51:482–7. 2. Krugman S, Ward R, Katz S. Infectious diseases of children. Sixth ed. St. Louis: CV Mosby; 1977. 3. Sergent J, Lockshin M, Christian C, Gocke D. Vasculitis with hepatitis B antigenimia. Medicine (Baltimore) 1976:55:1–18. 4. Inman R, McDougal JS, Redecha PB, Lockshin MD, Stevens C, Christian CL. Isolation and characterization of immune complexes in patients with hepatits B systemic vasculitis. Clin Immunol Immunopathol 1981;21:364 –74.

DOI 10.1002/art.20834

Reply To the Editor: We thank Dr. Christian for his stimulating comments on the classification and differential diagnosis of HBV-associated PAN. We fully agree that the fact that patients included in our trial fulfilled the ACR criteria for PAN (1) should be interpreted with caution. Because the ACR vasculitis criteria sets were established to distinguish one primary systemic vasculitis from others (2), these tools should be applied exclusively to patients with a definitive diagnosis of vasculitis. Because microscopic polyangiitis was separated from PAN (3), it has been demonstrated that it too could satisfy the PAN criteria (4). Conversely, in

1061 response to one of the points raised by Dr. Christian, our personal experience does not support that the presence of granulocytes in the vessel wall, a feature highlighted by the ACR PAN criteria, orients towards a diagnosis of PAN with adequate sensitivity or specificity. Regarding the potential limitations of the ACR criteria for PAN and in light of the observation that some of our patients experienced rapid HBe seroconversion under the treatment protocol, Dr. Christian raised the important question as to whether our patients might not have had a “dermatitis–arthritis syndrome,” rather than genuine PAN. Like PAN and glomerulonephritis, the dermatitis–arthritis syndrome is a well-recognized HBV infection-associated disease. All 3 entities result from immune complex-mediated tissue damage, but occur at different periods during the course of viral infection. Indeed, the dermatitis–arthritis syndrome is considered to be a serum sickness-like disease that occurs during the prodromal phase of infection and resolves spontaneously by the time jaundice develops, whereas PAN and glomerulonephritis develop at later stages as a consequence of sustained HBV antigenemia (5–7). Therefore, we persist in thinking that, on clinical grounds, the multisystem HBV-associated disorder of our 10 patients was unequivocally PAN. The median interval between the first systemic symptoms and therapy onset was 3.9 months (range 22 days–19.7 months). In addition, none of our patients had a transaminase peak or jaundice, findings that argue against the possibility that the extrahepatic manifestations pertained to prodromata of acute HBV infection. The fact that all patients initially had clinical manifestations involving one or more sites other than the joints or skin is also not suggestive of a dermatitis–arthritis syndrome. Furthermore, the vasculitis was biopsy-proven in 7 patients (2 of 5 positive neuromuscular samples with vessel inflammation in both tissues), and another patient had an abnormal angiogram. Because none of the patients had characteristic signs of microscopic polyangiitis (e.g., alveolar hemorrhage, glomerulonephritis, positive antineutrophil cytoplasmic antibodies), it can be considered that, at least for those 8 cases, the ACR criteria were accurately applied and would support their classification as PAN, with a reported specificity of 87%. Dr. Christian’s comments also give us the opportunity to briefly reemphasize the utility of the five-factor score (FFS). The FFS was derived from a survival analysis of 342 patients with PAN, microscopic polyangiitis or Churg– Strauss syndrome (8) that identified 5 variables predicting an increased risk of mortality. Therefore, the FFS assesses the prognoses of patients with 1 of these 3 vasculitides, but not disease activity. Consequently, the finding that 6 of our patients had an FFS of zero implies that PAN was morebenign in these individuals but not a “forme fruste” of the disease. However, it cannot be excluded nowadays that cli-

1062 nicians’ potentially heightened awareness of HBV-associated PAN might prevent, as a result of an earlier diagnosis, the development of the full-blown clinical picture of this entity. Alfred Mahr, MD Loı¨c Guillevin, MD Pascal Cohen, MD For the French Vasculitis Study Group Hoˆpital Cochin, Assistance Publique–Hoˆpitaux de Paris, Paris, France 1. 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 Rheum 1990;33:1088 –93. 2. Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 1990;33:1065–7. 3. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37:187–92. 4. Watts RA, Jolliffe VA, Carruthers DM, Lockwood M, Scott DG. Effect of classification on the incidence of polyarteritis nodosa and microscopic polyangiitis. Arthritis Rheum 1996;39:1208 –12. 5. Dienstag JL. Hepatitis B as an immune complex disease. Semin Liver Dis 1981;1:45–57. 6. Gocke DJ. Extrahepatic manifestations of viral hepatitis. Am J Med Sci 1975;270:49 –52. 7. Tre´po C, Guillevin L. Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case against autoimmune intervention in pathogenesis. J Autoimmun 2001;16:269 –74. 8. Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al. Prognostic factors in polyarteritis nodosa and Churg–Strauss syndrome: a prospective study in 342 patients. Medicine (Baltimore) 1996;75:17–28.

Letters tional angiography, the optimal means of these techniques in clinical practice require further investigations. We agree with this assessment and would like to provide some information on our recent research activities using highresolution MRI to detect mural inflammatory changes of the temporal artery in GCA (2). We investigated 20 patients with clinically suspected GCA (mean age 72.4 years), using high-resolution MRI on a clinical 1.5 Tesla system with a dedicated eight element phased-array head-coil. (Magnetom Sonata; Siemens, Erlangen, Germany) Multislice T1-weighted spin-echo sequences with a sub-millimeter spatial resolution of 0.2 mm ⫻ 0.3 mm and a slice thickness of 3 mm were acquired, perpendicular to the vessel’s orientation before and after intravenous injection of a contrast bolus (0.1mmole/kg, Magnevist, Schering, Germany) (Figure 1). Biopsy specimens of the temporal artery were obtained in 16 of 20 patients for definite diagnosis of GCA. The mean ⫾ SD thickness of the vessel wall and the

DOI 10.1002/art.20840

Magnetic resonance imaging depicts mural inflammation of the temporal artery in giant cell arteritis To the Editor: We read with interest the recent article by Seo and Stone (1). The authors provide a thorough review of giant cell arteritis (GCA) and briefly discuss new approaches to imaging in large vessel vasculitis. They state that even though magnetic resonance imaging (MRI), electron beam computed tomography, and positron emission tomography have theoretical and technical advantages over conven-

Figure 1. A, Photograph of a 63-year-old patient with giant cell arteritis demonstrating the swollen frontal branch of his left superficial temporal artery. Two nitroglycerine capsules (white balls) were placed along the artery’s orientation as fiducial markers. B, Small volume maximum intensity projection of the localizer sequence reveals the vessel’s track. C, T1-weighted spin- echo sequence before, and D, after intravenous contrast was planned perpendicular to the vessel’s orientation. Note bright contrast enhancement of the thickened vessel wall (arrow) indicating mural inflammation. Biopsy of the artery validated the diagnosis of giant cell arteritis.

Letters lumen diameter were 0.88 ⫾ 0.23 mm and 0.78 ⫾ 0.29 mm in GCA-positive patients and 0.57 ⫾ 0.25 mm and 0.7 ⫾ 0.1 mm in GCA-negative patients, respectively. In 16 of 20 cases, characteristic signs of mural inflammatory changes such as thickening of the vessel wall and/or an increased contrast enhancement were correctly demonstrated on MRI (2). In these cases, diagnosis of GCA was established according to the American College of Rheumatology (ACR) clinical criteria (3), which included positive histologic findings in 14 cases. In 3 of 20 cases, MRI was true negative, and in one case, MRI was false negative. In the false-negative case, histology was also false negative and the diagnosis of GCA was established according to the ACR criteria (3). Possibly, the GCA involvement occurred predominantly in the occipital arteries and was neither in the MRI field nor in the site of the biopsy specimen. Mural thickening and contrast enhancement on MR images is a direct indication of inflammation of the vessel wall and thus of active disease (4). Klein et al (5) have shown that inflammation of the temporal artery demonstrates a segmental distribution. This might be a reason for false-negative biopsy results. High-resolution MRI may be used to identify segments with the most intense mural inflammatory changes to determine the best biopsy site. Furthermore, the variable extent of involvement of each temporal artery and of each occipital or facial artery can be depicted within the same investigation. Potentially, this may reduce the number of false-negative biopsy specimens and reduce the number of bilateral biopsies performed because the first biopsy was not diagnostic. High-resolution MRI may also be used to monitor the activity of mural inflammatory changes with long-term corticosteroid use. We have shown how mural inflammatory changes decreased over the course of time during corticosteroid therapy (6). The clinical value of color duplex-sonography in the diagnosis of GCA has been debated (7–10). Comparison of MRI with duplex-sonography including the question of whether MRI adds incremental value to duplex-sonography would be of interest and will be investigated in the future. All patients investigated in this study were suspected of having GCA by either a rheumatologist or an ophthalmologist experienced in treating patients with GCA. This seems to be the reason for the high percentage of patients with positive biopsy results. Because all patients were referred to us for temporal artery evaluation, a possible referral bias cannot be ignored. Larger patient trials with a higher number of patients who ultimately do not have GCA will be needed to evaluate the reliability and diagnostic value of this imaging technique.

1063 We conclude that high-resolution MRI enables the visualization of the temporal artery and its mural inflammatory changes in GCA. This modality might be useful in determining the correct diagnosis and in increasing the likelihood of obtaining a positive biopsy specimen. We think that this novel, noninvasive imaging modality for detection of mural inflammatory changes of the temporal artery in GCA deserves further exploration.

T. A. Bley, MD O. Wieben, PhD P. Vaith, MD D. Schmidt, MD N. A. Ghanem, MD M. Langer, MD University of Freiburg, Freiburg, Germany

1. Seo P, Stone JH. Large-vessel vasculitis. Arthritis Rheum 2004;51:128 –39. 2. Bley TA, Wieben O, Uhl M, Schmidt D, Thiel J, Langer M. High-resolution MRI in giant cell arteritis: vessel wall imaging of the superficial temporal artery. AJR Am J Roentgenol. In press. 3. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122– 8. 4. Stanson AW. Imaging findings in extracranial (giant cell) temporal arteritis. Clin Exp Rheumatol 2001;18 Suppl 20: S43– 8. 5. Klein RG, Campbell RJ, Hunder GG, Carney JA. Skip lesions in temporal arteritis. Mayo Clin Proc 1976;51:504 –10. 6. Bley TA, Wieben O, Leupold J, Uhl M. MRI findings in temporal arteritis. Circulation. In press. 7. Schmidt WA, Kraft HE, Vorpahl K, Volker L, Gromnica-Ihle EJ. Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 1997;337:1336 – 42. 8. Reinhard M, Schmidt D, Hetzel A. Color-coded sonography in suspected temporal arteritis-experiences after 83 cases. Rheumatol Int. 2003 Nov 5 (Epub ahead of print). 9. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant cell arteritis. N Engl J Med 2002;347: 261–71. 10. Salvarani C, Silingardi M, Ghirarduzzi A, Lo Scocco G, Macchioni P, Bajocchi G, et al. Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis? Ann Intern Med 2002; 137:232– 8.

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DOI 10.1002/art.20838

Reply To the Editor: We thank Bley et al for their interest, and agree that noninvasive modalities for assessing vasculitis are promising and merit further study. The use of high-resolution magnetic resonance imaging to detect inflammatory changes in the temporal artery is one intriguing approach; we look forward to seeing this technique validated in larger patient populations. Despite the great potential of noninvasive techniques in the evaluation of large vessel vasculitis, caution is still warranted. It is difficult to say how early successes will

Letters fare in community practice, especially when these techniques are applied by practitioners who are inexperienced in the assessment of vasculitis. In many studies of noninvasive modalities, the differences between normal and abnormal are slight, and may be difficult to discern even by trained examiners. Considering the high stakes involved in diagnosing giant cell arteritis correctly, biopsy is likely to remain the test of choice for some time to come and the gold standard against which new approaches must be measured. Philip Seo, MD John H. Stone, MD, MPH The Johns Hopkins Vasculitis Center Baltimore, MD