c-ANCA-negative Wegener's granulomatosis which nasal cavity and lung disorders shows contrastive response to steroid therapy

Yuji Shimizu1), Tatsuo Suga1), Toshitaka Maeno1), Junichi Nakagawa1), Shinichiro Matsui2), Yasunobu Maehara3), Manabu Honma4), Toshikazu Nemoto5), and Masahiko Kurabayashi1)

1) Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, 2) Department of Otolaryngology, 3) Department of Radiology, 4) Department of Pathology, Tomioka General Hospital, 5) Department of Internal Medicine, Nanokaichi Municipal Hospital, Tomioka, Japan

Address correspondence to:
Yuji Shimizu, MD, PhD
Department of Medicine and Biological Science,
Gunma University Graduate School of Medicine,
3-39-15 Showa-machi,
Maebashi, Gunma 371-8511, Japan
TEL +81-27-220-8145
FAX +81-27-220-8158
E-Mail: yshimizu@med.gunma-u.ac.jp


Key words: Wegener's granulomatosis, Prednisolone,cyclophosphamide, c-ANCA, p-ANCA

Abbreviations used in this paper:

WG: Wegener's granulomatosis
PSL: prednisolone
ANCA: anti-neutrophil cytoplasmic antibody
CT: computed tomography

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A 78-year-old woman complained of left-side headache, cough, sputum, and appetite loss. Her physical examinations did not show any abnormalities. Serum cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) and perinuclear (p-) ANCA were not elevated. Chest X-ray and computed tomography (CT) showed nodular shadows at right S3, S5, and S10 areas adjacent to the pleura, and CT-guided needle biopsy revealed lung disorders which were consistent with Wegener's granulomatosis. There were no obvious granulomatous changes in the nasal cavities at this time. Prednisolone alone was therefore administered, and pulmonary disorders quickly improved. However, she continued to have headache, and it was found that a new granulomatous mass appeared at left nasal cavities in spite of the continuous administration of prednisolone. The association of the resistance of nasal cavity disorder to steroid therapy and normal level of C- and P-ANCA remains to be determined.


Wegener's granulomatosis (WG) consists of necrotizing granulomatous disorder in the nose and lung, necrotizing granulomatous vasculitis in generalized arterioles, and intractable vasculitis that features renal necrotic crescent forming nephritis1. It is recommended that either high doses of steroid therapy or combination therapy with steroid and immunosuppressor be prescribed as an induction therapy2, although relapse occurred frequently even after complete remission3. Here, we present a case of cytoplasmic (c-) anti-neutrophil cytoplasmic antibody (ANCA)-negative WG, in which pulmonary and nasal cavity disorder showed contrastive response to steroid therapy.

Case report

A 78-year-old Japanese woman was admitted to our hospital complaining of left-side headache, cough, sputum, and intermittent fever (102 F). She was exhausted because of appetite loss. Physical examinations revealed no typical abnormalities including chest auscultation, nasal deformities, and nervous system. Laboratory data showed hypergammaglobulinemia (total protein 66 g/l, -globulin 35.3%), increased C-reactive protein (137 mg/L) and increased white blood cell (1.2×109/L). Urinary test showed occult blood (2+), but no renal abnormalities were seen by computed tomography (CT). Both c- and perinuclear (p-) ANCA were below detectable level, and have not been elevated during the clinical course. Chest X-p (Fig 1A) and CT (Fig 1C) on admission showed multiple nodular shadows adjacent to the pleura in the right pulmonary areas. Transcutaneous lung biopsy with CT guide was performed, and histological stain by hematoxylin-eosin showed necrotizing granulomatous changes with Langhans giant cells and vasculitis, consistent with WG. Ziehl-Neelsen stain was performed for differential diagnosis with tuberculosis, which was negative. No gross nasal abnormalities determined by either nasal CT (Fig 1E) or endoscopic examination (data not shown), as well as no renal disorder, were observed. Prednisolone (PSL) therapy without immunosuppressor was therefore considered, since tuberculosis could not be completely ruled out, and it was not definitely diagnosed as WG because of the absence of nasal and renal dysfunction and low levels of ANCAs. As shown in Fig 1B and 1D, however, pulmonary disorders were responsive to steroid therapy (PSL 30 mg/day for 2 weeks, and tapered), and multiple nodular shadows were almost eliminated.

Her left headache has still remained for 8 months after PSL administration. Titer of c-ANCA and disease activity were not always parallel in WG patients. However, it is reported that neutrophils and neutrophil-related cytokines play an important role in the pathogenesis of c-ANCA-negative WG patients. Therefore, we were concerned that WG had recurred. Saddle nose stood out at this time, and it was found by nasal CT that the left nasal cavity was occupied by granulomatous changes (suspicious of bone formation with high density mass, Fig 1F), in spite that PSL (5 mg daily) was continuously administered. It is reported that a combination of bone destruction and new bone formation on sinonasal CT is virtually diagnostic of WG when c-ANCA is negative4. Also, an undetectable level of c-ANCA should not be used as the sole criteria to rule out the disease in a setting of strong clinical suspicion5.

The other possibility in this case is that neoplastic changes such as squamous cell carcinoma and lymphoma6 may be involved. Frequent nasal cavity biopsy was therefore performed; however, neither neoplastic cells nor typical histological findings of WG were obtained. It is reported a negative nasal biopsy does not exclude WG, since half of such patients go on to develop WG. It was therefore possible to hypothesize that local recurrence in the nasal cavity occurred, and standard therapy for generalized ANCA-associated vasculitis with a combination of corticosteroid and oral cyclophosphamide7 was finally induced. As anticipated, the nasal disorder responded well to systemic administration of PSL (30 mg daily) and cyclophosphamide (100 mg daily), and only a partial scar remained in the nasal cavity and lung field (data not shown).

In summary, a c-ANCA negative WG patient that showed contrastive response to steroid in pulmonary and nasal cavity disorder was reported. Even after complete remission with steroid, a recurrence in the targeted organ, such as lung, nasal cavity and kidney, should be carefully evaluated. The discrepancy between the contrastive response of lung/ nasal cavity disorder to steroid therapy, and undetectable level of c- and p-ANCA during the clinical course remains to be determined.




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7. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349:36-44.

Figure legends

Figures are available on 4 MB .PDF

Fig 1 Chest X-p, chest CT and sinonasal CT before (A, C, E, respectively) and after (B, D, and F, respectively) steroid therapy
Lung specimen obtained by transcutaneuos CT-guided biopsy stained with H-E showing necrotizing granulomatous changes with Langhans cells (G) and vasculitis with transluminal infiltration by inflammatory cells(H), which was consistent with WG. Original magnification 200

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