Clinical features were significantly different between the 2 groups for the presence of extrarespiratory localization, their number, and their severity (see Table 3). The frequency of each extrarespiratory manifestation was not significantly different between the 2 groups except lupus pernio, which was higher in patients with SNS (50% vs. 0%, p < 0.001). Chest X-rays, pulmonary function tests, and SACE were statistically similar between the 2 groups (see Table 3).
Comparisons between the SNS group and the control group regarding treatment revealed a difference in the rate of patients requiring systemic treatment (100% vs. 57.7%, respectively, p < 0.001) and in the duration of treatment (82 mo [range, 22-161 mo] vs. 22 mo [range, 14-73 mo], respectively, p < 0.0001). The probability of recovering from sarcoidosis was significantly lower in patients with SNS compared with controls (0% vs. 51.7% at 5 yr, 6.2% vs. 55.7% at 10 yr, and 21.9% vs. 66.8% at 15 yr, p = 0.0006).
To our knowledge, the present study is the first case-control series comparing patients with SNS to patients without SN involvement. The results suggest that SN involvement is a recalcitrant manifestation of sarcoidosis that is associated with more frequent and severe involvement of vital organs, with a particularly long-standing course. However, after prolonged and heavy systemic treatment, our patients were stabilized and none died from sarcoidosis or related complications.
Although admittedly a rare localization of sarcoidosis, the actual frequency of SNS is difficult to appraise accurately. Published data differ depending on whether SNS is defined according to symptoms, nasal endoscopy, sinus CT, or histopathology. Histologically proven SNS has been estimated between 0.7% and 6%9,17,18,24,25. On the basis of strict diagnostic criteria similar to those proposed by deShazo et al5, we found a prevalence of 1.6%.
In our experience as well as in the literature17,20, SN involvement occurred either before systemic involvement or during the course of previous sarcoidosis within a wide time interval, but symptoms were mostly present at the onset of sarcoidosis in patients with florid disease. Yet, in 20% of our patients the diagnosis of sarcoidosis was delayed because SN symptoms were initially isolated. In such cases with isolated chronic rhinosinusitis unresponsive to local treatment, biopsy should be systematically performed since SACE is rarely increased and local examination and sinus CT are nonspecific, although suggestive. Of course, the measure of ANCA, which was always negative in our patients, is helpful to rule out the possibility of Wegener granulomatosis, the trickiest differential diagnosis of SNS.
SN involvement may vary from an almost quiet to a very disabling manifestation of sarcoidosis. Symptoms of SNS are nonspecific but anosmia was particularly frequent in our population, affecting 70% of cases, which has not been emphasized in previous series3,5,6,17,24. We found a high percentage of purulent rhinorrhea, as did Wilson et al24. Nasal endoscopy was always abnormal in our population and suggestive although not specific. The most frequent pattern was hypertrophic or purplish coloring of the mucosa with pale yellowish nodules, which are believed to represent the sarcoid granulomas. As noted by other authors, the lesions predominated on the septum and inferior turbinates6,24.
SNS CT has been rarely described in the literature2,3,5,12. Three groups of abnormalities have been identified at CT by Bourjat and colleagues2: 1) nodules, mucosal hyperplasia, and filling; 2) lysis; and 3) atrophy. The nodules were considered the most evocative sign of sarcoidosis2. They are about 3 mm, numerous, localized on the nasal septum and the lower turbinates, and clearly visible on the axial slices. However, they were rare in the current series. The most characteristic lesions were medial osteo and chondrolytic lesions: septal perforation, atrophy of the skeleton of the lower turbinates, lysis of the nasal bones. The lytic lesions were always associated with a total or subtotal filling of the majority of the sinuses. They may reflect advanced irreversible SN lesions.
Demographic features and respiratory involvement did not differ significantly between sarcoid patients with or without SN involvement. There was no history of exposure to aero-contaminants that could have favored SN localization, and histopathology never revealed a foreign body-type reaction within granulomas. Among extrarespiratory localizations we found a highly positive association between SNS and lupus pernio, which was present in 50% of our cases. Lupus pernio is a chronic persistent violaceous skin lesion with a predilection for the nose, cheeks, and ears. This manifestation has been recognized as an indicator of chronic multisystem sarcoidosis by James and colleagues8. The association between SNS and lupus pernio has been described previously8,20,24 with a high frequency, similar to that in the current study. Neville et al20 reported a series of 34 patients in which 17 had evidence of upper respiratory tract sarcoidosis and 26 had lupus pernio. In 9 patients, these features coexisted. The pathogeny of such an association remains unclear but may result from contiguous extension of granulomas. Although the CNS was affected in 15% of our patients with SNS, the difference compared with controls did not reach the level of significance, perhaps because of the small number of patients. Indeed, it has been suggested that CNS sarcoidosis may sometimes be a consequence of perineural spread from SNS16,19, which involves areas of exceptional vascularity such as the hypothalamus, optic nerve, and pituitary gland14. It is noteworthy that these areas were the site of sarcoidosis in our 3 cases with SNS and CNS involvement. Another explanation may be the common embryogenic origin of both pituitary gland and SN mucosa.
Results of the current study clearly show that patients with SNS have a more severe illness in terms of number and severity of extrarespiratory localizations. This probably explains the poorer outcome of these patients compared with sarcoid controls, and their significantly lower probability of remission and higher requirement of systemic treatment. These findings have been mentioned by other authors1,3,11,12,23-25, but to our knowledge this is the first case-control study to ascertain them.
Although SNS is known to be a difficult problem in sarcoidosis, its therapeutic management has never been clearly codified. Krespi et al proposed a staging system to categorize the severity and sites of involvement and to guide the aggressiveness of therapy11. This approach is interesting but limited by 2 issues: first, the patients were recruited with SN symptoms as their primary manifestation of sarcoidosis and the extent of systemic disease was not well documented; second, the period of follow-up was rather short (mean of 20 mo). In our experience, local treatment was always inadequate; systemic therapy was always required, often with a high dosage of corticosteroids. The opportunity of sparing treatments should be discussed precociously, since patients with SNS have a chronic course of sarcoidosis and need prolonged therapy, which frequently leads to corticosteroid adverse effects. Importantly, the threshold level of corticosteroids to control sarcoidosis was dictated by SN involvement in 72% of our patients, while a complete resolution of SN symptoms was obtained in only 28% of them.
Surgery for SNS is controversial. Short-term results may help reduce symptoms, but surgery alone does not eradicate the disease or prevent recurrence15. Moreover, several authors have emphasized that the surgical procedure may be dangerous. Neville et al20 noted that submucous resection may provoke nasal septal or palatal perforation. Accordingly, 1 of our patients who underwent surgery experienced severe intra- or postoperative complications. Taken together, these results suggest that surgery should be avoided in patients with active SNS. However, 2 recent studies10,12 advocated the role of endoscopic sinus surgery in patients with nasal obstruction or chronic sinusitis due to anatomic blockage from SNS. In such a context, surgery may allow for improved SN hygiene through office endoscopic debridement, irrigation, and topical application of medicines.
Limitations of the current study are as follows: 1) this is a single-center and retrospective analysis with possible biases including the estimated prevalence of SN involvement and the validity of the control group. However, all patients with sarcoidosis seen in our department are systematically asked about the presence of SN symptoms at each visit; patients with SN symptoms undergo endoscopic examination by an experienced physician (MO) and, if abnormal, guided biopsies of the nasal or sinus mucosa. 2) We focused only on patients with histologically proven SN involvement, and therefore we may have selected patients with a more severe disease. In fact, some authors have suggested that SN mucosal biopsy may be negative in patients with authentic SNS6,12,24, and that patients with a positive biopsy had a worse prognosis12. However, we believe that the best and only reliable diagnostic criterion for SNS is histologic evidence, since there is no clinical or radiologic-specific sign of SNS.
We conclude that, although uncommon, SNS is associated with a local and general severity of sarcoidosis including disease dissemination, serious localizations, and absence of recovery. It is a recalcitrant localization that mostly requires high doses of systemic corticosteroids and represents a difficult therapeutic challenge. However, after a long and difficult period with systemic treatments, patients may finally be controlled. Further multi-center, prospective, observational studies are needed to evaluate the efficacy of specific medications such as methotrexate or thalidomide and the role of surgery.
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