INTRODUCTION
Sarcoidosis is a multisystem granulomatous disease of unknown cause. Although the lung is affected in 90% of cases, sarcoidosis may occur in any organ.17 The global incidence and prevalence of sarcoidosis vary between studies, mostly because of the selection bias when ascertaining the actual extent of sarcoidosis in a given community. The incidence of sarcoidosis is estimated to be between 15.3 and 21.7/100,000 according to sex and series.15,25 The estimated prevalence varies from 1 to 40 cases per 100,000 individuals, with a particular proclivity for adults aged less than 40 years. The female to male ratio is between 1.2 and 1.5 to 1.0.2,15,23,27 About 70% of the cases are aged 25–40 years old at presentation,21,23,27 while 30% are aged more than 50 years.2 Two studies—in Scandinavian5 in 2003 and in Japan22 in 2008—found a peak incidence between 25 and 35 years of age in both sexes, while women displayed a second, lower peak at between 50 and 65 years of age.
Although sarcoidosis does not seem uncommon in the elderly, with an annual incidence of about 10 cases per 100,000 inhabitants reported for this population,5,25 specific studies in this subgroup are scarce.8,26,29 One study conducted in a French university hospital included 30 patients with sarcoidosis diagnosed after the age of 70 years between 1986 and 2000 and investigated the clinical features and disease course.8 Alteration of general health and dyspnea were frequent. The intrathoracic form of sarcoidosis was most frequent (43.3%). Accessory salivary gland biopsy was an important contributing factor to diagnosis (70.6% were positive). Oral corticosteroid therapy was often required (60.7%). The disease course was satisfactory overall (81.8% of cases), but only for 50% of patients in intrathoracic stage IV.
To our knowledge, no study has compared the characteristics of patients with late-onset sarcoidosis (diagnosed in patients aged ≥65 yr) to those of younger patients. Thus, we conducted the current study to analyze the characteristics and outcomes of patients with late-onset sarcoidosis in 1 teaching institution, and compared them with those of randomly selected control patients diagnosed at a younger age.
PATIENTS AND METHODS
Patients
We undertook a retrospective study of all incident cases of sarcoidosis hospitalized in a French university hospital between 2002 and 2006, in whom the diagnosis was made after 65 years of age. Information was provided by the institutional database of diagnosis coding (Programme de Médicalisation du Système d’Information) of the Lyon University Hospital. All records were selected on the basis of the presence of the code D86 and decimals of the International Classification of Diseases.
Patients were included in the study if they met the following 5 criteria: 1) clinical features consistent with sarcoidosis; 2) age ≥65 years at diagnosis 3) absence of any known history of sarcoidosis; 4) biopsy analysis revealed noncaseating granuloma (except for patients presenting with Löfgren syndrome, for whom the diagnosis of sarcoidosis was made without requiring histologic evidence); 5) and exclusion of other possible causes, including other granulomatous disorders.16 Patients presenting with concomitant progressive neoplasia or isolated granulomatous hepatitis were excluded because of the uncertain nosology of these conditions.
Thirty patients met the inclusion criteria the “late-onset” group. Twenty-two cases were excluded: 5 due to lack of histologic evidence, 3 due to concomitant neoplasia, and 14 because of insufficient data. The 30 patients with late-onset sarcoidosis were compared to a group of 70 younger patients hospitalized during the same period. This group, randomly selected among all patients younger than 65 years of age at sarcoidosis diagnosis, constituted the “young-onset” sarcoidosis group. The method of selection and criteria for inclusion (except for age at diagnosis) were the same as those for the late-onset group.
Data Collection
Data were collected from a complete medical examination at diagnosis, including demographic characteristics, medical history, specialty of department where the patient was seen, and sites of tissue biopsies. Data from laboratory analyses including C-reactive protein (CRP), blood lymphocytes count, liver tests, calcemia, and serum angiotensin-converting enzyme level were gathered at baseline and during follow-up. Chest radiographs were rated according to the Scadding stage method3,10: normal radiography (stage 0), mediastinal adenopathy (stage I), parenchymal involvement associated with mediastinal adenopathy (stage II), infiltrating lung disease without mediastinal adenopathy (stage III), and pulmonary fibrosis (stage IV). Results of other imaging findings (including chest computed tomography [CT]), pulmonary function tests, bronchoscopies with bronchoalveolar lavage (BAL), cardiac investigations, and detailed medical treatments were also recorded when available.
Severity of the disease was assessed using the equation proposed by Wasfi et al,31 from the last available data:
- Severity score = 11.47 + 3.51 (C) + 2.27 (N) + 1.41 (IS) − 0.033 (DLCO%) − 0.047 (FEV1/FVC) + 1.23 (AA) − 0.027 (FVC% predicted) + 0.52 (skin)
where C = 1 if patient has cardiac involvement, 0 if not; N = 1 if patient has neurologic involvement, 0 if not; IS = 1 if patient was receiving noncorticosteroid immunosuppressant therapy at the end of follow-up, 0 if not; AA = 1 if patient was black, 0 if not; and skin = 1 if patient had skin involvement, 0 if not.
Statistical Analysis
Results were expressed as the mean standard deviation or percentage. The chi-square test or the Fisher exact test was used to compare qualitative values. Quantitative values were compared with an unpaired t test and Mann-Whitney test for rank test. All p values reported are 2-sided; they were considered significant when < 0.05. Statistical analysis was performed with IBM SPSS Statistics v. 19.0 (IBM Corp., Somers, NY).
RESULTS
Demographic and Clinical Characteristics
The late-onset sarcoidosis group included 25 women and 5 men (Table 1). The proportion of women was significantly higher in the late-onset group compared to the young-onset group (83.3% vs. 50%, respectively; p = 0.003). Mean age at the diagnosis of sarcoidosis was 70.6 years in the late-onset group (range, 65–84 yr). Groups were statistically similar in terms of ethnic and racial distribution. The elderly group had a higher number of associated illnesses (mean rank, 70.87 vs. 41.77; p < 0.0001). Only a quarter (26.7%) of the late-onset group were seen in a pulmonary medicine department, compared with two-thirds (68.6%) of the young-onset group (p < 0.0001). Most (56.7%) of the elderly patients were referred to an internal medicine department.
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TABLE 1: Demographic Features
The clinical characteristics at diagnosis for both groups are presented in Table 2. No patient among the elderly was asymptomatic at the time of diagnosis, whereas sarcoidosis was revealed by routine chest X-ray in 11 (15.7%) young patients. Clinical features were significantly different between the 2 groups for the frequency of asthenia (30% vs. 10%; p = 0.012) and of specific skin lesions (36.7% vs. 15.7%; p = 0.02), which was higher in the elderly group. Eighty percent of the patients with uveitis were women, and uveitis was more common in the elderly than the young patients (33.3% vs. 8.6%; p = 0.002). On the contrary, erythema nodosum was higher in the young-onset group (p = 0.016). There was no significant difference regarding pulmonary and neurologic manifestations, lymph nodes, fever, hepatosplenomegaly, dry mouth, or arthralgia.
TABLE 2: Clinical Features at Diagnosis
Extraclinical Investigations and Site of Tissue Biopsies
There was no significant difference between the 2 groups with regard to extraclinical investigations (Table 3). In the late-onset group, lymphopenia, defined as a blood lymphocyte count <1500 lymphocytes/μL, was noted in 10 of 27 (37%) cases with that information. CRP was elevated (>3 mg/L) in 15 of 24 (62.5%) cases. Elevated angiotensin-converting enzyme levels were found in 21 of 28 (45%) patients. Liver tests were abnormal in 13 of 25 (52%) patients, while hypercalcemia was noted in 1 of 27 (3.7%) patients. Lymphocytic BAL was significant in 61.1% of the studies (11/18 patients), although this examination was performed infrequently. Of the 25 late-onset patients with chest X-rays, 11 patients (44%) had radiographic stage I disease, 5 (20%) had radiographic stage II disease, and 3 (12%) had radiographic stage III disease. For the 6 patients (24%) with normal chest X-rays, chest CT showed abnormalities suggestive of sarcoidosis. Pulmonary function tests were available for 24 of 30 elderly patients (80%). Spirometry revealed restrictive ventilatory dysfunction (defined as forced vital capacity [FVC] <80% of predicted value) in 5 patients (20.8%) and obstructive pattern (defined as forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC] <70%) in 3 patients (12.5%). Impairment of the diffusing capacity of the lung for carbon monoxide (DLCO) was noticed in 7 of 20 tested patients, and in only 3 patients (15%) when corrected for the alveolar volume.
TABLE 3: Extraclinical Results at Diagnosis
Forty-eight biopsies were performed in the late-onset group; 34 were positive (Table 4). The bronchial mucosa was sampled most often (n = 18; 37% of 48 biopsies), and 39% (7/18) had positive results. Seven of 9 (78%) minor salivary glands biopsies performed in the elderly were positive. Mediastinal and peripheral lymph nodes constituted respectively 4% and 6% of the sites of tissue biopsies. Open lung biopsy, liver biopsy, bone marrow biopsy, and splenectomy were performed in 8% (4/48) of the cases. Biopsies of the minor salivary glands and skin were performed more frequently in the late-onset group than in the younger patients (respectively, 18% vs. 4%; p = 0.002 and 25% vs. 13%; p = 0.023). In contrast, the proportion of patients with transbronchoscopic biopsies was smaller in the late-onset group (0 vs. 10%; p = 0.022). We subsequently compared the contribution of site of biopsy to the diagnosis in both groups (data not shown). The proportion of patients with positive minor salivary glands biopsies and positive skin biopsies was higher in the late-onset group, although the difference was not statistically significant. For biopsies of other sites, no difference in the rate of diagnosis profitability was observed.
TABLE 4: Tissue Biopsy Sites
Treatment and Outcome
Among the late-onset group, 21 patients (70%) received systemic corticosteroid therapy (Table 5). Initial daily corticosteroid doses were usually 1 mg per kg of prednisone equivalent. Immunosuppressive agents were associated with corticosteroids in 5 patients: methotrexate in 2 cases for posterior uveitis, and azathioprine in 2 cases for severe lung involvement; 1 patient received methotrexate for myositis and then azathioprine because of lack of response. Five other patients received hydroxychloroquine alone for skin involvement. All the elderly patients who received corticosteroids developed at least 1 corticosteroid-related complication: infectious diseases (n = 9), hypertension (n = 6), diabetes (n = 6), osteonecrosis in the femoral head (n = 4), cataract (n = 4), weight gain (n = 3), osteoporotic vertebral fracture (n = 3), myopathy (n = 1), and ischemic heart disease (n = 1). Overall, in the late-onset group, the outcome was considered satisfactory in 80% of the cases (improvement in 60% and stabilization in 20%), and in 70% of the patients treated with general corticosteroid therapy. There was no significant difference between the late-onset and young-onset groups with regard to prevalence of oral corticosteroid therapy and immunosuppressive use. However, the elderly patients had more side effects with corticosteroid therapy compared with the younger patients (1.26/patient vs. 0.51/patient; p < 0.001).
TABLE 5: Treatment and Outcome
The mean follow-up after the diagnosis of sarcoidosis was 50 months (range, 5–127 mo). At the time of analysis, 3 of the 30 patients in the late-onset group had died: 2 from heart failure not related to sarcoidosis (at 23 and 50 mo after the diagnosis, respectively), and 1 from hemoptysis due to pulmonary mycetoma related to Aspergillus fumigatus (at 113 mo after the diagnosis). Three of the 70 younger patients had died: 1 from heart failure related to pulmonary hypertension (at 194 mo after the diagnosis), and 2 from infectious pneumonia with chronic respiratory failure (at 155 and 220 mo after the diagnosis, respectively). The 5-year and 10-year survival rates after diagnosis of sarcoidosis were 93% and 90% in the late onset-group, compared with 100% and 100% in the young-onset group (p = 0.03 and p = 0.007, respectively). There was no significant difference in the Wasfi severity score.
DISCUSSION
Little is known about the clinical features of sarcoidosis in the elderly. To our knowledge, the current study is the first to compare the clinical, extraclinical, and therapeutic characteristics of patients with sarcoidosis diagnosed after age 65 years to those of randomly selected younger subjects with sarcoidosis. The study provides important insights for the management of sarcoidosis in the elderly. In an earlier study (1988), Stadnyk et al29 retrospectively reviewed 17 cases with biopsy-proven sarcoidosis first diagnosed at age 65 years or older, over more than 30 years. More recently (2004), Chevalet et al8 reported a series of 30 French cases of elderly-onset sarcoidosis (patients aged ≥70 yr at diagnosis) seen from 1986 to 2000. As far as we know, these 2 studies are the only published series concerned specifically with the clinical characteristics and course of sarcoidosis in patients aged >65 years. The authors of these 2 series suggest the possibility of certain clinical and evolutive peculiarities of sarcoidosis in the elderly by comparing their results to those of other previous studies. We believe the current study is the first to compare the characteristics of older patients with sarcoidosis diagnosed after 65 years of age with those of younger patients. Two other studies evaluated the general clinical features of patients diagnosed at age 50 years or more and compared the features of those subjects with features of patients with disease diagnosed below age 50 years.20,33 In the study by Yanardag et al,33 extrapulmonary involvement was observed to be more common in older patients, while arthritis, clinical presentation in the form of Löfgren syndrome, erythema nodosum, and uveitis were less frequent. In the study by Lenner et al,20 patients in the 2 groups had similar presenting symptoms and organ involvement. There is no strict definition of late-onset sarcoidosis, but the cutoff age used most frequently to define “elderly” is 65 years at disease onset or diagnosis.
In the present study, the mean age at diagnosis was 70.6 years, which is comparable to that in the series of Stadnyk et al29 (70.9 yr) and Chevalet et al8 (74 yr). Female patients represented 83.3% of cases in the elderly-onset sarcoidosis group. The female to male ratio of 5:1 was significantly higher than the ratio observed in the young-onset group (1:1) while no difference in the ethnic or racial distribution was observed. This women’s preponderance was already noted in the studies by Stadnyk et al29 and Chevalet et al8 (76% and 70.3% women, respectively), but also in several epidemiologic studies in patients from 50 years of age, whatever the race.2,5,22,25 However, no physiopathologic data are available to explain the possible role of hormonal factors on sarcoidosis activity.
As expected in a study in a geriatric population, the number of comorbidities was higher in the late-onset group than in the young-onset group. The presence of comorbid conditions influences therapeutic decisions, and clinicians should be vigilant concerning the atypical forms of disease they may encounter when another disease is active. In this particular setting, the diagnosis of sarcoidosis may be more difficult to establish, or the activity of the disease may be incorrectly overestimated, or both.24
In the current study we were also interested in the specialty of the department where the patients were seen initially. We note that more elderly patients were referred to a department of internal medicine than pulmonary medicine. This difference could be explained by the atypical forms of disease or extrapulmonary involvement seen in elderly patients, and suggests certain disease management issues related to clinicians’ habits. The site of tissue biopsy illustrates these issues: while there was no difference between the 2 groups in the proportion of patients presenting with dryness syndrome, biopsy of the minor salivary glands was statistically done more often in the elderly-onset group than in the young-onset group. On the contrary, while transbronchial lung biopsies have a satisfactory and safe yield,7,13 this method was never used in the elderly patients in our series.
There was no asymptomatic case in our series in the elderly, whereas fortuitous discovery was common in the young. Alteration of general health (for example, asthenia, anorexia, weight loss) was significantly more frequent in the elderly-onset group, occurring in 33% of patients. This proportion is a little lower than that observed by Chevalet et al8 (43%), while the proportion in the young-onset group is consistent with proportions found in the literature (ranging from 6.3%18 to 16%6). These features may masquerade as malignancy.30 Specific skin lesions were also more frequently observed in our late-onset sarcoidosis group. Conversely, erythema nodosum occurred less frequently in the elderly, affecting no patient in the current study and only 1 patient in the study by Chevalet and colleagues.8 Our study confirms the high frequency of uveitis in elderly women as an initial feature of the disease. All cases of elderly-onset sarcoidosis-associated uveitis reported in our series were biopsy proven. In uveitis patients, sarcoidosis is probably underestimated depending on the extent of the workup diagnosis. As the biopsy of non-ocular tissue is often unacceptable to many patients with uveitis (anterior uveitis with a benign course particularly), some authors have developed criteria for the diagnosis of suspected sarcoidosis-associated uveitis in the absence of histologic proof.1 An international workshop has established criteria to make a diagnosis of “intraocular sarcoidosis” (sarcoidosis uveitis) on the basis of a combination of suggestive ophthalmologic findings and laboratory tests when a biopsy is not carried out or is negative.12
In the current study, the late-onset and young-onset sarcoidosis groups were statistically similar in terms of other extrapulmonary involvements, pulmonary clinical signs, radiographic stage, and pulmonary function data. Surprisingly, we observed a higher incidence of obstructive airway disease than restrictive ventilatory dysfunction in both groups, which is not in agreement with the data of the literature, where a predominance of restrictive ventilatory dysfunction has been reported.17 As in our series, several studies9,19 have shown that chest CT scan is helpful for the diagnosis of sarcoidosis, even in the case of a normal chest X-ray.
Early-onset childhood sarcoidosis occurs traditionally in the first year of life and differs from sarcoidosis in older children and adults.11 Patients with early-onset disease exhibit unique clinical features characterized by the triad of arthritis, rash, and uveitis. In children aged more than 4 years, as in adults, the leading feature is involvement of the respiratory system. Uveitis occurs in more than half the children with onset in the first 5 years of life, while this feature is relatively less common in children with later onset. This similarity in the clinical manifestations of the disease between the youngest children and the elderly-onset patients supposes a comparable immune response. Immunosenescence could at least partly account for differences in clinical features of sarcoidosis in the elderly.
Improvement or stabilization of the disease was observed in 80% of cases in the current series, which is comparable to that reported by Chevalet et al8 (82%) and Chapelon et al6 (82%). The latter included 554 patients of all ages taken together. Corticosteroid therapy was required in 70% of the elderly patients of our study, and immunosuppressant therapy in 16.7%. These percentages were comparable to those of the younger patients. Nevertheless, side effects of steroids were significantly more frequent in our older patients than in the younger patients. These findings have been reported already in studies on the metabolic,4 cognitive,14 and cardiovascular28 effects of corticosteroid therapy among the elderly. For patients affected by sarcoidosis requiring corticosteroid therapy, and particularly in older patients, the lowest effective dose should be sought, and treatment duration should be kept as short as possible after a careful evaluation of the risk/benefit ratio.
The Wasfi severity score31 is not yet a validated tool. However, contrary to other scores such as the CRP score,32 which takes into account only the lung involvement, it seems to be more adapted for systemic forms of the disease. Furthermore, taking into account the current treatment at the time of calculation, it is particularly interesting to compare the patients in a retrospective study. Based on this score, there was no difference in disease severity between the late-onset and young-onset groups. In contrast, the 5-year and 10-year survival rates after diagnosis of sarcoidosis were significantly better in the young patients. This poorer prognosis of late-onset sarcoidosis contrasting with the similar severity of the disease might reflect only the consequences of aging.
Although the current study provides important information on the clinical features of sarcoidosis in the elderly, our work has a number of limitations. First, the study was a retrospective comparative study. Because of this, data for some of the clinical and laboratory investigations were missing, in both of the 2 groups. It is likely that a prospective study would provide much clearer and more complete information. The second limitation is that the study was performed at a single teaching institution in France. We expect that cases referred to our institution are more severe on average than cases encountered in a primary setting, so our results are most generalizable to secondary or tertiary sarcoidosis practices. Moreover, it is well known that clinical features in patients with sarcoidosis vary by country, and disease management is related to the clinicians’ habits. Therefore, further studies performed by other institutions in different countries are mandatory to confirm our results.
Conclusion
Sarcoidosis has different characteristics in the elderly than in younger patients. The female to male ratio is higher in the late-onset group. In the current study, we found altered general health, specific skin lesions, and uveitis to be more common in elderly patients than in the young. On the other hand, no patients in the elderly group presented with erythema nodosum or asymptomatic chest roentgenogram abnormalities. Groups were statistically similar in terms of ethnic distribution, other organ systems involved, pulmonary function data, radiographic stage, laboratory values, and severity. Accessory salivary gland biopsy appears to have a higher accuracy for diagnosis in the elderly. The disease course and therapeutic management in older patients were similar to those in young patients. However, patients aged more than 65 years had more side effects related to general corticosteroid therapy. The reduced survival rate observed in the late-onset group compared with the younger patients may reflect only the consequence of aging.
ACKNOWLEDGMENTS
We thank Pr. C. Confavreux (Department of Neurology, Hôpital Pierre Wertheimer, Bron), Pr. JF. Cordier (Department of Pulmonary Medicine, Hôpital Louis Pradel, Lyon), Pr. I. Durieu (Department of Internal Medicine, Centre Hospitalier Lyon-Sud, Pierre Bénite), Pr. M. Faure (Department of Dermatology, Hôpital Edouard-Herriot, Lyon), Pr. JC. Guérin (Department of Pulmonary Medicine, Hôpital de la Croix-Rousse, Lyon), Pr. J Ninet (Department of Internal Medicine, Hôpital Edouard-Herriot, Lyon), Pr. Y. Pacheco (Department of Pulmonary Medicine, Centre Hospitalier Lyon-Sud, Pierre Bénite), Dr. PJ. Souquet (Department of Pulmonary Medicine, Centre Hospitalier Lyon-Sud, Pierre Bénite) and Pr. L. Thomas (Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre Bénite), France; who provided the observations; and Ms. Elisabeth Da Cunha for her expert assistance in the preparation of this manuscript.
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