3.3 Ancillary tests and histological confirmation
PPD was negative in 447 out of 513 patients (87.1%). One hundred and sixty-five of 436 patients (37.8%) showed hypergammaglobulinemia at diagnosis. SACE levels at diagnosis were increased in 278 out of 543 patients (51.2%) in whom SACE had been performed. 67-gallium scan was performed in 406 patients at diagnosis. Increased uptake was present in mediastinal lymph nodes in 339 patients (83.5%), in pulmonary parenchyma in 96 (23.5%), and in parotid and salivary glands in 74 (18.1%). Twenty-nine patients (7.1%) did not show increased 67-gallium uptake. FDG PET-CT was performed in 85 patients either at diagnosis or at any time during the follow-up. Mediastinal involvement was present in 62 patients (42.5%), pulmonary parenchyma in 36 (24.7%), and extrapulmonary sites in 34 (23.3%). Table 8 displays the different types of positive biopsy procedures.
3.4 Treatment, follow-up, and outcome
A total of 587 patients (91.7%) were followed-up and 53 (8.3%) were not, since they had been referred to our sarcoidosis unit from other hospitals only for diagnosis assessment. The mean follow-up was 112.4 ± 98.3 months (range, 6.4–475 months). Of this group, 266 (45.3%) received treatment for at least 3 months at some time during the follow-up. Corticosteroid treatment was administered in 255 patients (43.4%). Steroid-sparing agents, usually with a low-dose of corticosteroids, or a combination of them, were administered as follows: methotrexate in 25 patients (4.3%), antimalarials in 23 (4%), and azathioprine in 22 (3.7%). Other agents were used in a few cases: mycophenolate mofetil in 8 patients, cyclosporine in 3, infliximab in 3, minocycline in 2, cyclophosphamide in 2, rituximab in 2, and pentoxifylline in 1.
Table 9 summarizes the overall outcome of the 587 patients that were followed-up. One hundred and eleven patients (18.9%) showed active disease at the time of closing the present study. Two hundred and fifty patients (42.6%) showed spontaneous remission without treatment. Sixty-one patients (10.4%) had remission under treatment. One hundred and sixty-five patients (28.1%) showed active disease more than 5 years after diagnosis and were classified as chronic sarcoidosis. Among these, 115 patients (19.6%) showed mild activity and 50 patients (8.5%) were classified as having moderate to severe organ damage. The most frequently damaged organ was the lung (particularly pulmonary fibrosis), the nervous system, and the skin. Four patients are currently under assessment for pulmonary transplantation, and 1 is under hemodialysis and being assessed for a kidney transplant. One patient had a complication of mycetoma. Thirty out of 266 treated patients (11.3%) presented relapse after decreasing the dose of corticosteroids or the suppression of therapy. Twenty-two out of 587 patients (3.7%), 21 Löfgren, and 1 non-Löfgren, had recurrence of the disease years after spontaneous remission without treatment. Nine out of 587 patients (1.5%) died due to causes related to sarcoidosis (6 pulmonary fibrosis, 2 pulmonary hypertension, and 1 portal hypertension).
3.5 Predictor factors at diagnosis of chronic sarcoidosis
Table 10 shows the results of univariate and multivariate analysis of factors at diagnosis predicting active disease at 5 years (chronic sarcoidosis, including both mild and moderate to severe organ damage). Age more than 40 years, the presence of pulmonary involvement on chest radiograph, splenic involvement, and the need of treatment (both corticosteroids and steroid-sparing agents) were associated with a poor prognosis. Löfgren syndrome and the presence of mediastinal lymphadenopathy on chest radiograph were associated with a good outcome.
Table 11 shows the comparison between the first 2 and last 2 decades of the study as regards age of diagnosis, extrapulmonary organ involvement, treatment with steroid-sparing agents, and mortality.
The present study describes our 40-year clinical experience of a large cohort of 640 consecutive patients with sarcoidosis at Bellvitge University Hospital, Barcelona, Spain. Most of our patients were Caucasians, because immigration in Spain has been minimal until recently. Since there is no reliable official epidemiological data on sarcoidosis in our country, this large series of patients and its prolonged period of follow-up provide a representation of the situation of sarcoidosis in Spain.
4.1 Mode of presentation of sarcoidosis
Knowledge of the wide variety of presentations of sarcoidosis is crucial in initial diagnostic suspicion. The most outstanding feature of this series was the high frequency of erythema nodosum as a way of onset of the disease. The high frequency of Löfgren syndrome in Spain had been already reported in a cooperative study among 3 hospitals in Barcelona, performed more than 20 years ago. Several studies have also described a high prevalence of Löfgren syndrome in northern European countries.[35,36] It has been hypothesized that Löfgren syndrome is a consequence of a combination of environmental factors, with a genetic predisposition. Earlier studies showed that symptoms of erythema nodosum were, significantly, first noticed during springtime.[36,38,39] In addition, a genetic study involving Swedish and Spanish patients confirmed previous reports that the CCR2 haplotype 2 and HLA-DRB1*0301 were independent risk factors predisposing to Löfgren syndrome.[36,37,40] A small but significant number of patients (6.4%) presented only with ankle swelling without erythema nodosum, which is considered a variant of Löfgren syndrome.[35,39,41]
Three other forms of presentations in our series deserve some comments. In spite of 91% of our patients having intrathoracic radiographic involvement, respiratory symptoms were the way of presentation in only 16% of cases, which corroborates the frequent clinical-radiographic dissociation seen in sarcoidosis. A systemic work-up for sarcoidosis is indicated in any patient presenting with granulomatous cutaneous lesions (9.4% in our series). In previous reports we have stressed the presence of papules in the knees as a frequent form of onset of systemic sarcoidosis.[43,44] Not infrequently, sarcoidosis is discovered by chance in a chest radiograph or a thoracic CT performed for other reasons (8.4% in our series). Currently, the detection of sarcoidosis as an asymptomatic finding has increased with the use of FDG PET/CT scan performed during the follow-up of patients with cancer. The wide clinical variety of the other forms of presentations shown in Table 1 highlights the multisystem nature of sarcoidosis.
4.2 Pulmonary sarcoidosis
The chest radiograph stages distribution based on Scadding classification in our series is in concordance with most series of sarcoidosis. Thoracic CT was performed in 49% of our patients. Significantly, it demonstrated the presence of pulmonary involvement in 23% of patients with stage 0, and in 30% of those with stage I on chest radiograph. However, this finding by itself is not an indication for treatment, unless there is the concomitant presence of respiratory symptoms and/or decline in respiratory function. In sarcoidosis, thoracic CT is considered more important as a diagnostic modality than for treatment indications. However, it should not be performed systematically in patients with a typical chest radiograph. Most of our patients showed normal PFT at diagnosis. This finding reaffirms that clinical-radiographic dissociation is also extensive to pulmonary function in sarcoidosis. In our series the most frequent impairments were restrictive and/or obstructive patterns and/or decrease in DLco. Concomitant irreversible airflow obstruction is frequently present in stage IV. Although there is a significant overlap between radiological stages and impairment of PFT (as shown in Table 5), in general, the more advanced the radiological stage, the greater the decline in functional status. FVC is considered the simplest and most accurate parameter to reflect the impact of pulmonary involvement.[49,50]
4.3 Extrapulmonary sarcoidosis
The frequency of extrapulmonary manifestations in our cohort of patients agrees with other large international series.[6,7,33] The skin, specific (granulomatous) cutaneous lesions, was the second organ involved after the lung. The more frequent granulomatous cutaneous lesions were maculopapules and plaques. Lupus pernio, that has been reported to be frequent in African American and West Indian patients, with a woman predominance, and a hallmark of chronicity,[51–53] is not frequent in Spain. Mild cholestasis caused by granulomatous hepatitis is common, while severe cholestasis and portal hypertension are rare. It is important to recognize the presence of low-attenuation nodules on CT on the liver and spleen as a not infrequent finding of sarcoidosis. Eye involvement was not frequent in our series, in spite of systematically performing an ophthalmologic examination in the initial assessment.
Neurosarcoidosis was present in 8% of patients in our series. The most frequent manifestation was cranial neuropathy, particular facial palsy, sometimes bilateral. Leptomeningeal involvement, either as aseptic meningitis or as focal or diffuse gadolinium meningeal enhancement on MRI, on isolation or associated with cranial neuropathies, is a common abnormality in neurosarcoidosis and occasionally may result in hydrocephalus. The hypothalamus and the pituitary gland are the most frequent parenchymal brain involvement and may result in endocrinopathies. However, as shown in Table 6, any region of the brain and spinal cord can be involved, resulting in a variety of neurological symptomatology. Periventricular white matter lesions on MRI are not infrequently seen, but they are considered non-specific. Peripheral neuropathy is uncommon and small fiber neuropathy causing disabling pain is being increasingly recognized.
Table 6 also shows that other forms of extrapulmonary involvement, such as hypercalcemia and salivary and lacrimal glands, were less frequent. Recognition of sarcoidosis of the upper respiratory tract (SURT) is important since subtle symptoms of nasal obstruction may be overlooked by physicians. Bone sarcoidosis is being detected with increasing frequency in asymptomatic patients following the introduction of FDG PET/CT. Renal involvement is usually a consequence of granulomatous or lymphocytic interstitial nephritis. Symptomatic muscle involvement is rare. Cardiac sarcoidosis is very uncommon and difficult to recognize, although is frequent in Japan. Apart from the different organs involved, a considerable burden of disease may be caused by nonspecific but troublesome symptoms, termed by Lazar and Culver as “sarcoidosis penumbra.”  The most significant is fatigue, which accounted for almost 10% of patients in our series. Fatigue may be present even when the disease is already in remission, and may frequently be accompanied by depression and impair quality of life.[58,59]
Interestingly, although most extrapulmonary organ involvement took place in the first 6 months after diagnosis, some organs were affected during follow-up. Therefore, longitudinal screening should be maintained over time. Only symptoms related to Löfgren syndrome always occurred at onset.
4.4 Histological diagnosis
One positive biopsy may be sufficient when clinical-radiographic findings are typical; otherwise, 2 or more may be necessary. However, in some classic presentations, such as Löfgren syndrome, asymptomatic BHL, and Heerfordt syndrome, the diagnosis can be accepted without histological support. Given the multisystem nature of the disease, a wide variety of biopsies have been used in sarcoidosis. Currently, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming the diagnostic procedure of choice in many centers because of high sensitivity and low complications rate, and it is replacing the practice of mediastinoscopy and transbronchial lung biopsy.[61,62] Conjunctival and nasal mucosa biopsies also have a high yield, and their practice has been recommended as silent sites of granulomatous inflammation in patients with diagnostic difficulties, for instance, in isolated neurosarcoidosis. However, the demonstration of granulomatous inflammation by itself is not specific to sarcoidosis, and a differential diagnosis with other granulomatous diseases, according to the involved organ, is mandatory.
4.5 Treatment, follow-up and outcome
In sarcoidosis there is often a struggle to distinguish between treatable active disease and irreversible untreatable disease-related damage. In most patients, the disease resolves spontaneously without treatment (42.6% of patients in our series) or with treatment (10.4% of our patients). Some authors have suggested classifying sarcoidosis as chronic when the disease remains active for more than 2 years. However, chronicity is currently accepted when the disease remains active for more than 5 years, since a significant number of patients become inactive between 2 and 5 years spontaneously or under treatment. In our series, 28.1% of patients showed active disease for more than 5 years and were classified as chronic sarcoidosis. However, patients with chronic sarcoidosis may show a mild degree of activity without clinically significant organ dysfunction, in what has been called smoldering sarcoidosis (19.6% in our series), or with moderate to severe organ damage (8.5% of our patients). Signs and symptoms caused by organ damage may be a consequence of still active disease, which is theoretically susceptible to some response to therapy, or irreversible fibrosis, both often coexisting in the same organ. Signs and symptoms caused by active granulomatous inflammation and irreversible damage may be initially similar and a major challenge is to distinguish between these states in order to indicate appropriate therapy.
Treatment indications in sarcoidosis have been controversial for many years, as clinicians have to bear in mind a range of possibilities in evolution of the disease: spontaneous remission, mild persistent disease for years with almost no clinical repercussion, chronic disabling active disease, irreversible damage, and, equally important, a balance between the benefits and side effects of treatment. In our view, irreversible side effects caused by treatment should be included in the concept of damage in sarcoidosis. The main indications for treatment are symptomatic pulmonary progressive disease with functional derangement, and major extrapulmonary organ involvement.[31,47,63–68] In our series, 45.3% of patients received treatment, most of them with corticosteroids. A small but significant number of patients received other immunosuppressive agents, usually in combination with low-doses of corticosteroids. Anti-TNF therapies were used in very few cases. However, only about 10% of patients did complete remission take place during treatment. In addition, in most patients with chronic sarcoidosis, treatment just helped to keep the disease under relative control. These findings may put in question the true efficacy of current treatments in sarcoidosis. The most frequent and clinically significant forms of end-stage organ damage were pulmonary fibrosis, neurosarcoidosis, and cutaneous disfiguring lesions such as lupus pernio. Pulmonary fibrosis from sarcoidosis is usually slowly progressive, and may range from asymptomatic to be life-threatening because of the development of respiratory failure, bronchiectasis, or pulmonary hypertension.[69–71]
4.6 Predictor factors at diagnosis of chronic sarcoidosis
This study corroborates that Löfgren syndrome and the presence of mediastinal lymphadenopathy are clinical factors associated with good prognosis, whereas advanced age, pulmonary, and splenic involvement are associated with poor outcomes. These results are similar to those reported by our previous and other prognostic studies.[21,25,26,72] However, variables representing some of the extrathoracic manifestations that have been previously associated with poor prognosis in the literature, such as cardiac sarcoidosis and others, did not reach statistical significance because of the few patients with these manifestations in our series (Table 6). In several studies the use of corticosteroids has been associated with chronic sarcoidosis. An intense immune response, as noted by BAL studies, is usually indicative of a favorable outcome, and it has been hypothesized that its suppression with corticosteroids may be harmful. However, it seems more plausible that the indications of therapy, according to current guidelines, simply reflexes the more severe cases at the beginning of the disease. The important differences between Löfgren syndrome and other forms of sarcoidosis in clinical presentation and outcome, and the existence of at least 2 clear genetic markers of Löfgren syndrome, such as HLA class II haplotype DRB1*0301 and CCR2-haplotype 2, strongly suggest that they may represent distinct entities.
4.7 Comparison between the first 2 and last 2 decades
Our study allows a number of interesting comparisons to be made. Firstly, the age of diagnosis increased slightly in the last 2 decades. This may be due to the frequency of patients with Löfgren syndrome being much higher during the first 2 decades. We believe that the main reason for the decrease of patients with Löfgren syndrome in the last 2 decades is a more accurate selection of difficult cases for referral from other centers. Secondly, the detection of other organ involvement may have increased with the introduction of more advanced imaging techniques, despite data not always being statistically significant. Finally, a clear increase in the use of steroid-sparing agents can be observed in the last 2 decades.
Our study has some limitations. The high frequency of Löfgren syndrome in our country limits comparisons with other series of sarcoidosis based on different ethnicities. Besides, as we only analyzed patients assessed at a tertiary reference center, the sample selection could be somehow slightly biased. The study is also limited by the observational nature inherent to studies of clinical series of sarcoidosis. The follow-up of the patients was not uniform, the analysis of cases was made at different moments of their disease course, and some data were missed. The absence of validated criteria to define the presence of activity of sarcoidosis and in particular to evaluate the degree of organ damage is an additional important limitation of the study as well.
In summary, the present observational and prognostic investigation reports a 40-year overview of the clinical spectrum and long-term follow-up of the disease in a large series of 640 patients with sarcoidosis at a single reference center in Barcelona, Spain. This extended and consistent experience in managing a large number of patients with sarcoidosis firmly emphasizes the value of a multidisciplinary approach by specialized teams in the clinical assessment and long-term follow-up of the disease.
The authors would like to acknowledge the fundamental contribution to this study made by Dr Francesc Badrinas, who set up the Sarcoidosis Unit at the Bellvitge University Hospital in the 1970s, working as director until his death in 1992.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
Löfgren's syndrome; observational; prognosis; sarcoidosis