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Background: Tumour necrosis factor-alpha (TNF-α) plays a crucial role in sarcoidosis. In severe disease, treatment with TNF-α inhibitors may be effective., Objectives: Changes in sarcoid disease activity were assessed by fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with recalcitrant sarcoidosis treated with adalimumab., Methods: Prospective 24-week observational study. Patients continued medication with steroids and antimetabolites and received adalimumab 40 mg subcutaneously every other week. Ten patients with biopsy-proven sarcoidosis (two men) were included with a median age of 47 years (range 35-73). An FDG-PET showing uptake indicating sarcoid activity was required at inclusion and repeated at the end of the study. FDG-PET uptake was assessed by calculated standardised uptake value (SUV). Blood samples and lung function tests were performed regularly. Quality of life was assessed by the short-form health survey (SF-36) questionnaire., Results: Following treatment with adalimumab, FDG-PET uptake decreased in nine patients (P = 0.011) and increased in one patient. Maximum SUV fell from median 14.1 to 7.0 (P < 0.03), and mean SUV fell from median 6.5 to 2.9 (P < 0.02). Six patients had uptake in the lungs, which decreased after treatment (P = 0.035). Six patients had uptake in the lymph nodes, which decreased after treatment in five patients (P = 0.035). Four patients had non-lymphatic extrathoracic uptake, which decreased after treatment (P = 0.05). There was no effect of adalimumab on pulmonary function tests, serum angiotensin I converting enzyme and blood lymphocyte (CD3+, CD4+, CD8+) concentrations. Physical component summary score (SF-36) increased during treatment, mental component summary score was unchanged., Conclusion: In sarcoidosis, treatment with adalimumab can reduce disease activity, as assessed by FDG-PET., (© 2011 Blackwell Publishing Ltd.)

Background: Tumour necrosis factor-alpha (TNF-α) inhibitors have been introduced in the treatment of refractory sarcoidosis. These biologics may reactivate latent tuberculosis infection (LTBI). Despite its known limitations, the tuberculin skin test (TST) is currently used for the diagnosis of LTBI in Danish sarcoidosis patients. We report the results of a screening using the interferon-gamma release assay (IGRA) QuantiFERON TB Gold (QFN) for the diagnosis of LTBI. We aimed to assess whether the QFN is reliable for diagnosing LTBI among sarcoidosis patients and if results are influenced by disease activity or immunosuppressive treatment., Methods: A prospective study was performed from 2005 to 2007 among sarcoidosis patients who were candidates for TNF-α inhibitor treatment. Information on immunosuppressive treatment was obtained from the medical records. Disease activity was assessed by biochemistry, chest roentgenograms and pulmonary function tests. The predictive value of QFN results was evaluated by follow-up in the Danish National Tuberculosis Registry., Results: A total of 44 sarcoidosis patients (22 men) with a median age of 39 y (range 25-59 y) were enrolled; 93% had a negative QFN test result and 7% had an indeterminate result. Forty-three percent had disease activity and 57% (n = 25) received immunosuppressive treatment. There was no significant difference in QFN interferon-γ response between subjects with or without disease activity (p > 0.4) and between treated vs non-treated patients (p > 0.5). At follow-up using the Danish tuberculosis registry, there was no occurrence of tuberculosis among study participants., Conclusions: The predictive value of the QFN seems good among Danish sarcoidosis patients and the results appear to be unaffected by sarcoidosis disease activity and immunosuppressive treatment.

Background: Based on earlier research, Rickettsia helvetica could possibly be involved in the pathogenesis of sarcoidosis. Rickettsiae are transmitted to humans by a tick vector, Ixodes ricinus; this tick is highly prevalent in Northern Europe. We aimed to investigate the association between evidence of rickettsiae and sarcoidosis in histological samples., Methods: We included formalin-fixed, paraffin-embedded mediastinal lymph node biopsies from 52 ethnic Danish patients with sarcoidosis and compared these with 50 biopsies from ethnic Danish patients with mediastinal lymphadenopathy of other causes. Samples were analysed for: (1) rickettsial DNA by real-time polymerase chain reaction (PCR) and (2) rickettsial rDNA (ribosomal DNA) by a specific fluorescence in situ hybridization technique (FISH)., Results: Rickettsia was not detected in biopsies by real-time PCR and/or FISH analyses., Conclusion: Our results do not support the hypothesis that Rickettsia is involved in the pathogenesis of sarcoidosis.

Background: The butyrophilin-like 2 (BTNL2) gene is located on chromosome 6p21.3 close to the HLA-class II genes. An association has been reported between sarcoidosis and a single nucleotide polymorphism in BTNL2, rs2076530, also termed the A allele., Objectives: To evaluate whether patients with sarcoidosis carry the A allele more frequently than healthy subjects., Methods: The series comprised 87 ethnic Danes with sarcoidosis and 113 healthy control subjects. Analysis of rs2076530 was performed by Taqman assay, polymerase chain reaction and sequencing of genomic DNA., Results: Sarcoidosis patients had a higher frequency of the A allele than controls (73.9% vs 55.8%) (P < 0.025). The frequency of GG, GA and AA genotype was 5.7%, 40.2% and 54.0% in patients vs 16.0%, 56.6% and 27.4% in controls (P < 0.001). The AA genotype was associated with increased risk of sarcoidosis in both a dominant [odds ratio (OR) 3.1; 95% confidence interval (CI) 1.1-8.7; P < 0.03] and a recessive model (OR 3.1; 95% CI 1.72-5.61; P < 0.001). Population attributable fraction for disease was 50% in a dominant model and 25% in a recessive model., Conclusions: The BTNL2 A allele variant occurs with a high frequency in Danish patients with sarcoidosis and the AA genotype is associated with a ∼threefold higher risk of sarcoidosis than the GG genotype. Our results should encourage future studies on the interrelationship between the BTNL2 protein and granuloma formation in sarcoidosis., (© 2010 Blackwell Publishing Ltd.)

Background: Severe pulmonary sarcoidosis is often complicated by pulmonary hypertension (PH) caused by different pathophysiological mechanisms., Objectives: To assess the acute vasoresponsiveness in patients with sarcoidosis and PH and the relation to the therapeutic effect of sildenafil., Methods: A retrospective chart review of 25 patients with recalcitrant pulmonary sarcoidosis being evaluated for lung transplantation at our centre. Haemodynamics were evaluated by right heart catheterisation in 24 patients of whom 19 had PH. Eight of the 19 patients received vasodilator challenge with inhaled nitric oxide (iNO)., Results: The study group of eight patients (seven men) had a median age of 51 years (range 38 years-58 years). During iNO we observed a reduction in all patients' mean pulmonary arterial pressure (MPAP) of median 9 mmHg (range 1 mmHg-20 mmHg) (P = 0.01) and in all patients' pulmonary vascular resistance of median 2.0 Wood Units (0.7 Wood Units-5.8 Wood Units) (P = 0.01). Acute vasoresponsiveness defined as reduction in MPAP of >or=10 mmHg to a MPAP of

Aim: To describe health-related quality of life (hrQOL) in adult subjects who had sarcoidosis in childhood., Methods: Forty-six children (24 boys), all ethnic Danes

Rickettsia helvetica has previously been proposed as an aetiological agent in sarcoidosis. The purpose of the present study was to detect possible signs of Rickettsia infection in a Danish population of patients with sarcoidosis. Twenty-six patients with newly diagnosed sarcoidosis were prospectively enrolled in the study. The diagnosis was confirmed by biopsy in 18 and by clinical characteristics in 8 patients; 11 patients with different non-sarcoid lung diseases were recruited as controls. We obtained information regarding tick exposure and sarcoid disease manifestations by a structured interview. Evidence of rickettsial infection was assessed by an immunofluorescence assay testing for antibodies towards Rickettsia as well as specific real-time polymerase chain reaction (PCR) on lung biopsy specimens. We performed fluorescent in situ hybridization (FISH) on the biopsies to detect rickettsial and eubacterial rRNA. One sarcoidosis patient had serum rickettsial IgG antibodies above the chosen cut-off level. We found no positive rickettsial PCR or FISH analyses in any of the biopsy specimens. One sarcoid patient sample and 1 control sample contained unidentified bacteria. There was no difference in the reported frequency of tick bite between patients and controls. In conclusion, we found no evidence of Rickettsia being involved in the pathogenesis of sarcoidosis in Denmark.

Introduction: Rickettsia helvetica has been proposed as an aetiological agent in sarcoidosis., Objectives: To assess the prevalence of plasma anti-Rickettsia antibodies in a Danish population of patients with sarcoidosis and control subjects. In addition, we evaluated the presence of plasma antinuclear antibodies (ANAs)., Methods: Plasma samples from 49 consecutive patients (27 male, 22 female, median age 38 years, interquartile range 32-51 years) were compared with plasma from 51 age- and sex-matched controls (28 male, 23 female, median age 40 years, interquartile range 33-49 years), using a commercially available immunofluorescence assay testing for antibodies towards spotted fever group and typhus group Rickettsia as well as an assay for ANA. We obtained information regarding tick exposure and sarcoid disease manifestations from the medical records., Results: The prevalence of antibodies to Rickettsia in patients with sarcoidosis 1/49 (2%) was not significantly different from the prevalence in the controls 4/51 (8%). The prevalence of ANA was 2/49 (4%) in the patients and 3/51 (6%) in the controls., Conclusions: The results do not support the hypothesis that Rickettsia or ANAs should be involved in the pathogenesis of sarcoidosis. Seventy-one per cent of the patients were under treatment with prednisolone in the 3 months leading up to the blood sample. We assume that antibody-related serological methods for various reasons could be inadequate to diagnose a chronic rickettsial infection.

Background: Sarcoidosis is a multiorgan granulomatous inflammatory disease of unknown aetiology. Familial clustering of cases and ethnic variation in the epidemiology suggests a genetic influence on susceptibility to the disease. This paper reports twin concordance and heritability estimates of sarcoidosis in order to assess the overall contribution of genetic factors to the disease susceptibility., Methods: Monozygotic and dizygotic twins enrolled in the Danish and the Finnish population-based national twin cohorts (61,662 pairs in total) were linked to diagnostic information on sarcoidosis obtained from the Danish National Patient Registry or the Social Insurance Institution, Finland registry of reimbursed medication using the 8th and 10th editions of the International Classification of Diseases. The Fisher exact test was used to compare probandwise concordance rates in different zygosity groups. Heritability was estimated based on a multifactorial threshold liability model., Results: A total of 210 twin pairs with at least one proband with a diagnosis of sarcoidosis were identified. The probandwise concordance rate was higher in monozygotic than in dizygotic twins (0.148 vs 0.012). Compared with the general population there was an 80-fold increased risk of developing sarcoidosis in co-twins of affected monozygotic brothers or sisters. The increased risk in dizygotic twins was only 7-fold. Aetiological model fitting gave a heritability of sarcoidosis of 0.66 (95% CI 0.45 to 0.80)., Conclusions: This study suggests that genetic factors play an important role in the susceptibility to sarcoidosis. This result should encourage the search for molecular genetic markers of susceptibility to the disease.

Heart transplantation (HTx) is a well-established treatment for severe cardiac failure. However, HTx for cardiac sarcoidosis is rare; less than 80 patients have been reported worldwide. In many patients, the diagnosis was not made prior to HTx. The aim of this study was to describe the use of HTx in the treatment of severe cardiac sarcoidosis. The series was comprised of four Caucasian patients (1 male, 3 females), aged 25-57 years. HTx were performed in the period 1990-2006. None of the patients had clinically overt extra-cardiac sarcoidosis. In one patient the diagnosis of sarcoidosis was proven prior to HTx. In three patients, all with dilated cardiomyopathy due to myocardial sarcoidosis, the final diagnosis was obtained by examination of the explanted heart. Arrythmias (supraventricular and ventricular), heart block, mitral valve insufficiency and dilated cardiomyopathy were prominent clinical features. None of the patients had recurrence of sarcoid disease in the allograft. Two patients are long-term survivors and two are deceased, one of primary graft failure, the other from Cytomegalovirus myocarditis. In conclusion, HTx is a viable treatment for cardiac sarcoidosis with end stage cardiac failure. Cardiac sarcoidosis is difficult to diagnose. Myocardial biopsy has a low diagnostic sensitivity. However, when the newest non-invasive diagnostic methods, including magnetic resonance imaging and positron emission tomography, are applied, an endomyocardial biopsy should not be mandatory to make a diagnosis of cardiac sarcoidosis.

Mannose-Binding Lectin (MBL) is a prognostic marker in pulmonary diseases. Ficolins, sharing many structural and functional similarities with MBL, may also be involved in the pathogenesis of pulmonary diseases. The objectives of the study were to establish whether plasma concentrations of Ficolin-2, -3, and MBL in Danish patients with sarcoidosis and control persons differed and whether they were of prognostic significance. We retrospectively included 46 consecutive patients (26 male, 20 female) and 51 age- and sex-matched healthy control persons (28 male, 23 female). Information about the patients was obtained from their medical records. We measured plasma concentrations of Ficolin-2, -3, and MBL using ELISA. There was a significant difference in the patients' mean Ficolin-3 plasma level (14.9 microg/ml; +/-2SD: 6.7-23.1) compared with the control persons' (21.6 microg/ml; +/-2SD: 12.7-30.5). The difference was 6.7 microg/ml (95% CI: 5.0-8.4 microg/ml; p<0.001). In the patients, Ficolin-3 correlated inversely with the CD4(+)/CD8(+)-ratio (Spearman's Rho=-0.37; p=0.021; n=39). There were no significant differences in plasma concentrations of Ficolin-2 or MBL between the two groups. Ficolin-3 concentrations were lower in plasma from patients with sarcoidosis. This suggests a possible involvement of Ficolin-3 in the complex pathophysiology of sarcoidosis. However, we could not show the applicability of Ficolin plasma level measurement as a marker of disease activity or of prognostic significance in sarcoidosis.

Background: Distinct mutations of the caspase activating recruitment domain 15 (CARD15) gene (also known as nucleotide-binding oligomerisation domain protein 2) on chromosome 16q are associated with the chronic granulomatous disease called Blau syndrome. Sarcoidosis is a systemic granulomatous disease, which has features in common with Blau syndrome., Aim: The aim of this study was to evaluate whether ethnic Danes with sarcoidosis have CARD15 mutations associated with Blau syndrome., Methods: Analysis of exon 4 of the CARD15 gene containing mutations associated with Blau syndrome was performed by polymerase chain reaction and sequencing of genomic DNA from 52 patients with histologically verified sarcoidosis., Results: None of the patients had mutations in CARD15 associated with Blau syndrome. Eight other variations were found in exon 4: single nucleotide polymorphism (SNP)6 in 40% of the 104 alleles examined, SNP7 in 26%, c. 1833 C > T and SNP8 in 4%, c. 2107 C > T in 2%, and c. 931 C > T, c. 1292 C > T and c. 2377 G > A in 1%. One variation was found in intron 4 (IVS4 + 10 A > C) in 3% of the alleles. The frequencies of the variations in sarcoidosis patients were not statistically significant compared with frequencies in a control group of 103 healthy subjects. The course of disease was not significantly different in patients with or without variations in CARD15 or in the 46 patients with SNP6 and/or SNP7., Conclusions: Danish sarcoidosis patients have frequent variations in CARD15 exon 4, but do not present any mutation associated with Blau syndrome. The variations found had no influence on the course of disease.

Background: Mutations of the caspase-activating recruitment domain 15 (CARD15) gene on chromosome 16 are associated with chronic inflammatory granulomatous bowel disease (Crohn's disease). Sarcoidosis is a systemic granulomatous disease with unknown etiology, which shares histological features with Crohn's disease., Objectives: To evaluate whether ethnic Danes with sarcoidosis have an increased frequency of CARD15 mutations compared to healthy control subjects., Methods: Genotyping for CARD15 mutations R702W, G908R, and L1007fsinsC, also designated single nucleotide polymorphism (SNP) SNP8, SNP12 and SNP13, respectively, were performed by capillary electrophoresis single-strand confirmation polymorphism in 53 patients with histologically verified sarcoidosis and in 103 healthy controls., Results: The frequencies of CARD15 mutations in sarcoidosis patients were: SNP8, 4/106 chromosomes (3.8%); SNP12, 2/106 chromosomes (1.9%); SNP13, 2/106 chromosomes (1.9%); SNP8+SNP12+SNP13, 8/106 chromosomes (7.6%). All 8 patients were heterozygous. The frequencies in controls were: SNP8, 9/206 chromosomes (4.4%); SNP12, 2/206 chromosomes (1.0%); SNP13, 4/206 chromosomes (1.9%); SNP8+SNP12+SNP13, 15/206 chromosomes (7.3%). All controls were heterozygous. The differences were not statistically significant (p>0.05). Furthermore, the course of disease was not significantly different in the 8 patients with CARD15 mutations and the 45 patients without mutations., Conclusion: The frequency of CARD15 mutations is not increased in ethnic Danish patients with sarcoidosis, and heterozygosity for such mutations apparently has no influence on the course of disease., (Copyright (c) 2007 S. Karger AG, Basel.)

During the period 1984-2005, eight patients aged 25-57 years were treated for cardiac sarcoidosis. Diagnosis was obtained in three patients by endomyocardial biopsy, in three at heart transplantation (HTx) and in two at autopsy. Two patients had heart block, five ventricular arrhythmias and six dilated cardiomyopathy with congestive heart failure. Five patients died, one by sudden death, two of heart failure and two after HTx. Diagnosing cardiac sarcoidosis remains difficult, although MRI and PET scan have renewed the awareness of the disease.

The paper gives a review of the epidemiology, clinical manifestations, diagnosis, treatment and prognosis of cardiac sarcoidosis. Approximately 30% of patients with systemic sarcoidosis have granulomas in the myocardium, and 5% have clinical signs of cardiac affection. Cardiac manifestations comprise pericarditis, heart block, ventricular arrhythmias, valvular disease, ventricular aneurism, congestive heart failure and sudden cardiac death. Most frequent causes of death are sudden death and heart failure. Adequate treatment improves the prognosis of the disease.

Background: The MHC class Ib molecule Human Leukocyte Antigen (HLA)-G may be important in induction and maintenance of immunological tolerance, and HLA-G expression may have a role in different cancers, in certain diseases with associations to HLA, and in organ transplantation. Sarcoidosis is a systemic granulomatous disease with unknown etiology but at the molecular level several studies have shown HLA associations., Methods: In the present study, HLA-G alleles/polymorphisms were studied in sarcoidosis patients (n = 47) and controls (n = 129) by PCR techniques and HLA-G protein expression was investigated in granulomas from sarcoidosis patients with the use of immunohistochemistry., Results: The HLA-G*010102/-G*0106 alleles were observed more often in sarcoidosis patients (39.4%) than in controls (26.4%), p = 0.025 (Fisher's exact test); however, not significant after correction (p(c) = 0.15). When HLA-G expression was investigated by immunohistochemistry in granulomas from sarcoidosis patients, weak HLA-G expression was observed in only one patient., Conclusions: HLA-G alleles that include a 14-bp sequence polymorphism in exon 8 of the HLA-G gene are observed more often in sarcoidosis patients than in controls. The sequence variation may influence HLA-G mRNA stability and influence the expression of soluble isoforms of HLA-G. Only rare and weak expression of HLA-G was observed in granulomas from sarcoidosis patients. More studies are needed to further elucidate the possible role for HLA-G in sarcoidosis.

Some patients with severe sarcoidosis are resistant to conventional treatment with corticosteroids and cytostatics. We describe a 29-year-old man with histologically verified sarcoidosis and persistent, pronounced enlargement of the peripheral lymph nodes, resistant to treatment with prednisolone and methotrexate. Following treatment with TNF-alpha-inhibitor (infliximab 3 mg/kg body weight), the lymph nodes regressed to normal size and the patient improved clinically. The patient had a total of four infliximab infusions, and the effect has persisted for more than two years.

Aim: To describe the incidence, clinical presentation and paraclinical findings in childhood sarcoidosis in Denmark, 1979-1994., Methods: Patients (n = 5536) with a diagnosis of sarcoidosis were drawn from the nationwide Patient Registry; 81 patients were < or = 15 y of age. The diagnosis of sarcoidosis was reconfirmed in 48/81 (59%) patients. In 35/48 (73%) patients, diagnosis was verified by histology, and in 13 it was substantiated by paraclinical/clinical findings., Results: The series comprised 26 boys and 22 girls (male/female ratio 1.18). Median age at diagnosis was 13 y (range 0.7-15). In 1979-1994 the incidence was 0.29 per 100000 person-years < or = 15 y of age. The incidence was 0.06 in children < or = 4 y of age and increased gradually with age to 1.02 in children aged 14-15 y. General malaise, fever, weight loss, abdominal discomfort, respiratory symptoms, lymphadenopathy and central nervous system symptoms were common; 31% of patients had erythema nodosum, 12.5% sarcoid skin lesions, 25% uveitis/iridocyclitis and 4.2% sarcoid arthritis. Chest X-rays were normal (stage 0) in 10% of patients, and showed pulmonary infiltrates stage I in 71%, stage II in 8.3% and stage III in 8.3%. Lung function tests were examined in 13 patients: 50% had decreased FEV1 and vital capacity, 80% decreased DLCO. Haemoglobin values were normal. Some patients had mild leukopenia, some moderate leukocytosis and a few had moderate eosinophilia. Erythrocyte sedimentation rate was elevated in 40% of the patients. Plasma calcium was elevated in 30% of the patients; 4 patients had severe hypercalcaemia and elevated plasma creatinine, and 1 patient had nephrocalcinosis. Serum angiotensin-converting enzyme was elevated in 55% of the patients. Liver function tests were normal with no sarcoid hepatitis. Urinary examination (glucose, albumin, haemoglobin) was normal in 96% of the patients; the patient with nephrocalcinosis had albuminuria and haematuria., Conclusion: The incidence of sarcoidosis in Danish children is low and increases with age. Sarcoidosis in young children may present clinical features that are different from the appearance of those in older children and often constitute a diagnostic challenge. In older children, the clinical appearance has many features in common with the presentation in adults.

Background and Aim: To evaluate the incidence of sarcoidosis in Denmark 1980-1994., Methods: Patients with a diagnosis of sarcoidosis were identified from the Danish National Patient Registry. The file contained information about the year in which the diagnosis was reported, gender, age, and residential county., Results: 5536 persons (2816 men) with sarcoidosis were registered. Median age in men was 38 years, in women 45 years. The male/female incidence ratio was 1.06. The incidence (per 100,000 person years) declined gradually from 8.1 in 1980-1984 to 6.4 in 1990-1994. The overall incidence in 1980-1994 was 7.2. Incidence rates 1980-1994 increased from eastern to western parts of Denmark: Zealand 5.7, Funen 6.8, and Jutland 8.4. The peak incidence in men occurred at 30-34 years of age (14.8). Women displayed two similar peak incidences at 25-29 years of age (10.5) and at 65-69 years of age (11.0)., Conclusion: Incidence rates in the present study are lower compared with previous mass-screening surveys showing an incidence rate of 13.8 (in persons examined). Peak incidences occurred at higher ages in both men and women. Previous surveys showed peak incidences at 20-25 years in men and at 25-30 years and 50 years in women. The overall incidence of sarcoidosis in Denmark ranges from 7-10 per 100,000 person years. With 5,500,000 residents, the expected number of new cases of sarcoidosis in Denmark is between 385 and 550 per year.

This paper reviews current knowledge of childhood sarcoidosis with regard to the epidemiology in Danes, clinical presentation, diagnostic procedures, treatment and prognosis. Sarcoidosis is a granulomatous disease of unknown aetiology, with multiorgan involvement. The diagnosis is confirmed by the demonstration of epitheloid cell granulomas in tissue biopsy specimens. During the period 1980-92, three cases of childhood sarcoidosis were recorded in Copenhagen County, which has a total population of 610,000. The approximate incidence of clinically recognized sarcoidosis in Danish children younger than 15 y of age was 0.22-0.27/100,000 children per year, corresponding to approximately three new cases in Denmark each year. The true incidence is unknown, since the disease is often asymptomatic and resolves without a clinical diagnosis being made. In children younger than 5 y of age, the disease is characterized by involvement of skin, eyes and joints, whereas in older children involvement of lungs, lymph nodes and eyes predominate. The mainstay of treatment consists of oral corticosteroids. The risk/benefit ratio of using long-term corticosteroids needs to be evaluated in each individual patient. Some patients may benefit from additional therapy with methotrexate. The long-term prognosis is not well established, but it seems to be poorer in children younger than 5 y. Older children appear to have as favourable a prognosis as young adults.

Sarcoidosis is a granulomatous disease of unknown aetiology, which may affect various organs. The diagnosis is obtained by the demonstration of epytheloid cell granulomas in an affected organ. The incidence of sarcoidosis in Danish children less than 15 years of age is 0.22-0.27/100.000 children/year, corresponding to approximately three new cases in Denmark each year. The disease often takes an asymptomatic course. During the period 1980-1992, three cases of paediatric sarcoidosis were observed in Copenhagen Country. All three had pulmonary involvement, and one had severe hypercalcaemia. In children less than five years of age, the disease is characterized by involvement of lungs, lymph nodes and eyes. Treatment, which is symptomatic, consists of systemic steroids. Due to the risk of growth retardation, the indication for treatment should be carefully considered and steroids administered at the lowest effective dose. Due to the lack of follow-up studies, the long term prognosis is unclarified.

We report a case of hypercalcaemic crisis due to sarcoidosis in a 15-year-old boy. The clinical suspicion of sarcoidosis was confirmed by a liver biopsy. At admission serum calcium, 1,25(OH)2 and ACE were elevated and iPTH was suppressed. The levels of serum total and ionized calcium, iPTH, ACE, 1,25(OH)2 and 25-OH were followed and chest X-ray and pulmonary function tests were performed during systemic steroid treatment. The clinical condition improved during treatment and the paraclinical measurements normalised within 5 weeks. The mechanism whereby hypercalcaemia occurs in childhood sarcoidosis is clarified.

The etiology of sarcoidosis has not yet been established, but several mycobacterial species have been implicated in the pathogenesis of this disease. We have used a nested primer polymerase chain reaction (PCR) specific for the IS900 Mycobacterium paratuberculosis insertion element to analyse paraffin-embedded mediastinal lymphoid tissue from 18 patients with pulmonary sarcoidosis verified by mediastinoscopy. Only the positive control contained M. paratuberculosis-specific DNA. The present study does not support a role for M. paratuberculosis in the pathogenesis of sarcoidosis. However, further studies are needed in order to clarify the possible role of other mycobacteria in this disease.

The clinical appearance of sarcoidosis and the changes seen on x-ray of the thorax are often typical. However, several other conditions may present the same symptoms and identical x-ray findings. The present case report emphasizes the importance of an invasive approach and of histological investigation in patients in whom carcoidosis is suspected. For almost one year, a man aged 29 years was considered to be suffering from sarcoidosis on account of the clinical symptoms and bilateral hilar adenitis on x-ray op the thorax. He was treated with steroid for several months with clinical and radiological response. After the illness has lasted for one year, bronchoscopy was performed and bronchial biopsies revealed the diagnosis of malignant lymphoma.

The distribution of HLA class II (DR, DQ, and DP) antigens was studied in 41 patients with symptomatic sarcoidosis (SA) and ethnically matched healthy controls. HLA-DR, -DQw1 and -DQw3 typings were performed with alloantisera in the conventional microcytotoxic test, whereas -DP typings were done using primed lymphocyte typing. The frequencies of DRw6 were 41.5% in SA patients and 17.9% in controls (relative risk, RR = 3.2, p = 0.00087, p less than 0.05 when corrected). DR3 was decreased to 14.6% in SA patients compared to 25.9% in controls (RR = 0.49, p = 0.07, i.e., not statistically significant). The decreased frequency of DR3 was only seen in patients with severe, long-standing disease. In contrast, the DRw6 increase was most pronounced in patients with severe disease (RR = 6.4; p = 0.003). There were no statistically significant deviations in the frequencies of DQ and DP alleles between patients and controls. In conclusion, our data suggest that DRW6 confers susceptibility and DR3 resistance to severe, long-standing disease.

The review is based on studies of pulmonary sarcoidosis from Denmark, Finland and Sweden during 1950-1982, focusing on the course and prognosis of the disease. Cases with acute onset with chest X-ray stage I, fever, arthritis and erythema nodosum had a 85-90% remission rate during the first two years. The overall 5 year remission rate for stage I was 82%, stage II 66% and stage III 30%. Among cases with stage I, 2-5%, and among cases with stage II and III, 6-10% developed chronic pulmonary disease. Patients with stage I had a normal mortality rate, whereas those with stage II, III and IV had a rate threefold higher than expected due to sarcoidosis-related cardiopulmonary complications.

The alveolitis of sarcoidosis is dominated by lymphocytes and mononuclear phagocytes and chronic macrophage activation may play a role in the pulmonary interstitial fibrosis of sarcoidosis. We measured superoxide anion release of alveolar macrophages from sarcoidosis patients after in vitro stimulation, as toxic oxygen radicals have been proposed as mediators of chronic tissue damage. In untreated patients alveolar macrophage activity was normal, but significantly lower than in blood monocytes. However, a negative correlation between lymphocytosis in bronchoalveolar lavage fluid and macrophage oxidative metabolism was observed, showing that only patients with high intensity alveolitis have a decreased oxidative burst response after in vitro stimulation. This may reflect in vivo activation of the cells with subsequent reduced ability to respond after additional stimulation in vitro. Patients with radiological stage I had lower alveolar macrophage response than patients in stage II or III. There was no correlation with SACE levels, lung function tests or smoking habits. Nine patients were reinvestigated after treatment with prednisolone. Although the lymphocytosis of lavage fluid was only insignificantly changed, all but one patient showed improved macrophage release of superoxide anion. Blood monocyte oxidative burst response was normal in all patients before and after treatment. In conclusion, only mononuclear phagocytes of the target organ (lung) showed an altered function and the most pronounced decrease was observed in sarcoid patients with active alveolitis. Chronic low grade toxic oxygen radical release of alveolar macrophages may be involved in the pathology of pulmonary sarcoidosis.

The review is based on studies from Denmark, Finland, Norway and Sweden during 1950-1982. In general sarcoidosis was slightly more frequent in females than in males, especially after 40 years of age. The majority of cases were diagnosed before 35 years; 59% had symptoms, 41% were found by chance. Radiological stage I was present in 50%, stage II in 35%, and stage III-IV in 14%. The prevalence was age dependent with maximum between 18-35 years, varying from 8-102/10(5) examined persons in Finland to 27 in Norway and 64 in Sweden. The incidence was likewise age related, being highest in 18- to 20-years-old males (57/10(5) examined persons/year); overall incidence varied from 14-15/10(5) examined persons/year in Denmark, Finland and Norway to 24 in Sweden. No definite change in incidence figures has occurred. The accumulated lifetime risk of acquiring sarcoidosis was identical in the two sexes up to 45 years of age, and then increased in females; at 65 years the risk was 1.6% in females and 1.2% in males based on the population examined.

Sarcoidosis is a systemic granulomatous disorder of unknown genesis with an average annual incidence of 10/100,000 population in Denmark. The clinical picture and prognosis are dominated by the pulmonary changes in the majority of cases. The patho-anatomical picture consists of a T-lymphocyte-dominated interstitial inflammation with non-caseating epithelioid granulomas followed by fibrosis in varying degrees. The different types and courses of pulmonary disease are reviewed. Clinical examination, chest radiography, pulmonary function tests (especially the carbon dioxide diffusion capacity) and S-angiotensin-converting enzyme (S-ACE) are the most important measures of disease activity. The value of systemic corticosteroids is critically evaluated; most patients in this country can be observed without treatment because the spontaneous resolution rate is high. It is recommended that steroids should be administrated primarily in symptomatic and progressive parenchymal lung disease, or when critical or disabling extrathoracic sarcoidosis is present. If the pulmonary parenchymal infiltrates do not disappear within approximately 18 months, a course of prednisolone for at least one year should be considered to prevent disabling or even lethal pulmonary fibrosis.