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Sarcoidosis is a systemic inflammatory disease characterized by granuloma formation in affected organs and caused by dysregulated immune response to an unknown antigen. Sarcoidosis patients receiving immunosuppressive medications are at increased risk of infection. Lymphopenia is also commonly seen among patient with sarcoidosis. In this review, risk of infections, including opportunistic infections, will be outlined. Recommendations for vaccinations and prophylactic therapy based on literature review will also be summarized. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 87-98) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Background: Methotrexate (MTX) is a second line agent for treatment of sarcoidosis. Its long term safety and efficacy in sarcoidosis remains unclear., Methods: This was a retrospective review of patients seen at the University of Cincinnati Sarcoidosis Clinic over a six year period. For each visit, complete blood count, liver function testing, and dosing and outcome of MTX was noted. For efficacy, we compared the outcome of therapy of a matching subgroup of patients treated with either MTX or infliximab for one year and results scored as improved, stable, or worse based on response of the target organ., Results: Over six years, 1606 sarcoidosis patients were seen with a total of 13,576 clinical visits. During the study period, 607 patients (38% of total) were receiving MTX and had available blood work. Moderate elevation of alanine aminotransferase (ALT) (>3 times upper limit normal) was seen in nine (1.6%) patients. White blood count of <1500 cells per cu mm was seen in one patient. At six months, over half of the 44 patients initiated on infliximab and with at least six months of follow-up were better, while only 23% of the 44 of a matched subset of MTX treated patients were better (Chi square=10.566, p=0.0143). At the 12 month assessment, the infliximab treated patients were still more likely to be better than those treated with MTX (Chi square=10.033, p=0.0183). Only 23% of those treated with MTX were worse at twelve months., Conclusion: In our study, MTX therapy was associated with very few hepatic or hematologic complications. MTX was less likely than infliximab to improve clinical status. However, only 20% were worse after one year of MTX. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (3): e2020001) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Background: It has been suggested that sarcoidosis patients, especially those on immunosuppressive medications, are at increased risk for COVID-19 infection and more severe disease., Methods: A questionnaire was developed in four languages (English, Dutch, Italian, and Spanish). The questionnaire queried whether patients had been infected with COVID-19 and outcome of the infection. Risk factors for COVID-19 infection were collected., Results: A total of 5200 sarcoidosis patients completed the questionnaire with 116 (2.23%) reporting infection and 18 (15.8%) required hospitalization. Increased hazard ratio (HR) for COVID-19 infection were seen for those with a COVID-19 infected roommate (HR=27.44, p<0.0001), health care provider (HR=2.4, p=0.0001), pulmonary sarcoidosis (HR=2.48, p=0.001), neurosarcoidosis (HR=2.02, p<0.01), or rituximab treatment (HR=5.40, p<0.0001). A higher rate of hospitalization was found for those with underlying heart disease (HR=3.19 (1.297-7.855), p<0.02). No other feature including race, other immunosuppressive agent, age, or underlying condition was associated with a significant increased risk for infection or more severe disease., Conclusion: The overall rate of COVID-19 was 2.23%, suggesting an increased rate of COVID-19 infection. However, when an analysis of the questionnaires of sarcoidosis and non-sarcoidosis patients was performed in one localized area over this time period, the rate of COVID-19 infection was similar in both groups. Sarcoidosis patients who cohabitated with COVID-19 infected individuals, worked in health care, had pulmonary or neurologic sarcoidosis, or were treated with rituximab had an increased risk for COVID-19 infection. No significant increased risk for hospitalization could be identified based on age, race, gender or any specific immunosuppressive treatment. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (4): e2020009) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Background: Cognitive failure is associated with memory and concentration problems. Previously, a prevalence of one third was found in a general sarcoidosis population. The aim of this study was to assess if neurosarcoidosis patients are at higher risk for developing everyday cognitive failure using the Cognitive Failure Questionnaire (CFQ) and to determine what factors were associated with cognitive failure., Methods: A cross-sectional web-based survey was conducted from April to May 2017 in a national sample of neurosarcoidosis patients. The survey asked about complaints and included 3 questionnaires (Fatigue Assessment Scale [FAS], Small Fiber Neuropathy Screening List [SFNSL] and CFQ. Data were compared to a general sarcoidosis population., Results: Of the 152 patients who completed the survey, 131 had neurosarcoidosis. The mean CFQ score was significantly higher in the neurosarcoidosis (45.6±20.7) compared to the general sarcoidosis population (36.2±15.9; p< 0.0001). High CFQ scores (≥43) were found in 55.7% and 33.9%, respectively (p<0.0001). The FAS score (OR 21.4) and SFNSL score (OR 4.3) were the strongest positive predictors of a high CFQ score., Conclusion: Cognitive failure is a significant problem in neurosarcoidosis. More than half of the patients reported cognitive deficits, compared to one third of a general sarcoidosis population. Fatigue and small fiber neuropathy play a role in cognitive failure., (Copyright: © 2019.)

Background: Previous studies found that 40-60% of the sarcoidosis patients suffer from small fiber neuropathy (SFN), substantially affecting quality of life. SFN is difficult to diagnose, as a gold standard is still lacking. The need for an easily administered screening instrument to identify sarcoidosis-associated SFN symptoms led to the development of the SFN Screening List (SFNSL). The usefulness of any questionnaire in clinical management and research trials depends on its interpretability. Obtaining a clinically relevant change score on a questionnaire requires that the smallest detectable change (SDC) and minimal important difference (MID) are known. Objectives: The aim of this study was to determine the SDC and MID for the SFNSL in patients with sarcoidosis. Methods : Patients with neurosarcoidosis and/or sarcoidosis-associated SFN symptoms (N=138) included in the online Dutch Neurosarcoidosis Registry participated in a prospective, longitudinal study. Anchor-based and distribution-based methods were used to estimate the MID and SDC, respectively. Results: The SFNSL was completed both at baseline and at 6-months' follow-up by 89/138 patients. A marginal ROC curve (0.6) indicated cut-off values of 3.5 points, with 73% sensitivity and 49% specificity for change. The SDC was 11.8 points. Conclusions: The MID on the SFNSL is 3.5 points for a clinically relevant change over a 6-month period. The MID can be used in the follow-up and management of SFN-associated symptoms in patients with sarcoidosis, though with some caution as the SDC was found to be higher. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 333-341) ., (Copyright: © 2018 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of surfactant phospholipids and lipoproteins within the alveoli. Here we report on a female patient who was diagnosed with autoimmune PAP and successfully treated with whole lung lavage (WLL). 15 months after PAP diagnosis the patient developed marked fatigue. Additional tests revealed the diagnosis of sarcoidosis. We can only speculate that PAP and sarcoidosis in our patient are linked to each other based on the fact that other autoimmune disorders have also been associated with sarcoidosis.

Background: The King's Sarcoidosis Questionnaire (KSQ) is a brief questionnaire assessing health status using five modules (General Health Status, Lung, Eyes, Skin, Medication) in patients with sarcoidosis. The KSQ was only validated in one English sarcoidosis cohort., Objective: The aim of this study was to validate the KSQ in a Dutch sarcoidosis population., Methods: The KSQ was translated according to international guidelines and tested in interviews with patients. Consecutive outpatients completed multiple questionnaires twice, two weeks apart. Construct validity, internal consistency and repeatability were determined., Results: Of the 98 patients included 85 had lung, 22 skin and 24 eye disease. There was good construct validity of the KSQ General Health Status module against the World Health Organization Quality of Life-BREF questionnaire. The Medication module correlated weak to moderate with most questionnaires. The correlations with organ-specific questionnaires varied from strong for Eyes (r=0.75), Skin (r=-0.62) to moderate for Lung (r=-0.45 with MRC breathlessness scale). Internal consistency was good for all KSQ modules (Cronbach's α 0.72-0.93). Intraclass correlation coefficients (0.70-0.90) and Bland-Altman plots showed good repeatability of the KSQ., Conclusion: The Dutch KSQ is the first translation of the English KSQ, validated in a Dutch sarcoidosis population.

Background: Limited evidence exists demonstrating an effective treatment for chronic cutaneous sarcoidosis., Objective: To determine infliximab's effectiveness in sarcoidosis., Methods: We conducted a subset analysis from a randomized, double-blind, placebo-controlled trial for chronic pulmonary sarcoidosis to determine infliximab's effectiveness. Patients with chronic cutaneous sarcoidosis received infliximab (3 or 5 mg/kg) or placebo over 24 weeks. Of 138 patients, the subset analysis evaluated 17 patients with chronic facial and another 9 patients with nonfacial skin involvement. The SASI evaluated lesions for degree of erythema, desquamation, induration, and percentage of area involved. Facial and nonfacial lesions were scored in a blinded manner., Results: Among 5 placebo-treated and 12 infliximab-treated patients, an improvement was observed with infliximab versus placebo in change from baseline to weeks 12 and 24 in desquamation (P<0.005) and induration (P<0.01) at week 24. Erythema, percentage of area involved and the evaluation of paired photographs did not reveal significant differences., Limitations: Sample size; more extensive disease in placebo patients; chronic therapy upon enrollment; lung as primary organ of sarcoidosis involvement; limited investigator experience with SASI., Conclusions: Infliximab appears to be a beneficial treatment for chronic cutaneous sarcoidosis. The SASI scoring system demonstrated significant improvement versus placebo in lesion desquamation and induration.

Background: Sarcoidosis patients frequently experience fatigue, exercise intolerance and muscle weakness, resulting in reduced quality of life (QOL). Scientific studies on the benefits of physical training in sarcoidosis have been scarce, so the aim of this pilot study was to examine the impact of a 13-week physical training program on fatigue, physical functions and QOL in fatigued sarcoidosis patients and/or patients with exercise intolerance., Methods: 18 sarcoidosis patients participated in a 13-week physical training program. The Fatigue Assessment Scale (FAS), World Health Organization Quality of Life-BREF assessment instrument (WHOQOL-BREF),Medical Research Council (MRC) dyspnea scale, Visual Analogue Scale (VAS), six-minute walk test (6MWT), submaximal bicycle test and muscle strength of the quadriceps and elbow flexors were assessed at baseline and after the program., Results: FAS scores had decreased (mean difference -2.7 points, 95% CI -4.4 to -1.1) after completion of the training program, along with improvements in WHOQOLBREF psychological health domain (mean difference 0.9 points, 95% CI 0.2 to 1.7) and MRC dyspnea score (mean difference -0.4 points, 95% CI -0.8 to -0.1). 6MWD improved by 34.6 m (95% CI 20.3 to 49.0) and mean heart rate on the bicycle test improved (mean difference 8.4 beats/minute, 95% CI -13.8 to -3.0), as did quadriceps strength (mean difference 10.7 kg, 95% CI 5.5 to 15.9)., Conclusion: Fatigue reduced after a period of physical training in sarcoidosis patients. Moreover, psychological health and physical functions improved. Future studies are warranted to assess the benefits of physical training in sarcoidosis.

Background: The natural history of disease in patients with stage IV (fibrotic) sarcoidosis may mirror that of patients with idiopathic pulmonary fibrosis (IPF). Both are bothered by progressive dyspnea, exercise limitation and fatigue., Objective: To establish whether patients suffering from pulmonary fibrosis might benefit from a physical training program., Study Design: Twenty-four eligible patients referred to the out-patient clinic of the ild care expertise team of Hospital Gelderse Vallei, Ede, The Netherlands between November 2012 and November 2013 were included in this observational pilot study of a 12-week physical training program. Outcomes, including exercise capacity, skeletal muscle strength, lung function and fatigue were assessed at two time points: 1) baseline; and 2) after completion of a 12-week physical training program., Results: At baseline, the percentage predicted DLCO, FVC, FEV1 and exercise capacity (assessed by six-minute walking distance (6MWD) or maximal oxygen uptake) was reduced in both groups. After program completion, exercise capacity improved (&gt;10% improvement 6MWD) in 13 subjects (54.2%): 7 with IPF and 6 with sarcoidosis subjects. Other secondary endpoints, including pulmonary function tests and patient-reported outcome measures improved in some subjects., Conclusion: A 12-week physical training program improved or maintained exercise capacity in patients with IPF (despite disease progression) or fibrotic sarcoidosis. The results from this pilot study could be used to design prospective studies aimed at answering lingering questions about exercise training in patients with these progressive, incurable conditions.

Background: In severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment, the third-line tumor necrosis factor-alpha (TNF-α) inhibitors infliximab and adalimumab might be an alternative. However, appropriate studies to guide the clinician are lacking. The aim of this study was to establish practical recommendations for the use of TNF-α inhibitors in the management of refractory sarcoidosis patients., Methods: Based on a literature search and the opinion of sarcoidosis experts worldwide, the recommendations were established. Studies conducted in sarcoidosis were supplemented with data obtained from relevant studies in other inflammatory diseases. A Delphi method of polling, using an online survey addressing 12 clinical questions, was performed amongst 20 of the world's leading sarcoidologists to investigate consensus in case of inadequate data to determine an objective answer., Results: Of the 256 papers found, 101 were included. Randomized controlled trial studies about the use of TNF-α inhibitors in sarcoidosis are limited. Ninety-five percent (19 of 20) of the sarcoidologists contacted, completed the questionnaire (Europe 68%, North America 32%). Nine recommendations were formulated concerning general aspects of TNF-α inhibitor use; Specific sarcoidosis related items, including indications, starting and maintenance dosage, interval of treatment, treatment duration, and discontinuation regimen of infliximab and adalimumab, were addressed., Conclusion: Based on earlier studies and consensus amongst world's leading sarcoidologists, practical recommendations for the use of TNF-α inhibitors in sarcoidosis were established. These recommendations, with emphasis on indications, dosage and discontinuation regimens, have been developed to support the clinician in the management of refractory sarcoidosis patients.

Background: Quality of life (QOL) is often reduced in patients with sarcoidosis. Studies of the associations between physical functions and QOL are lacking., Objectives: So the aims of this study were (i) to evaluate the associations between QOL and physical functions, including muscle strength and exercise capacity, and other clinical characteristics, and (ii) to evaluate whether these associations change over a two-year period., Methods: Eighty-eight sarcoidosis patients (61 men; mean age: 46.1 ± 10.2 years) participated in a two-year follow-up to cross-sectional study. All patients completed the short World Health Organization Quality of Life assessment instrument (WHOQOL-BREF) and Fatigue Assessment Scale (FAS) at the baseline and follow-up assessments. Patients also performed a six-minute walk test (6MWT) and elbow flexor muscle strength, quadriceps and hamstrings peak torque tests. Maximal inspiratory pressure was recorded., Results: QOL in sarcoidosis remained stable over a two-year course of the disease, and was reduced compared with healthy controls, particularly regarding the physical health domain. Fatigue and the six-minute walking distance showed strong associations with QOL at both baseline and follow-up. Fatigue and exercise capacity predicted the scores for the WHOQOL-BREF physical health domain at baseline (59%) and follow-up (64%). QOL at baseline was the best predictor of QOL at follow-up., Conclusions: QOL is reduced in sarcoidosis. Fatigue and exercise capacity showed important stable associations with QOL, especially in the physical health domain. FAS and 6MWT should therefore be included in the management of sarcoidosis.

Introduction: A Case Control Etiology of Sarcoidosis Study (ACCESS) sarcoidosis organ assessment instrument has been used for more than a decade to establish uniform standards for the probability of sarcoidosis organ involvement. The ACCESS instrument has become increasingly outdated as new technologies have been developed. Furthermore, the ACCESS instrument failed to address all possible organs involved with sarcoidosis. For these reasons, the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) developed a new sarcoidosis organ assessment instrument., Methods: Clinical sarcoidosis experts assessed various clinical manifestations for the probability of sarcoidosis organ involvement. Two criteria were required to apply this assessment: 1) histologic evidence of granulomatous inflammation of unknown cause in an organ that was not being assessed; 2) the clinical manifestation being addressed required that alternative causes other than sarcoidosis had been reasonably excluded. Clinical manifestations were assessed as either: a) highly probable: likelihood of sarcoidosis causing this manifestation of at least 90%.; b) probable: likelihood of sarcoidosis causing this manifestation of between 50 and 90%; c) possible: likelihood of sarcoidosis causing this manifestation of less than 50%. The sarcoidosis experts voted on the likelihood of sarcoidosis causing each manifestation using Delphi study methodology where at least 70% agreement of the experts was needed for consensus., Results: Various clinical manifestations were classified as highly probable, at least probable, possible, or indeterminate when no consensus could be reached., Conclusion: An instrument was developed by expert opinion that may be useful for the clinician and researcher in establishing criteria for sarcoidosis organ involvement.

Background: Sarcoidosis is characterized by a wide range of disease manifestations. In the management and follow-up of sarcoidosis patients, knowledge of extent of disease, activity and severity is crucial. Objectives The aim of this study was to assess the extent, distribution and consistency of inflammatory organ involvement using 18F-FDG PET/CT (PET) in sarcoidosis patients with persistent disabling symptoms., Methods: Retrospectively, sarcoidosis patients who underwent a PET between 2005 and 2011 (n=158) were included. Clinical data were gathered from medical records and PET scans were evaluated. Positive findings were classified as thoracic and/or extrathoracic. RESULTS :Of the studied PET positive sarcoidosis patients (n=118/158; 75%), 93% had intrathoracic activity (79% mediastinal and 64% pulmonary activity, respectively) and 75% displayed extrathoracic activity (mainly peripheral lymph nodes, bone/bone marrow, and spleen). Hepatic positivity was always accompanied by splenic activity, whereas the majority of patients with parotid gland, splenic or bone/bone marrow activity showed lymph node activity. A substantial number of patients with PET positive pulmonary findings (86%) had signs of respiratory functional impairment. No obvious association between hepatic, splenic or bone/bone marrow activity and their corresponding laboratory abnormalities suggestive of specific organ involvement, was found., Conclusions: The majority of studied patients appeared to have PET positive findings (75%), of which a high proportion (75%) displayed extrathoracic activity. Hence, PET can be especially useful in the assessment of extent, distribution and consistency of inflammatory activity in sarcoidosis to provide an explanation for persistent disabling symptoms and/or to provide a suitable location for biopsy.

Unlabelled: Muscle atrophy is a common problem in many chronic inflammatory diseases. It may occur as part of a generalized wasting process (cachexia) or be hidden due to preservation of fatmass (sarcopenia, sarcopenic obesity)., Objectives: The aim of this study was to assess the prevalence of cachexia and muscle atrophy in sarcoidosis and their association with disease activity and severity., Methods: A cross-sectional study was performed in 423 sarcoidosis patients. Fat-free mass was assessed as an indirect measure of muscle mass by bioelectrical impedance analysis. Patients were stratified based on body mass index (BMI) and fat-free mass index (FFMI).Muscle atrophy was defined as FFMI <15 kg/m2 for women and <17 kg/m2 for men corresponding to <10th percentile of current reference values; cachexia as BMI <20 combined with muscle atrophy.Multivariate linear regression models were used to adjust for potential confounders., Results: Of the patients examined, 58% were categorized as overweight (37%) or obese (21%), whereas 7% were underweight.Muscle atrophy was present in 25% and cachexia in 5%. Patients with muscle atrophy showed significantly worse lung function (DLCO, FEV1, FVC, all p-values <0.01) and impaired exercise capacity (VO2max, p<0.001). The associations were most pronounced in patients with cachexia. Associations remained significant after adjustment for potential confounders., Conclusions: Muscle atrophy was present in 25% of sarcoidosis patients and was associated with more severe pulmonary disease. Prospective studies with longitudinal design are needed to assess the association between muscle atrophy and disease severity in sarcoidosis.

Over the past few years an increasing number of prospective controlled sarcoidosis treatment trials have been completed. Unfortunately, these studies utilize different endpoints making comparisons between studies difficult. At the recent World Association of Sarcoidosis and other Granulomatous disease (WASOG) meeting, a session was dedicated to the evaluation of clinical endpoints for various disease manifestations. These included pulmonary, pulmonary hypertension, fatigue, cutaneous, and a classification of clinical disease phenotypes. Based on the available literature and our current understanding of the disease, recommendations for clinical evaluation were proposed for each disease category. For example, it was recommended that pulmonary studies should include changes in the forced vital capacity. Additionally, it was recommended that all trials should incorporate measurement of quality of life.

Background: Personality factors have shown to be related to mortality, morbidity, and psychological aspects in chronic disorders. Little is known about the effect of personality on disease severity in sarcoidosis and idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the prevalence of Type D personality and its relation with relevant clinical characteristics in sarcoidosis and IPF patients., Methods: The study included 441 sarcoidosis and 49 IPF patients from the outpatient clinic of the ild care team of the MUMC, the Netherlands. They completed the DS14 (Type D questionnaire), the fatigue assessment scale (FAS), the WHO quality of life-BREF (WHOQOL-BREF) and the Centre for Epidemiological Studies-Depression Scale (CES-D). Moreover, relevant clinical data were collected. The control group consisted of 3678 subjects from a general population., Results: Type D personality was found in 25.6% of the sarcoidosis patients compared to 21% in the controls, but only in 18.8% of the IPF patients. No relation with disease severity was found in either of these disorders. Fatigue was a substantial problem in both populations. Depressive symptoms but not Type D personality predicted fatigue and poorer QOL in sarcoidosis and IPF., Conclusion: Prevalence of Type D personality is not higher in sarcoidosis and IPF patients than in the general population and does not explain QOL impairment. Depressive symptoms explain QOL impairment and fatigue substantially. Therefore, in the multidisciplinary management of sarcoidosis and IPF psychological screening and psychological counselling concerning adequate coping strategies should be incorporated.

The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis.

Background: Fatigue is a major problem in sarcoidosis. Fatigue has mainly been examined in patients from The Netherlands., Objective: The aims of the study were to establish the prevalence of fatigue in US and Dutch patients and to determine whether fatigue was related to the common demographic and clinical parameters., Design: Two patients groups were studied: Dutch outpatients at Maastricht University Medical Center in The Netherlands (n = 121) and US patients at the University of Cincinnati Medical Center in the USA (n = 126). Both groups completed the Fatigue Assessment Scale. Clinical data were gathered from the patients' medical files., Results: The prevalence of fatigue was similar in the US and Dutch patients, but more severe in the latter group. Fatigue was unrelated to demographic and clinical parameters in the total group. However, when examining the US and Dutch patients separately, fatigue was associated with age, extrapulmonary involvement and drug use in the US group., Conclusions: Dutch patients report more severe fatigue compared with US patients. Interestingly, fatigue was related to clinical and demographical parameters in the US patients, although no such relationships was found in the Dutch patients.

Some patients with sarcoidosis can have cardiac involvement. Impairment of the cardiac sympathetic nerve activity is seen in about 50% of the sarcoidosis patients with small fiber neuropathy. In this case we present a sarcoidosis patient with small fiber neuropathy and cardiac symptoms with a cardiac sympathetic dysfunction, assessed with I-123 MIBG SPECT. After 5 months of treatment with carvedilol, which has besides adrenergic receptor blocking effects also antioxidant action, we saw a clear improvement of the cardiac sympathetic function demonstrated on a repeated I-123 MIBG SPECT. Future studies should explore the clinical relevance of the relation of oxidative stress, antioxidant therapy and cardiac dysfunction in sarcoidosis.

Sarcoidosis is a systemic granulomatosis disease of unknown origin where a number of microbes, in particular M. tuberculosis and non-tuberculous mycobacteria, have been hypothesized to play a role in disease pathogenesis, possibly through bacterial antigen-driven hypersensitivity. To test this concept, we used bioinformatic tools allowing the identification of antigenic peptides in whole microbial genomes to analyze the interaction between the expressed HLA-DR gene allelic variants and the HLA-DR immunome of all pathogenic bacteria in a population of 149 sarcoidosis affected subjects and 447 controls, all HLA-typed at high resolution. We show here that patients with the Löfgren's syndrome, express HLA-DR alleles that recognize in silico a significantly higher number of bacterial antigen epitopes compared to the control population (18,496+9,114 vs 17,954+8,742; p<0.00001), and the chronic sarcoidosis affected population (17,954+8,742; p<0.00001 vs Löfgren's and controls). Further, the analysis of the ability of the HLA-DR allele combinations expressed by the Löfgren's and the chronic sarcoidosis affected subjects to recognize M. avium epitopes demonstrates that a significantly larger number of Löfgren's are capable of top affinity recognition, compared to chronic sarcoidosis (45% vs 17%, p<0.0037). Finally, both Löfgren's and chronic sarcoidosis subjects expressed HLA-DR allele combinations capable of M. tuberculosis and M. avium epitope recognition at higher affinity than tuberculosis affected subjects (p<0.01 all comparisons). In conclusion, we propose that - at least in a subgroup of affected subjects - sarcoidosis might be part of a spectrum of granulomatous responses to several agents where the Löfgren's syndrome represents the hyper-reactive end of the spectrum while pulmonary tuberculosis and atypical mycobacterial infections might represent the opposite end.

Background and Aim of the Work: Sarcoidosis is a chronic inflammatory T-cell-driven disease that can also affect bone. We evaluated bone remodelling and bone mineral density (BMD) in patients with sarcoidosis and their dependency of disease-related and treatment-related factors., Methods: In 124 patients BMD of the hip (DXA) and markers of bone resorption (ICTP) and formation (PINP) were evaluated. Furthermore a lateral DXA of the spine for morphometric assessment of vertebral deformities was performed in 87 patients. Potential predictors of bone markers, BMD and determinants of prevalent vertebral deformities were assessed using multiple and logistic regression analysis., Results: The population studied comprised untreated patients (n=51), patients that previously used glucocorticoids (n=31) and patients currently using glucocorticoids (n=42). In all these groups the age- and gender corrected Z-scores of the hip were normal, except in untreated patients, which revealed an increased Z-score at the trochanter (p = 0.004). In all but the patients currently on glucocorticoids the Z-scores for PINP and ICTP were increased (p < 0.05). In patients currently on glucocorticoids the Z-ICTP was also increased (p < 0.05), but the Z-PINP decreased (p < 0.01 compared to untreated patients). In 20.6% of patients one or more morphometric vertebral deformities were found., Conclusions: Hip BMD is normal in patients with sarcoidosis, despite an increased bone turnover. This may imply that in sarcoidosis mechanisms are involved that compensate for the well-known effects of cytokines in inflammatory diseases on osteoclastogenesis and bone resorption. Nonetheless, vertebral deformities suggestive of fracture were found in a significant number of patients which indicates that patients with sarcoidosis still have a relevant fracture risk.

Sarcoidosis is a multisystemic disorder of unknown cause. Diagnosis is established when clinical and radiological findings are supported by histological evidence of noncaseating epitheloid cell granulomas. Exclusion of granulomas of known causes and sarcoidlike reactions is mandatory. A lot of infections may mimic a sarcoidlike granulomatous reaction. Even with well advanced pathological and microbiological examination, it could be hard to make the appropriate diagnosis. Moreover, sarcoidosis patients receiving corticosteroids are susceptible to opportunistic infections. The challenge is, however, making the right diagnosis because opportunistic infections can resemble sarcoidosis. The case reports presented in this paper are meant to stress the importance of excluding granulomatous infections in patients with (suspected) sarcoidosis. Appropriate diagnostic procedures are important to exclude an infectious condition mimicking sarcoidosis. Accordingly, appropriate treatment can start without further delay.

We describe a patient with severe small fiber neuropathy (SFN) accompanied by autonomic involvement, who was experimentally treated with infliximab, an anti-tumour necrosis factor-alpha (TNF-alpha) therapy. Six months after this treatment was started his symptoms completely resolved. Until now they did not return. Repeated temperature threshold testing (TTT) as well as cardiovascular autonomic function test clearly improved after one year therapy. This case reveals two important issues. First, it shows that SFN seems not an irreversible disorder, even in severe cases. Second, TNF-alpha may be a crucial cytokine in the pathogenesis of SFN in sarcoidosis and eventually also in other immune mediated inflammatory diseases.

Background and Aim: Fatigue is an unspecific symptom, but a major problem in sarcoidosis patients. There is a need for a reliable and valid way to measure fatigue. The Fatigue Assessment Scale (FAS) has good psychometric properties in healthy and sarcoidosis samples in the Netherlands, but nothing is known about the psychometric qualities of the FAS in sarcoidosis samples from other countries. Therefore, we examined the reliability, construct, and content validity in Croatian sarcoidosis patients., Methods: Croatian sarcoidosis patients from a pulmonary outpatient clinic completed the FAS and a symptom inventory questionnaire., Results: The internal consistency of the FAS was 0.91. Using exploratory factor analysis and Mokken scale analysis, the scale was unidimensional. A dichotomous fatigue item distinguished between individuals who scored high or low on the FAS. Concerning discriminant validity, individuals reporting health complaints were more tired. The FAS correlated moderately with a number of neurological and psychological problems. Females and lower educated individuals reported more fatigue., Conclusions: The Croatian translation of the FAS has good reliability and validity in a sarcoidosis sample. Future research is needed to explore the psychometric qualities (i) of the Croatian FAS in healthy individuals and (ii) of the FAS in other languages.

Background and Aim: Sarcoidosis has been reported to be associated with the HLA genes, in particular DQB1., Methods: High resolution DQB 1 of 103 sarcoidosis patients was obtained by sequence-based typing; low resolution HLA-A/B/DRB 1 typing was performed by serological and molecular methods. Small fiber neuropathy (SFN) was established by thermal threshold testing., Results: Sixty-seven patients suffered from SFN (SFN+), in 36 patients SFN was absent (SFN-). Comparing HLA DQB 1 typings of SFN+ patients, SFN- patients and control individuals revealed a significant increase of the allele DQB 1 0602 in SFN+ patients compared to controls., Conclusion: This association might be correlated with a severe course of the disease.

Background and Aim: Recently we found that small fiber neuropathy (SFN) occurs frequently in sarcoidosis. Autonomic dysfunction may be a feature of SFN. Since cardiac autonomic dysfunction has been identified as a strong predictor of morbidity and mortality, recognition of cardiac autonomic involvement is of clinical relevance. It was hypothesised that SFN might be related to cardiac sympathetic denervation in sarcoidosis., Methods: In the present study 45 consecutive sarcoidosis patients (13 without SFN assessed by thermal threshold testing (TTT), 32 with SFN (abnormal TTT) were enrolled. To rule out bias due to myocardial ischemia, cases with abnormal Thallium (201Tl) perfusion scintigraphy were excluded (n = 2). Cardiovascular autonomic function testing (Ewing tests) and 123I-MIBG (metaiodobenzylguanidine) scintigraphy were used to assess cardiac autonomic function. Further cardiac diagnostic work-up included ECG, Holter recording and echo Doppler cardiography., Results: Mild to moderate heterogeneity of 123I-MIBG uptake regional in the myocardium was demonstrated in a substantial number of the studied sarcoidosis population, especially in those with SFN (abnormal TTT). Mean inferior-anterior ratios were 0.85+/-0.17 (SFN) and 1.0+/-0.17 (no SFN; p = 0.003), respectively. Four out of the 14 cases with abnormal MIBG scintigraphy and SFN showed an abnormal Ewing test., Conclusion: Cardiac sympathetic dysfunction assessed by use of 123I-MIBG myocardial scanning appeared to be heterogeneous in sarcoidosis patients and dependent on the presence or absence of SFN. MIBG scintigraphy may be of additional value in the management and follow-up of sarcoidosis patients. Future study is warranted to explore possible prognostic and therapeutic implications of these findings in sarcoidosis.

Background and Aim of the Work: Many sarcoidosis patients suffer from fatigue and sleep disturbances. Recently, it was demonstrated that obstructive sleep apnea (OSA) is rather common in sarcoidosis. Moreover, sheet intolerance and painful legs are frequently reported in sarcoidosis patients. These symptoms might interfere with sleep quality., Methods: In order to determine the relationship between objective and subjective sleep disturbance full polysomnography, including leg EMG analysis, was performed in 46 chronic sarcoidosis patients indicating awakening unrefreshed in the morning., Results: In 20 (44%) patients OSA activity [60% with PLM (n=12), 40% without (n = 8)] was demonstrated, while in 7 patients (15%) significant PLM without OSA were found. In 19 patients (42%) no OSA or PLM activity was present. Moreover restless legs (RLS) were reported by 52% of the patients (45% in OSA; 71% in PLM; 47% in others). Distribution of sleep stages and sleep fragmentation was comparable in all groups. In a healthy snoring control group (n = 102) a prevalence of PLM was found in 13.7% (17.8% in men; 3.4% in women), while RLS were only reported by 1.4% (men) and 6.9% (women)., Conclusions: Sleep disturbance (OSA and/or PLM) and RLS were demonstrated in more than half of the studied sarcoidosis patients. A high prevalence of RLS or PLM (primary and secondary) has not been reported before in sarcoidosis. Further studies are needed to establish whether RLS, OSA and/or PLM might contribute to fatigue and whether fatigue complaints improve after treatment of RLS/PLM/OSA.

Background and Aim of the Work: Studies on the relationship between fatigue and clinical parameters are sparse. In the present study this relationship was examined in a systematic way., Methods: Patients with time since diagnosis < or = 2 years, visiting the outpatient clinic of the University Hospital Maastricht (n = 60; 34 untreated, 26 treated) were clinically evaluated and completed the Fatigue Assessment Scale (FAS). A representative sample of the Dutch population (n = 1893) also completed the FAS. Pulmonary disease severity was estimated from lung function test results and measures of metabolic derangement. Acute phase response markers high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA) and sarcoidosis activity parameters, soluble interleukin-2-receptor (sIL2R), and angiotensin-converting enzyme (ACE) were also measured., Results: Only 27% of the sarcoidosis patients were diagnosed as non-fatigued (FAS score < 22), compared to 80% in the control population (n = 1893). In the sarcoidosis patients no sex differences and no differences in fatigue scores between the treated and the untreated groups were found. Patients with fatigue (FAS-score > or = 22) had lower DLCO values (p < 0.05). However, none of the tested clinical or serological parameters appeared to be a significant predictor of fatigue., Conclusions: In the present study, it was confirmed that fatigue is a major problem in sarcoidosis. The extent of fatigue could not be explained by clinical parameters. Thus, up to now, no clinical or physiological variable seems useful in predicting which patients are fatigued. In this light, the Fatigue Assessment Scale might be considered as a supplementary tool in sarcoidosis.

Background and Aim: A relationship between stress and sarcoidosis has been considered. However, studies concerning perceived stress, appraisal of life events, are scarce in sarcoidosis patients. Therefore, the aim of the present study was to further examine the role of perceived stress in sarcoidosis., Methods: Members of the Dutch Sarcoidosis Society (n = 1046; 59.0% females; the age range 40-49 contained the most persons) completed the Perceived Stress Scale (PSS), a symptom inventory, the Beck Depression Inventory (BDI), and the Fatigue Assessment Scale (FAS)., Results: The PSS score of sarcoidosis patients was high (p < 0.001), especially those of females (p < 0.001). Moreover, patients with psychological problems had higher PSS scores (p < 0.001). Notably, the presence of psychological problems and gender appeared to be unrelated. Furthermore, perceived stress was related to the BDI (r = 0.67, p < 0.001), especially to the cognitive subscale (r = 0.67, p < 0.001) and, to a lesser extent, to the physical depression subscale (r = 0.42, p < 0.001)., Conclusions: Perceived stress was found to be high and related to symptoms in sarcoidosis. Moreover, depressive symptoms appeared to be related to perceived stress. Therefore, the management of sarcoidosis should include coping and appraisal therapy aiming to reduce stress and depressive symptoms.

Background and Aim: Although pain is prevalent in sarcoidosis, this has never been studied systematically. The aim of the present study was to evaluate the presence and impact of pain in sarcoidosis., Methods: Members from the Dutch Sarcoidosis Society without co-morbidity (n = 821) participated in this study. The World Health Organisation Quality of Life assessment instrument (WHOQOL-100) was completed, as well as a symptom inventory questionnaire addressing the presence of various categories of pain, i.e., muscle pain, chest pain, abdominal pain, arthralgia, and/or headache., Results: Pain was reported by 594 patients (72.4%). Arthralgia was experienced most frequently (53.8%), followed by muscle pain (40.2%), headache (28.0%) and chest pain (26.9%). The number of types of pain a patient was suffering from (ranging from 0-5) was related to the WHOQOL- 100 Pain and Discomfort scale (r = 0.49, p < 0.001). Patients with more types of pain had lower quality of life (QOL). In addition, the total amount of experienced pain categories was associated with the WHOQOL-100 domain Level of Independence (r = -O.43, p < 0.001), and the facet Energy and Fatigue (r = -0.38, p < 0.001). The number of types of pain was predicted by using analgesics, psychological/neurological medication, NSAIDs, being female, indicating to feel tired, more negative feelings and less energy (F(7.635) = 35.2, p < 0.001; R2 = 27.9%)., Conclusions: Pain appeared to be a major problem in sarcoidosis, especially arthralgia. Although negative feelings and fatigue were related to pain, it could not fully explain pain. Future studies are needed to address mechanisms of pain, pain behaviour, and the best therapeutic approach to pain in sarcoidosis.

Background and Aim of the Work: The glutathione system has a key role in the defence against oxidative stress. To function properly, this system needs NADPH to maintain glutathione (GSH) in its reduced form. We hypothesized that the clinical problems associated with sarcoidosis might be related to a decreased anti-oxidant defence and we therefore measured the activity of the NADPH-generating enzyme glucose-6-phosphate dehydrogenase (G6PD), the GSH-regenerating enzyme glutathione reductase (GR) and indirectly the level of NADPH in red blood cells from patients with sarcoidosis., Methods: In a population of sarcoidosis (n = 88) patients, G6PD, GR and GR activity after incubation with chromate (GR-Cr) were measured in erythrocytes. A decreased concentration of NADPH was revealed by an increased GR-Cr (> 0.6 IU/g Hb). To exclude a mutation in the G6PD gene, sequencing was performed in cases with an abnormal GR-Cr. Sarcoidosis pulmonary disease severity was evaluated by means of laboratory data, radiographic staging, HRCT scoring, pulmonary function and exercise capacity testing., Results: Fourteen (29.2%) females and one (2.5%) male demonstrated an increased GR-Cr test, indicative of a decreased NADPH level. Patients with an abnormal test result demonstrated also significantly increased ACE and GR values (p < 0.05). Only one female case (of 6 tested) appeared to have a mutation in the G6PD gene., Conclusion: In a considerable percentage of female patients with sarcoidosis, a decreased level of NADPH in the erythrocytes was found.

Background and Aim: Sarcoidosis is an inflammatory disorder of unknown origin. The nuclear regulatory factor-kappaB (NF-kappaB) appears to play a key role in immune and inflammatory processes such as asthma, rheumatoid arthritis and inflammatory bowel disease. We hypothesized that NF-kappaB activation might be involved in the pathological process of sarcoidosis., Methods: Twelve sarcoidosis patients, biopsy proven, and five healthy control subjects, all nonsmokers, were studied. Blood samples were taken and routinely analysed for several parameters including the serum angiotensin converting enzyme (sACE) level. Mononuclear cells were isolated from these patients in order to quantify the NF-kappaB contents in the nuclear extract of the mononuclear cells., Results: Mononuclear cells NF-kappaB expressed per mg protein were twice as high in both untreated (n = 5) and treated (n = 7) patients with sarcoidosis compared to the control subjects (p < 0.001). In contrast, the sACE level appeared to be low in the treated patients compared to the untreated patients (p < 0.01)., Conclusions: These results indicate that the inflammation in sarcoidosis is associated with NF-kappaB activation. Moreover, the suppression of the activated NF-kappaB response by glucocorticoids seems less successful than the suppression of the sACE activity. Future studies should focus on the clinical relevance of this observation and establish the possible therapeutic consequences of the increased NF-kappaB activation in sarcoidosis.

Unlabelled: BACKGROUND AND AIMS OF THE WORK: Although it often has been suggested that members of patient organisations concerning a particular disease might not be representative of patients with that particular disease in general, this hypothesis has not been tested. Therefore, the aim of this study was to evaluate whether the quality of life (QOL) of members of the Dutch Sarcoidosis Society (DSS) is comparable with the QOL of a random non-member sample of the Dutch sarcoidosis population., Subjects and Methods: The study included 64 out-patients (Group I), 192 DSS members matched for age and gender (Group II), and 192 DSS members matched for age, gender, as well as symptoms (Group III). All subjects filled in a questionnaire to make an inventory of physical symptoms and the World Health Organization Quality of Life assessment instrument (WHOQOL-100). The Student's t-test was used to evaluate the differences between (i) the two DSS groups and (ii) the non-member group., Results: Group III differed significantly from Group I in only one QOL domain and five facets. Moreover, considering only the patients with symptoms from Group I and Group III, differences emerged on one domain and two facets., Conclusions: It appeared that more members of the DSS declared they suffered from physical symptoms than non-members. When the experience of symptoms was partialled out fewer QOL differences remained.

Background: Apart from the disease status, chronically ill patients are confronted with stressors like dependence, limitations in mobility and physical complaints. Data on patients with sarcoidosis, however, are lacking. The aim of this study was to investigate the quality of life (QOL) and the influence of QOL factors on depressive symptoms in these patients., Patients and Methods: Sixty-four patients with histologically proven sarcoidosis participated in this study. Significant co-morbidity was excluded. The Sickness Impact Profile (SIP) was used to determine the QOL. Depressive symptoms were measured with the Beck Depression Inventory (BDI), of which a subset of items measured cognitive symptoms, the Cognitive Depression Index (CDI). Disease status was assessed by pulmonary function parameters (FEV1, Dco), complaints and illness duration. To control for a confounding cognitive style of self-report, the Positive Affect Negative Affect Schedule (PANAS) was administered., Results: The major complaint was fatigue. QOL was related to the perception of complaints, but not to the assessed disease status. In a multivariate regression 86% of the variance could be explained in BDI-scores, and 83% in CDI-scores. After controlling for demographical factors, disease status and cognitive style, QOL contributed to the regression, explaining another 17% of variance of BDI-scores as well as CDI-scores. Problems with sleeping were associated positively with depressive symptoms in general (beta = 0.38) and depressive cognitions only (beta = 0.32)., Conclusions: In sarcoidosis, QOL factors were associated with depressive symptoms. These results suggest that patients with sarcoidosis may profit from attention to the psychosocial as well as the somatic aspects of this disease.

Background: Sarcoidosis is generally characterized by a CD4+ lymphocyte predominance in bronchoalveolar lavage fluid (BALF), whereas in extrinsic allergic alveolitis (EAA) a CD8+ lymphocyte predominance is found. However, we have previously demonstrated an increase in CD4+ lymphocytes in BALF obtained from EAA patients as well. The aim of this study was to evaluate whether in sarcoidosis and EAA the BALF cellular profile-even without the help of cytokine detection-might reflect differences in the CD4+ T-lymphocyte subpopulations, i.e. T helper (TH)-1 and TH2 lymphocytes., Methods: For this purpose, we analyzed BALF analysis results obtained from 77 nonsmoking patients with histologically proven sarcoidosis and 54 nonsmoking patients suffering from EAA., Results: Patients with EAA showed the highest mean absolute numbers of lymphocytes, CD8+ as well as CD4+ T lymphocytes, whereas the percentage of CD4+ T lymphocytes in BALF was low. In contrast, patients with sarcoidosis showed the lowest absolute and relative number of CD8+ T lymphocytes, the highest percentage of CD4+ T lymphocytes and CD4+/CD8+ ratio. Moreover, patients with Löfgren's syndrome demonstrated an alveolitis suggesting a TH1 lymphocyte-subset-like predominant related profile, characterized by lower numbers of eosinophils and mast cells, whereas sarcoidosis patients with respiratory symptoms formed a more mixed TH1/TH2 pattern. Patients with EAA showed a cellular BALF profile suggesting a functional predominance of TH2 lymphocytes., Conclusion: These preliminary data suggest a different distribution of the CD4+ T lymphocyte subtypes characterized by a functional heterogeneity of CD4+ T lymphocytes between-as well as within-these various pulmonary disorders. The exact role of this imbalance of TH1 and TH2-like activity in the lung with regard to the pathogenesis and prognosis needs to be further elucidated.