The St. George's Respiratory Questionnaire in Pulmonary Sarcoidosis.

RATIONALE: The Saint George's Respiratory Questionnaire (SGRQ) is a frequently used tool to assess health status in pulmonary disease patients. However, its performance characteristics in sarcoidosis patients are not well characterized. METHODS: Data from a clinical trial of 138 symptomatic adults with sarcoidosis were used to examine the performance characteristics of SGRQ. Data were available at both baseline and week 24. Other assessments included FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6-min walk distance (6MWD), and Short Form-36 Physical Component Summary (SF-36 PCS) score. RESULTS: Baseline SGRQ was 46.8, indicating impaired health status. At baseline, SGRQ total score correlated significantly with % predicted FVC, FEV1, ATS dyspnea score, Borg's CR 10 dyspnea score, 6MWD, and SF-36 PCS (r = - 0.37, - 0.32, 0.57, 0.40, - 0.55, and - 0.80, respectively, p < 0.001). Change from baseline in SGRQ score also statistically significantly correlated with change from baseline in these parameters at week 24: r = - 0.25, - 0.20, 0.30, 0.22, - 0.20, - 0.45, respectively (p < 0.05). CONCLUSIONS: The SGRQ correlated with other outcome measures in sarcoidosis initially and with treatment. Improvement in FVC % predicted correlated with improvement in SGRQ. These data suggest the SGRQ may function as a reliable endpoint in clinical sarcoidosis trials.

Sarcoidosis extent relates to molecular variability.

The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)-12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T cell receptor signalling, were similar among phenotypes. We also identify differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial. We find that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement. These findings may help to explain the difficulty in identifying clinically efficacious sarcoidosis treatments and suggest hypotheses for improved therapeutic strategies.

Tadalafil therapy for sarcoidosis-associated pulmonary hypertension.

Sarcoidosis-associated pulmonary hypertension (SAPH) is estimated to occur in at least 5% or more of sarcoidosis patients, and it contributes to significant morbidity and mortality. Optimal therapy for SAPH is not well established. We performed a 24-week open-label trial of tadalafil for SAPH at 2 academic medical centers. Subjects were required to have confirmed sarcoidosis plus a right heart catheterization within 12 months of enrollment showing a mean pulmonary artery pressure ≥ 25 mmHg, a pulmonary artery wedge pressure ≤ 15 mmHg, and a calculated pulmonary vascular resistance ≥ 3 Wood units. Subjects received 20 mg/day of tadalafil for the first 4 weeks and then 40 mg/day for the subsequent 20 weeks. Sixteen patients were screened, 12 of whom met criteria for enrollment. At 24 weeks, there was no overall improvement in 6-minute walk distance (6MWD). Five of the 12 subjects dropped out of the study early (2 for social reasons, 3 for medical reasons). There was no significant change in short form 36, St. George's respiratory questionnaire, or maximum Borg dyspnea scores over the 24 weeks. There were no significant adverse events or laboratory abnormalities clearly related to tadalafil in the cohort. The study did not meet the primary end point of change in 6MWD because of the small sample size. Tadalafil was generally safely administered in this cohort of SAPH patients. There was a relatively high dropout rate but no major adverse events and no clinical worsening. Larger studies are needed to explore this question further. (Trial registration: ClinicalTrials.gov identifier: NCT01324999).

Real-time quantitative reverse transcription-polymerase chain reaction to detect propionibacterial ribosomal RNA in the lymph nodes of Chinese patients with sarcoidosis.

The aim of this study was to investigate the diagnostic value of using the copy number of propionibacterial rRNA as a biomarker for sarcoidosis. Ribosomal RNA of Propionibacterium acnes and P. granulosum was measured by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using formalin-fixed and paraffin-embedded tissue of lymph node biopsy from 65 Chinese patients with sarcoidosis, 45 with tuberculosis and 50 controls with other diseases (23 with non-specific lymphadenitis and 27 with mediastinal lymph node metastasis from lung cancer). The receiver operating characteristic (ROC) curve was analysed to determine an optimal cut-off value for diagnosis, and the diagnostic accuracy of the cut-off value was evaluated in additional tissue samples [24 patients with sarcoidosis and 22 with tuberculosis (TB)]. P. acnes or P. granulosum rRNA was detected in 48 of the 65 sarcoidosis samples but only in four of the 45 TB samples and three of the 50 control samples. Analysis of the ROC curve revealed that an optimal cut-off value of the copy number of propionibacterial rRNA for diagnosis of sarcoidosis was 50·5 copies/ml with a sensitivity and specificity of 73·8 and 92·6%, respectively. Based on the cut-off value, 19 of the 24 additional sarcoidosis samples exhibited positive P. acnes or P. granulosum, whereas only one of the 22 additional TB samples was positive, resulting in a sensitivity and specificity of 79·2 and 95·5%, respectively. These findings suggest that propionibacteria might be associated with sarcoidosis granulomatous inflammation. Detection of propionibacterial rRNA by RT-PCR might possibly distinguish sarcoidosis from TB.

Calcium and vitamin D metabolism in sarcoidosis.

BACKGROUND: Sarcoidosis associated hypercalcemia (SAHC) may be secondary to excessive levels of 1,25-(OH)2 vitamin D3 produced by autonomous 1-alpha-hydroxylase activity within the granulomas.  The frequency, treatment, and consequences of hypercalcemia remain unclear. STUDY DESIGN AND METHODS: Two patient cohorts were studied.  In Cohort 1, the prevalence of hypercalcemia in 1606 sarcoidosis patients seen during a six year period was analyzed along with treatment and outcome. Cohort 2 consisted of  261 sarcoidosis patients with measured 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 levels. In forty patients, serial levels of 25-(OH) vitamin D3 and 1,25-(OH) vitamin D3 were measured at least three months apart without change in therapy. RESULTS: SAHC was identified in 97 of 1606 (6%) of patients studied and additional nine (0.6%) patients had primary hyperparathyroidism. Post treatment follow up was available in 86 SAHC patients. Hypercalcemia improved in >90% of patients, including eight patients treated solely with vitamin D supplement withdrawal. Renal insufficiency, documented in 41 (42%) of SAHC patients, improved with hypercalcemia treatment.  In 80% of Cohort 2 patients low 25-(OH) vitamin D3 levels were measured with only one patient having a low 1,25(OH)2 vitamin D3 level. Elevated 1,25(OH)2 vitamin D3 levels, which were measured in 11% of patients, were higher for those with a history of hypercalcemia. CONCLUSION: Sarcoidosis associated hypercalcemia, which is often accompanied by renal insufficiency, responds to treatment of sarcoidosis and withdrawal of vitamin D supplementation. Measurement of serum vitamin 1,25(OH)2 vitamin D3 appears to best evaluate vitamin D status in sarcoidosis patients.

Treatment of sarcoidosis.

The treatment of pulmonary sarcoidosis is based on several factors. These include changes in pulmonary physiology, presence of extra-pulmonary disease, and symptoms. Several immunosuppressive agents have been studied and recommendations regarding the utility of these different agents have evolved. While glucocorticoids remain the most commonly used agent, other drugs have been used as steroid sparing and for those patients who progress despite routine treatment. Non immunosuppressive agents also play a role in the therapy of pulmonary sarcoidosis patients. These include treatments for pulmonary hypertension, infection, and fatigue.

Effect of obesity on patient-reported outcomes in sarcoidosis.

OBJECTIVES: To assess the impact of high body mass index (BMI) on patient-reported outcomes in sarcoidosis patients and healthy persons. METHODS: In this case-control study, we investigated symptoms of fatigue and dyspnoea, health status, BMI and spirometric tests in 184 sarcoidosis patients and the same number of sex- and age-matched healthy subjects. Fatigue was assessed using the fatigue scale (FS), dyspnoea was determined by the baseline dyspnoea index (BDI) and health status was measured using the respiratory-specific St George's Respiratory Questionnaire (SGRQ). RESULTS: There were significantly more subjects with increased BMI (≥25 kg/m(2)) among the sarcoidosis patients than among the healthy volunteers ((2) 37.675, P < 0.01). Sarcoidosis patients also had a greater probability of having a higher BMI (P < 0.01, OR 1.18, 95%CI 1.071.3). We found significantly lower BDI scores and forced expiratory volume in 1 s/forced vital capacity, as well as higher total SGRQ and total FS scores in sarcoidosis patients than in healthy individuals (P < 0.01 for all differences). CONCLUSION: Sarcoidosis significantly reduces patients' health status, both independently and also due to increased BMI. Reduction in BMI may contribute to improved spirometry results and health status of patients with sarcoidosis.

A novel multi-parameter scoring system for distinguishing sarcoidosis from sputum negative tuberculosis.

BACKGROUND: Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs. Tuberculosis is the world's second most common cause of death from infectious diseases. Due to the similar clinical, radiological and histopathological pictures in sarcoidosis and tuberculosis, Mycobacterium tuberculosis has been considered as potential infectious factor. However, it remains difficult to distinguish sarcoidosis from tuberculosis, especially when sputum examinations for mycobacterium are negative. METHODS: 1. to establish a scoring system for differentiating sarcoidosis and tuberculosis: We collected the risk factors, laboratory data and the data of clinical, radiographic, pathological manifestations from the 117 of sarcoidosis patients and 181 of sputum negative tuberculosis patient. And we put them into the designed form. Based on the results of univariate analysis, clinical experience and the literature, we further selected 13 variables that were more supportive to distinguish the two diseases. Finally 9 variables were selected based on logistic regression to establish the scoring systems with significant differences between the two diseases. The beta-coefficient form the logistic regression were used to calculate the weight of each variable. Four types of comprehensive scoring models were established in the end (clinical-- radiographic; clinical--radiographic--radionuclide; clinical--radiographic--pathological and clinico-radiographic--radionuclide--pathological group). Receiver operating characteristics (ROC) analysis was used to determine an optimal cutoff point for each scoring system. 2. to validate the accuracy of the established scoring system: 73 of new sarcoidosis patients and 57 of new tuberculosis patients were chosen to assess the diagnosis accuracy of the four scoring systems. RESULTS: 1. we established four types of comprehensive scoring models, included clinical--radiographic; clinical--radiographic--radionuclide; clinical--radiographic--pathological and clinico--radiographic--radionuclide--pathological scoring models, the optimal cutoff values respectively were 9, 17, 18 and 22, the sensitivity and specificity of the four scoring system to distinguish the two diseases respectively were: 93.16% (109/117) and 97.79% (177/181), 92.31% (108/117) and 98.90% (179/181); 93.16% (109/117) and 98.90% (179/181); 94.87% (111/117) and 98.90% (179/181). 2. Validation of the scoring systems with 130 new patients (73 of sarcoidosis and 57 of tuberculosis):, the sensitivity and specificity of CR, CRE, CRP, CREP were 91.78% (67/73) and 87.72% (50/57), 97.26% (69/73) and 98.25% (56/57), 94.52% (71/73) and 96.49% (55/57), 98.63% (72/73) and 98.25% (56/57) respectively. CONCLUSIONS: The four scoring systems established by this study can be utilized to differentiate sarcoidosis and sputum negative tuberculosis effectively. Based on the availability of clinical-radiographical/histopathological data, any of the four diagnostic scoring systems were reliable tools for differential diagnosis, with increased information leading to better discrimination.

Management of ocular sarcoidosis.

BACKGROUND: A step wise approach to the use of cytotoxic and anti-tumor necrosis factor (TNF) antibodies has been developed for managing chronic sarcoidosis. OBJECTIVES: To provide a summary of our experience with immunosuppressive agents especially methotrexate and the anti-tumor necrosis factor antibodies in treating chronic ocular sarcoidosis. STUDY DESIGN AND METHODS: This was a retrospective review of 1587 sarcoidosis patients seen at one center over a six year period. All patients with definite or probable ocular sarcoidosis were identified. RESULTS: A total of 465 (29%) of the sarcoidosis patients experienced ocular disease. Of these, 365 patients were treated with methotrexate (MTX) for their eye disease with 281 (77% of those started on MTX) still receiving MTX at the end of the study. Methotrexate was the only systemic therapy prescribed in 115 patients while 101 patients also received concurrent prednisone. Other combinations administered include MTX plus azathioprine and/or leflunomide. A total of 25 patients were treated with the monoclonal anti-TNF antibodies infliximab (19 patients) or adalimumab (6 patients). While all patients initially responded to anti-TNF therapy, only ten patients experienced a sustained response with ongoing therapy or complete remission of ocular disease. Recurrent infections, adverse drug events, or financial constraints were responsible for most drug discontinuations. CONCLUSION: Most cases of chronic ocular sarcoidosis respond well to immunosuppressive therapy. However, patients may require combination therapy to achieve and maintain disease control. The use of anti-TNF agents for refractory disease is encouraging but can be accompanied by significant toxicity.

Endpoints for clinical trials of 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.

Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.

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.

Fatigue in sarcoidosis: American versus Dutch patients.

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.

Inhaled iloprost for sarcoidosis associated pulmonary hypertension.

RATIONALE: Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy. OBJECTIVES: To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH. METHODS: Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires. MEASUREMENTS AND MAIN RESULTS: Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease. CONCLUSION: Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.

Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial.

The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.

Inhibitors of tumor necrosis factor (TNF) in sarcoidosis: who, what, and how to use them.

Sarcoidosis patients with chronic disease often require prolonged treatment. Although alternatives to corticosteroids have been frequently administered in this disease, corticosteroids remain the mainstay of treatment. However disabling side effects which accompany prolonged treatment can necessitate the use of alternative, steroid-sparing agents. The tumor necrosis factor (TNF) inhibitors can be useful in treating chronic sarcoidosis. Among the biologic agents which inhibit TNF, infliximab has been studied most extensively in sarcoidosis with fewer reports available for adalimumab and etanercept. This review will summarize the available evidence to identify the best candidate to receive an anti-TNF regimen as well as the relative benefits and side effects of the three anti-TNF biological agents for treating sarcoidosis. A stepwise approach is proposed to increase the likelihood of disease improvement for patients who experience an inadequate response to an anti-TNF agent.

Differentiation of sarcoidosis from tuberculosis using real-time PCR assay for the detection and quantification of Mycobacterium tuberculosis.

BACKGROUND: The clinical and pathological features of sarcoidosis and tuberculosis may mimic each other, and when the caseous necrosis is not seen in tuberculosis tissue, differentiation is not easy. OBJECTIVE: This study evaluates the ability of real-time PCR quantification and sets the quantitive value to differentiate sarcoidosis from TB. METHODS: Formalin-fixed and paraffin-embedded sections of biopsy samples, from 104 patients with sarcoidosis, 31 patients with tuberculosis, and 55 controls with other respiratory diseases (26 with nonspecific lymphadenitis and 29 with emphysema bullae), were collected to amplify insertion sequence IS986 of Mycobacterium tuberculosis (MTB) genome by real-time quantitative PCR. The diagnostic performance of qualitative and quantitative analysis of real-time quantitative PCR was assessed by receiver-operating characteristic (ROC) curves. RESULTS: MTB DNA was detected in 20 of the 104 sarcoidosis samples and 7 of the 55 control samples, but was detected in all of the 31 tuberculosis samples. The numbers of MTB genomes were 0-4.71x10(3) copies per ml in sarcoidosis samples, 1.58x10(2)-5.43x10(7) copies per ml in tuberculosis samples and 0-1.02x10(3) copies per ml in controls with quantitative analysis. Receiver-operating characteristic (ROC) curves showed that MTB genome quantification had greater diagnostic performance than MTB genome qualitation in discriminating patients with sarcoidosis from those with tuberculosis (area under the ROC curves: 0.994 vs 0.904, P<0.001). The sensitivity and specificity of qualitative analysis were 100% and 80.8% respectively. At cutoff value of 1.14x10(3) copies per ml for MTB genome quantification, the sensitivity was 96.8% and specificity was 98.1%. CONCLUSIONS: The real time PCR quantification is a valuable test for differentiation between sarcoidosis and tuberculosis, and the MTB genome copies number of 1.14x10(3) copies per ml should be preferred as quantitative cutoff value for the differentiation.