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.

The internal consistency of PRO fatigue instruments in sarcoidosis: superiority of the PFI over the FAS.

INTRODUCTION: The Fatigue Assessment Scale (FAS) is a 10-item patient reported outcome (PRO) questionnaire that is used to measure fatigue in sarcoidosis. After several months of use, we began to question the reliability of the FAS in our clinic population. Therefore, we administered an additional fatigue PRO, the Patient Reported Outcomes Measurement Information Systems (PROMIS) Fatigue Instrument (PFI). Our hypothesis was that the internal consistency/reliability (Cronbach's alpha) of the PFI would be superior to the FAS in sarcoidosis patients because two of the ten FAS items (items #4 and #10) required reverse scoring (these items were scaled in the opposite direction to the other 8 items). METHODS: The FAS and PFI were administered during the same clinic visit to consecutive patients in our sarcoidosis clinic. We calculated a) the Cronbach's alpha for a) the FAS; b) the FAS without items #4 and #10; and c) the PFI. RESULTS: 107 consecutive sarcoidosis patients underwent FAS and PFI testing. The Cronbach's alpha was 0.740, 0.911, and 0.963 for the FAS, FAS with items #4 and #10 removed, and the PFI respectively. In female patients, the Cronbach's alpha of the FAS was 0.663, which is considered as "questionable" in terms of internal consistency. CONCLUSION: We found that the PFI had "excellent" consistency in our sarcoidosis clinic. The FAS did not demonstrate the same degree of internal consistency. The Cronbach's estimate of the FAS with items #4 and #10 removed was vastly superior to the FAS. These data support our contention that FAS items #4 and #10 detract from the internal consistency of this PRO. They also suggest that the PFI is superior to the FAS in terms of reliability.

Detection of sarcoidosis associated fasciitis by uptake on a FDG PET scan: a novel finding.

We report a case of a sarcoidosis patient with bilateral calf and thigh stiffness who was noted to ha ve intense linear FDG uptake on a PET scan that localized to the fascia of his calves and theighs. His serum creatine kinase level was normal. Fasciitis has rarely been reported to be detected on FDG PET scans, and, to our knowledge, never in a sarcoidosis patient. FDG PET may have a role in identifying fasciitis or myositis when a patient has muscular complaints and no clinical or laboratory evidence of muscle injury.

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.

The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States.

BACKGROUND: Although numerous reports have described the clinical features of sarcoidosis in various ethnic and racial groups, many have been limited by small size, homogenous populations, and relatively short follow-up periods. We report the clinical characteristics of a large, race-sex-age diverse cohort of sarcoidosis clinic patients followed in a large university medical center for an extended period of time. METHODS: This study included clinical data for sarcoidosis patients followed over a 12-year period at a sarcoidosis clinic at the Medical University of South Carolina. RESULTS: 1774 sarcoidosis patients were identified. Black females were more common (44%) than other race/gender combinations (p = 0.01). The diagnosis of sarcoidosis occurred > 3 months after the onset of symptoms in 48% of the cohort and > 1 year after the onset of symptoms in 25%. Anti-sarcoidosis treatment was required in 61% of the patients. Pulmonary function improved over time and the median corticosteroid requirement lessened. Compared to whites, blacks had more advanced radiographic stages of sarcoidosis (p < 0.0001), more organ involvement (p < 0.0001), and more frequently required anti-sarcoidosis medication (p < 0.0001). Compared to women, men had more advanced radiographic stages of sarcoidosis (p < 0.0001). CONCLUSIONS: The analysis indicates that sarcoidosis tends to improve over time in terms of pulmonary function and medication requirements. The disease was found to be more severe in blacks than whites. Treatment was not necessarily required. These results provide a comprehensive model of the course and treatment of sarcoidosis in the clinical setting.

Ambrisentan for sarcoidosis associated pulmonary hypertension.

BACKGROUND: Sarcoidosis associated pulmonary hypertension (SAPH) is associated with significant morbidity and mortality. There is a paucity of information concerning therapy for this condition. METHODS: We performed a prospective, open-label, proof of concept trial of ambrisentan for SAPH. 21 subjects with SAPH received 5 mg/day of ambrisentan for 4 weeks and then 10/mg day for 20 subsequent weeks. RESULTS: No significant change was noted in the 6-minute walk distance over the course of the study (mean change between week 0 and 24: 9.8 +/- 54.6 meters, p: NS). There were also no significant differences between weeks 0 and 24 in terms of dyspnea as measured by the modified Borg scale, serum brain naturetic peptide, diffusing capacity, and quality of life as measured by the Short Form-36. There was a high dropout rate: overall: 11/21, 52%; social reasons: 3/21, 14%; medical reasons: 8/21, 38% because of dyspnea: 6/21, 29% and/or edema: 4/21, 19%. Of those who completed the 24 week study (10/21, 48%), there was an improvement in their WHO functional class and a marked improvement in their health related quality of life as measured by the St. George Respiratory questionnaire (-15.3 +/- 25.0). However both these improvments did not reach statistical significance possibly because of the small sample size. CONCLUSION: Although ambrisentan was not well tolerated by many of these subjects with SAPH, in those who remained in this 24-week trial, improvements in WHO functional class and in health related quality of life suggested a possible benefit of this drug in selected patients.

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.

C-reactive protein predicts response to infliximab in patients with chronic sarcoidosis.

BACKGROUND: This study assessed the value of C-reactive protein as a predictor of disease severity and response to infliximab therapy in patients with chronic pulmonary sarcoidosis. DESIGN: Sera were collected through week 52 from 138 patients with chronic pulmonary sarcoidosis who received placebo or infliximab in a randomized, double-blind, placebo-controlled study. We evaluated the response to therapy by baseline CRP using a dichotomous cutpoint (0.8 mg/dL) for the change from baseline in percent-predicted forced vital capacity (FVC), Saint George's Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), Borg's CR10 dyspnea score, and Physician Organ Assessment (POA). RESULTS: CRP was elevated in 36% of patients at baseline, and was significantly reduced by infliximab by week 2. Among patients with elevated baseline CRP, infliximab-treated patients improved significantly compared with placebo-treated patients in percent-predicted FVC (+2.5 versus -2.6%), 6MWD (+8.0 versus -34.1), Borg's CR10 dyspnea score (pre-6MWD -0.8 versus +0.9, post-6MWD -1.1 versus +0.8), and POA (-3.1 versus -0.3). Patients with lower CRP levels at baseline did not show significant differences between the placebo and infliximab groups in most endpoints evaluated. CONCLUSIONS: In chronic sarcoidosis patients, elevated CRP appears to identify a subset with more severe disease who may respond better to treatment with infliximab.

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.

Presenting characteristics as predictors of duration of treatment in sarcoidosis.

BACKGROUND: Some sarcoidosis patients never need therapy, but many still require therapy more than 2 years after initial diagnosis. AIM: To determine what features at initial presentation are associated with treatment 2 years later. METHODS: Patients with biopsy-confirmed sarcoidosis enrolled in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study were initially evaluated within 6 months of diagnosis. Pulmonary function, chest X-ray and dyspnoea score were measured, and systemic therapy for the sarcoidosis recorded. Organ involvement was assessed using a standardized instrument. A subset (n = 215) were seen 18-24 months later for follow-up, and these patients constitute our study group. RESULTS: Ten patients had only received therapy before the first visit, with no further therapy, and were excluded from analysis. Of the remaining 205, 95 were not on therapy at the initial visit and 75 (79%) of these were never treated during follow-up. Of the 110 initially on therapy, 52 (47%) remained on therapy at follow-up. Other initial features associated with continued therapy were the level of dyspnoea and predicted vital capacity. On logistic regression, only dyspnoea and therapy at initial visit remained significant. Patients on systemic therapy at initial evaluation were more likely to be on therapy at follow-up (OR 3.6, p = 0.003). Neither ethnicity nor gender independently predicted therapy at follow-up. DISCUSSION: This study group represents a sample of newly diagnosed sarcoidosis patients. However, this is a referral population, and there was no set protocol for treatment. Use of systemic therapy within the first 6 months after diagnosis appears to be strongly associated with continued use of therapy 2 years later.

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Sarcoidosis: social predictors of severity at presentation.

To determine relationships among social predictors and sarcoidosis severity at presentation, demographic characteristics, socioeconomic status, and barriers to care, A Case-Control Etiologic Study of Sarcoidosis (ACCESS) was set up. Patients self-reported themselves to be Black or White and were tissue-confirmed incident cases aged > or =l8-yrs-old (n=696) who had received uniform assessment procedures within one of 10 medical centres and were studied using standardised questionnaires and physical, radiographical, and pulmonary function tests. Severity was measured by objective disease indicators, subjective measures of dyspnoea and short form-36 subindices. The results of the study showed that lower income, the absence of private or Medicare health insurance, and other barriers to care were associated with sarcoidosis severity at presentation, as were race, sex, and age. Blacks were more likely to have severe disease by objective measures, while women were more likely than males to report subjective measures of severity. Older individuals were more likely to have severe disease by both measures. In conclusion, it was found that low income and other financial barriers to care are significantly associated with sarcoidosis severity at presentation even after adjusting for demographic characteristics of race, sex, and age.

Is endosonography guided fine needle aspiration (EUS-FNA) for sarcoidosis as good as we think?

BACKGROUND: Preliminary data show that endosonography guided fine needle aspiration (EUS-FNA) may be an accurate method for diagnosing sarcoidosis. However, these data were obtained in a small selected group of patients with a very high pretest probability of sarcoidosis. This retrospective study reports on the use of EUS-FNA in an unselected group of patients with mediastinal lymphadenopathy of unknown origin. METHODS: The EUS database of a single tertiary referral centre was reviewed for patients who underwent EUS-FNA for mediastinal lymphadenopathy of unknown origin. Clinical presentation and imaging studies of each case were carefully reviewed and the diagnosis "sarcoidosis" or "no sarcoidosis" attributed if possible. The diagnoses were compared with the result of EUS-FNA. RESULTS: One hundred and twenty four patients were investigated. In 35 cases EUS-FNA identified granulomas (group 1); in the other 89 cases (group 2) no granulomas were detected. The definite diagnoses in group 1 were sarcoidosis (n = 25), indefinite (n = 7), no sarcoidosis (n = 3). The definite diagnoses in group 2 were sarcoidosis (n = 3), indefinite (n = 9), no sarcoidosis (n = 77). Of the 77 cases with no sarcoidosis, 44 were diagnosed with other diseases. The other 33 showed non-specific changes in the FNA and sarcoidosis was excluded by negative non-EUS pathology (n = 17) and clinical presentation. The sensitivity and specificity for EUS-FNA were 89% (95% CI 82 to 94) and 96% (95% CI 91 to 98), respectively, after exclusion of the indefinite cases in both groups. CONCLUSIONS: EUS-FNA is an accurate method for diagnosing sarcoidosis in an unselected group of patients with mediastinal lymphadenopathy. The reported sensitivity and specificity must be appreciated in the context of the difficult and often incomplete clinical diagnosis of sarcoidosis.

Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).

Despite reports of familial clustering of sarcoidosis, little empirical evidence exists that disease risk in family members of sarcoidosis cases is greater than that in the general population. To address this question, we estimated sarcoidosis familial relative risk using data on disease occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age, sex, race, and geographically matched cases and controls who participated in the multicenter ACCESS (A Case-Control Etiology Study of Sarcoidosis) study from 1996 to 1999. Familial relative risk estimates were calculated using a logistic regression technique that accounted for the dependence between relatives. Sibs had the highest relative risk (odds ratio [OR] = 5.8; 95% confidence interval [CI] = 2.1-15.9), followed by avuncular relationships (OR = 5.7; 95% CI = 1.6-20.7), grandparents (OR = 5.2; 95% CI = 1.5-18.0), and then parents (OR = 3.8; 95% CI = 1.2-11.3). In a multivariate model fit to the parents and sibs data, the familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI = 2.3-9.7). White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p = 0.098). In summary, a significant elevated risk of sarcoidosis was observed among first- and second-degree relatives of sarcoidosis cases compared with relatives of matched control subjects.

Clinical characteristics of patients in a case control study of sarcoidosis.

Sarcoidosis may be affected by sex, race, and age. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled 736 patients with sarcoidosis within 6 mo of diagnosis from 10 clinical centers in the United States. Using the ACCESS sarcoidosis assessment system, we determined organ involvement for the whole group and for subgroups differentiated by sex, race, and age (less than 40 yr or 40 yr and older). The study population was heterogeneous in terms of race (53% white, 44% black), sex (64% female, 36% male), and age (46% < 40 yr old, 54% > or = 40 yr old). Women were more likely to have eye and neurologic involvement (chi(2) = 4.74, p < 0.05 and chi(2) = 4.60, p < 0.05 respectively), have erythema nodosum (chi(2) = 7.28, p < 0.01), and to be age 40 yr or over (chi(2) = 6.07, p < 0.02) whereas men were more likely to be hypercalcemic (chi(2) = 7.38, p < 0.01). Black subjects were more likely to have skin involvement other than erythema nodosum (chi(2) = 5.47, p < 0.05), and eye (chi(2) = 13.8, p < 0.0001), liver (chi(2) = 23.3, p < 0.0001), bone marrow (chi(2) = 18.8, p < 0.001), and extrathoracic lymph node involvement (chi(2) = 7.21, p < 0.01). We conclude that the initial presentation of sarcoidosis is related to sex, race, and age.

Carpal tunnel syndrome in sarcoidosis.

Sarcoidosis is a systemic disease that may affect the musculoskeletal system. An association between carpal tunnel syndrome (CTS) and sarcoidosis has not been demonstrated. Consecutive patients from the sarcoidosis clinic at our institution were questioned about history and symptoms of carpal tunnel syndrome: hand numbness and nocturnal paresthesias with relief of symptoms by shaking of the hands (flick sign). A physical exam was performed to evaluate for Tinel's and Phalen's signs. A comparison of the presence of arthritis, prednisone treatment, spirometry, and number of organs involved with sarcoidosis was made in patients with a history or clinical findings of CTS versus those without. Eighty-nine patients were evaluated. Thirty-five patients (39%) had nocturnal paresthesias with a positive flick sign. Fourteen patients (16%) had physical findings of CTS. A history of CTS was present in 14 (16%) of the patients, four of which were documented by EMG. There was no significant difference between the frequency of prednisone treatment in patients with or without CTS history, nocturnal paresthesias, or Phalen's sign. There were significantly fewer patients with a positive Tinel's sign who were receiving prednisone. There was a trend toward an increased frequency of wrist arthritis in patients with a history or clinical findings of CTS. There was no significant difference in disease severity, assessed by spirometry or organ involvement, when comparing sarcoidosis patients with or without a history or clinical findings of CTS. Thirty-nine (44%) had symptoms and/or signs of CTS. Even when we adjusted our sarcoidosis population for other factors associated with CTS, the prevalence of symptoms and signs of CTS was much higher in our patient population than in studies of the general population. Our findings suggest that CTS is common in sarcoidosis.

Current pharmacotherapy of allergic bronchopulmonary aspergillosis.

Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of allergic bronchopulmonary aspergillosis (ABPA). Neither the optimal steroid dose nor the duration of therapy has been standardised but limited data suggest the starting dose should be prednisone (approximately 0.5 mg/kg/day). The decision to taper steroids should be made on an individual basis, depending on clinical course. The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph and worsening spirometry suggest that steroids should be used. Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic steroid therapy should be used. Itraconazole appears useful as a steroid sparing agent.