Reverse phenotyping in sarcoidosis.
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Erythema Nodosum↗
Biomedical subjects
Robert P Baughman
Publications and source records attributed to Robert P Baughman.
Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
RATIONALE: Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis. OBJECTIVES: To assess the efficacy of infliximab in sarcoidosis. METHODS: A phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis. Patients were randomized to receive intravenous infusions of infliximab (3 or 5 mg/kg) or placebo at Weeks 0, 2, 6, 12, 18, and 24 and were followed through Week 52. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the change from baseline to Week 24 in percent of predicted FVC. Major secondary efficacy parameters included Saint George's Respiratory Questionnaire, 6-min walk distance, Borg's CR10 dyspnea score, and the proportion of Lupus Pernio Physician's Global Assessment responders for patients with facial skin involvement. Patients in the combined infliximab groups (3 and 5 mg/kg) had a mean increase of 2.5% from baseline to Week 24 in the percent of predicted FVC, compared with no change in placebo-treated patients (p = 0.038). No significant differences between the treatment groups were observed for any of the major secondary endpoints at Week 24. Results of post hoc exploratory analyses suggested that patients with more severe disease tended to benefit more from infliximab treatment. CONCLUSIONS: Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24. The clinical importance of this finding is not clear. The results of this Phase 2 clinical study support further evaluation of anti-TNF-alpha therapy in severe, chronic, symptomatic sarcoidosis.
Adult↗
Comparison of sarcoidosis phenotypes among affected African-American siblings.
STUDY OBJECTIVE: To test the hypothesis that sibling pairs, who share genes and environmental exposures, might have similar phenotypic expressions of sarcoidosis beyond what would be expected by chance alone. DESIGN: Multicenter family study with study subjects recruited from 11 clinical centers. SUBJECTS: Subjects were African-American sibling pairs with sarcoidosis. Sarcoidosis and organ pattern involvement were defined according to specific criteria. Fifteen different organ systems were evaluated. RESULTS: For full-sibling pairs, ocular involvement was found in both siblings more often than expected by chance alone (p < 0.05), but the concordance was weak (kappa = 0.18). When analyzing full-sibling and half-sibling pairs, ocular and liver involvement showed a significant concordance between sibling pairs (p < 0.05), but again the agreement was poor (kappa = 0.16 for both). Concordance in pulmonary function change over time was also weak. Clinical outcomes of sibling pairs were not significantly correlated except for whether treatment was prescribed, and this level of agreement was poor (kappa = 0.14 for full-sibling and half-sibling pairs; kappa = 0.15 for full-sibling pairs only). Modeling phenotypic expression in sibling pairs using logistic regression did show that the presence of ocular and liver sarcoidosis in the first affected sibling conferred a statistically significant increased risk to the second affected sibling for having those organs involved (odds ratio [OR], 3; 95% confidence interval [CI], 1.7 to 5.4 for ocular; OR, 3.3; 95% CI, 1.5 to 7.4 for liver). CONCLUSIONS: The phenotypic features and clinical outcomes of sarcoidosis in sibling pairs show minimal concordance, with the possible exception that the presence of ocular or liver involvement in the first sibling with a diagnosis of sarcoidosis makes involvement of these organs more likely in other affected siblings.
Adult↗
Diagnosis and management of spinal cord sarcoidosis.
BACKGROUND: Sarcoidosis of the spinal cord is very rare, affecting less than 1% of patients with sarcoidosis. METHODS: We retrospectively reviewed the charts of all patients with biopsy proven sarcoidosis and spinal cord involvement seen in our Interstitial Lung Disease and Sarcoidosis Clinic at the University of Cincinnati over a nineteen year period. Presentation of disease, method of diagnosis, and response to immunosuppressive therapy (methotrexate, azathioprine, or cyclophosphamide) were noted. RESULTS: Seventeen patients with spinal cord sarcoidosis were identified. All patients presented with insidious parethesias or weakness. Diagnosis was confirmed by biopsy of spinal cord lesions in two patients, dural biopsy in three patients, mediastinoscopy in eight patients, bronchoscopy in two patients, skin biopsy in one patient, and liver biopsy in one patient. Only four patients were diagnosed with sarcoidosis prior to spinal cord involvement. Cytotoxic therapy was initiated to reduce the daily dose of prednisone to less than 10 mg. Fourteen patients were evaluated at least six months after starting cytotoxic therapy. Of these evaluable patients, ten patients received methotrexate plus low dose prednisone and five responded. One patient received azathioprine plus low dose prednisone and responded. One patient received azathioprine, methotrexate, and low dose prednisone and responded. All seven patients that received cyclophosphamide responded. CONCLUSIONS: Spinal cord sarcoidosis should be considered in any patient presenting with gradual onset of paresthesias or weakness regardless of the diagnosis of sarcoidosis. Prompt treatment is important in long term outcome. Cyclophosphamide was an effective, well tolerated corticosteroid-sparing agent for patients with spinal cord sarcoidosis.
Adult↗
High-output heart failure associated with anagrelide therapy for essential thrombocytosis.
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Adult↗
Diagnosis of ventilator-associated pneumonia.
The diagnosis of ventilator pneumonia remains a controversial area. Use of standard clinical criteria has been found to be inadequate. Use of a clinical pulmonary infection score (CPIS) has improved the diagnostic utility of clinical criteria. For the intubated patient, there is ready access to the lower respiratory tract. Samples include endotracheal aspirates, bronchoalveolar lavage and protected brush specimen. The latter two can be obtained blindly or via a bronchoscope. The culture results are more meaningful if reported in a semi-quantitative model. There is increasing evidence that culture results predict mortality and can be used to direct duration and type of therapy.
Bacteria↗
Microbiologic diagnosis of ventilator-associated pneumonia.
No single test will provide all the information needed to diagnose ventilator-associated pneumonia (VAP), and the clinician must use multiple clinical criteria for the diagnosis. The use of culture techniques allows one to enhance the sensitivity and specificity of the diagnosis of pneumonia. In addition, the clinician can be kept up to date about potential new pathogens as they occur in the intensive care unit. Knowledge of the local flora allows one to make a better choice of empiric therapy for VAP.
Bronchoalveolar Lavage Fluid↗
Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS).
OBJECTIVES: To determine whether specific occupations and industries may be associated with sarcoidosis. METHODS: A Case Control Etiologic Study of Sarcoidosis (ACCESS) obtained occupational and environmental histories on 706 newly diagnosed sarcoidosis cases and matched controls. We used Standard Industrial Classification (SIC) and Standard Occupational Classification (SOC) to assess occupational contributions to sarcoidosis risk. RESULTS: Univariable analysis identified elevated risk of sarcoidosis for workers with industrial organic dust exposures, especially in Caucasian workers. Workers for suppliers of building materials, hardware, and gardening materials were at an increased risk of sarcoidosis as were educators. Work providing childcare was negatively associated with sarcoidosis risk. Jobs with metal dust or metal fume exposures were negatively associated with sarcoidosis risk, especially in Caucasian workers. CONCLUSIONS: In this study, we found that exposures in particular occupational settings may contribute to sarcoidosis risk.
Adolescent↗
Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial.
PURPOSES: Study a tumor necrosis factor receptor antagonist (etanercept) in the treatment of chronic ocular sarcoidosis. SUBJECTS AND METHODS: Eighteen patients with ocular sarcoidosis and ongoing inflammation in the eyes. All patients had received at least 6 months of therapy with methotrexate and were currently receiving corticosteroids. Patients were randomized to receive either etanercept, 25 mg subcutaneously twice a week, or placebo in a double-blind randomized trial. Treatment for ocular inflammation with systemic and local corticosteroids at the beginning and end of 6 months of treatment was noted. All patients underwent an ocular examination at the beginning and the end of the study by one ophthalmologist who was unaware of what treatment the patient was receiving. RESULTS: Three of the patients treated with etanercept and one treated with placebo were being treated with lower doses of corticosteroids by the end of the study. However, three of the etanercept patients and one of the placebo patients required larger doses of corticosteroids by the end of the study. The ophthalmology global assessment improved for two of the etanercept-treated patients and three of the placebo-treated patients. CONCLUSION: For most patients, therapy with etanercept was not associated with a significant improvement in their chronic ocular disease.
Aged↗
A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.
BACKGROUND: Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the United States of America, African Americans have a higher sarcoidosis incidence and suffer greater morbidity than Caucasians. METHODS: A sarcoidosis genetic linkage study consortium was established to recruit African-American affected sib pair (ASP) families to identify chromosomal regions that may harbor sarcoidosis susceptibility genes and to determine if environmental factors modify any genetic effects. RESULTS: We successfully met our goal of enrolling 359 ASPs using a multifaceted recruitment approach. In the total 559 sib pairs that were enrolled, genetic analyses revealed incorrectly specified relationships that required reclassification or removal from the analysis dataset of 10.4% of reported full and 1.4% of reported half sib pairs. The final study sample comprised 415 full and 104 half sib pairs with complete data. This included 338 ASPs. Within sib pairs, affection status was not associated with sex. Only 15 per cent of the 229 families had three or more affected sibs, but they contributed 42 per cent of the ASP total. CONCLUSIONS: The SAGA study experience should provide useful lessons and information to serve others in conducting genetic studies of complex diseases in African-American families.
Black or African American↗
The spectrum of biopsy sites for the diagnosis of sarcoidosis.
BACKGROUND: The diagnosis of sarcoidosis is most secure when supported by a tissue biopsy exhibiting noncaseating epithelioid granulomas with absence of known granulomagenic agents in a patient with multi-organ disease. Clinicians must decide which site offers the best chance of achieving a diagnostic biopsy with the least patient risk and discomfort. METHODS: 736 cases were enrolled in the NHLBI supported A Case Controlled Etiologic Study of Sarcoidosis (ACCESS) from November 1996 to June 1999. All cases required diagnostic organ biopsy (Bx) exhibiting non-caseating epithelioid granulomas without identifiable granulomagenic agent, within six months of recruitment. Positive Kveim-Siltzbach test was accepted in patients with Löfgren's syndrome. Bx sites were correlated with demographic data, chest radiographic stages, symptoms, pulmonary function and associated organ involvement. RESULTS: Seven hundred and seventy-six diagnostic biopsies were performed. Five hundred and sixty-seven were intrathoracic, 198 extrathoracic. Eleven Kveim tests were positive. When cutaneous sarcoidosis or an enlarged extrathoracic lymph node was present, skin or lymph node Bx was the preferred procedure. Twenty-three different organs yielded diagnostic biopsies. CONCLUSIONS: Biopsy diagnosis in sarcoidosis is almost always easily obtained. As shown by ACCESS, sarcoidosis offers a wide spectrum of diagnostic biopsy sites. The choice for biopsy is influenced by the presenting clinical constellation of organ involvement and the ease and safety of the biopsy procedure.
Adolescent↗
Pulmonary and psychosocial findings at enrollment in the ACCESS study.
AIM: To assess lung involvement and the association of demographic and psychosocial factors with respiratory health in 736 persons with sarcoidosis at enrollment in A Case Control Etiologic Study of Sarcoidosis (ACCESS). METHODS: 736 patients with biopsy diagnosis of sarcoidosis within 6 months of enrollment were studied at 10 US centers. Lung involvement was evaluated by chest radiography, spirometry and dyspnea questionnaire. Demographics, number of involved extrathoracic organ systems, comorbidities, and health-related quality of life (HRQL) were assessed. RESULTS: 95% of patients had lung involvement. 8% were Scadding Stage 0, 40% I, 37% II, 10% III, and 5% IV 51% reported dyspnea. Increasing radiographic lung stage was associated with decreasing Forced Vital Capacity (FVC) (p < 0.01). Patients with higher stages had more airways obstruction and dyspnea. 46% of cases and 27% of controls had Center for Epidemiologic Studies Depression Scale (CES-D) scores of 9 or greater, (p < 0.001). Age > or = 40, African-American race, body mass index > or = 30kg/m2, and CES-D scores > 9 were associated with decreased FVC and greater dyspnea. Impaired spirometry and greater dyspnea were associated with poorer quality of life. CONCLUSION: A "global" approach to the sarcoidosis patient, including careful assessment of dyspnea and health related quality of life, as well as of lung function and radiographic changes, and any extrathoracic involvement, is important, not only in management of the individual patient, but should also prove beneficial in assessing outcomes in clinical trials in the future.
Adult↗
A case control etiologic study of sarcoidosis: environmental and occupational risk factors.
Past research suggests that environmental factors may be associated with sarcoidosis risk. We conducted a case control study to test a priori hypotheses that environmental and occupational exposures are associated with sarcoidosis. Ten centers recruited 706 newly diagnosed patients with sarcoidosis and an equal number of age-, race-, and sex-matched control subjects. Interviewers administered questionnaires containing questions regarding occupational and nonoccupational exposures that we assessed in univariable and multivariable analyses. We observed positive associations between sarcoidosis and specific occupations (e.g., agricultural employment, odds ratio [OR] 1.46, confidence interval [CI] 1.13-1.89), exposures (e.g., insecticides at work, OR 1.52, CI 1.14-2.04, and work environments with mold/mildew exposures [environments with possible exposures to microbial bioaerosols], OR 1.61, CI 1.13-2.31). A history of ever smoking cigarettes was less frequent among cases than control subjects (OR 0.62, CI 0.50-0.77). In multivariable modeling, we observed elevated ORs for work in areas with musty odors (OR 1.62, CI 1.24-2.11) and with occupational exposure to insecticides (OR 1.61, CI 1.13-2.28), and a decreased OR related to ever smoking cigarettes (OR 0.65, CI 0.51-0.82). The study did not identify a single, predominant cause of sarcoidosis. We identified several exposures associated with sarcoidosis risk, including insecticides, agricultural employment, and microbial bioaerosols.
Adolescent↗
Leflunomide for chronic sarcoidosis.
BACKGROUND AND AIM: Leflunomide (Arava) is a cytotoxic drug which has been used as a single agent or in combination with methotrexate for the treatment of rheumatoid arthritis. It appears to have less toxicity than methotrexate. The use of leflunomide for sarcoidosis patients has not been systematically evaluated. METHODS: The records were reviewed from all patients treated at a tertiary sarcoidosis center from July 2002-July 2003, and information from patients treated with either leflunomide or methotrexate was analyzed for efficacy and toxicity. RESULTS: Thirty-two patients were treated with leflunomide; fifteen patients received concurrent therapy with methotrexate. The most common indications for therapy were ocular and lung disease. Complete or partial response to leflunomide was seen in 12 of 17 treated with leflunomide alone, and 13 of 15 treated with leflunomide plus methotrexate. There was no difference in the response rate for eye [23/28 (82%)] versus pulmonary disease [12/16 (75%)]. Seventeen patients were treated with leflunomide alone because of methotrexate toxicity (nausea in 12 and pulmonary symptoms in five). All but two tolerated leflunomide. Three patients experienced nausea leading to drug discontinuation, but no other serious adverse reaction was encountered with leflunomide. CONCLUSION: Leflunomide was well tolerated in patients with chronic sarcoidosis. It appears to be as effective as methotrexate, with less toxicity. It should be considered as an alternative in chronic sarcoidosis patients who cannot tolerate methotrexate.
Adult↗
Pulmonary sarcoidosis.
Pulmonary sarcoidosis is one of the most common causes of idiopathic interstitial lung disease. Clinical presentation can range from asymptomatic to respiratory failure. Although some patients never require therapy, many patients with pulmonary sarcoidosis become symptomatic enough to require therapy. Treatment options include corticosteroids.In the past few years, alternatives to corticosteroids have been developed,especially for patients with a chronic condition.
Antibodies, Monoclonal↗
Newer therapies for cutaneous sarcoidosis: the role of thalidomide and other agents.
Skin involvement occurs in a third of patients with sarcoidosis. The type of lesions can range from the transient erythema nodosum to the chronic facial lesion lupus pernio. For some patients with sarcoidosis, lesions on the face or elsewhere on the body may be the major or only indication for therapy. These lesions are often chronic and the use of corticosteroids may lead to more long-term complications. Conventional alternatives to corticosteroids include antimalarial agents, methotrexate, and azathioprine. Recently, several drugs have been studied for chronic cutaneous sarcoidosis; thalidomide has been the most widely used. Thalidomide has been demonstrated to suppress tumor necrosis factor (TNF) release, which may be important at both the initial and chronic phases of the inflammation of sarcoidosis and appears to be crucial as part of the initial granulomatous response. Thalidomide has a different toxicity profile than corticosteroids or immunosuppressives. The usual dosage has recently been investigated in a dose-escalation trial, with the majority of patients responding to 100 mg/day. Drug toxicity has been reported in the sarcoidosis trials. The most serious adverse effect has been peripheral neuropathy, which often resolves by reducing the dose or discontinuing the medication. Other drugs that have been studied for sarcoidosis include infliximab and tetracyclines. Infliximab is a chimeric monoclonal antibody against TNF, and several published reports have shown it to be effective for the treatment of cutaneous sarcoidosis. The efficacy of tetracyclines for cutaneous sarcoidosis could be on the basis of their immunologic properties. In addition, these drugs have potent antimicrobial activity against Propionibacterium acnes; there is increasing evidence to suggest this may be one of the causes of sarcoidosis. However, most of the newer agents for cutaneous sarcoidosis have only been studied in small series. Over the next few years, it is hoped that there will be clinical trials to determine the role of each new therapy in the treatment of cutaneous sarcoidosis.
Chronic Disease↗
Sarcoidosis.
There have been several new insights into the cause and treatment of sarcoidosis. Studies of genetic variation have shown that specific genetic polymorphisms are associated with increased risk of disease or affect disease presentation. These polymorphisms include variation of MHC and cytokines such as tumour necrosis factor (TNF). Not all investigators have come to the same conclusion, suggesting an interaction of various factors, including the patient's ethnic origin. Treatment of sarcoidosis varies considerably. Patients with symptomatic disease for more than 2-5 years have been of particular interest. Corticosteroids remain the standard of care in such cases, but immunosuppressive drugs have proved steroid-sparing in many patients. New agents, including pentoxifylline, thalidomide, and infliximab have proved useful in selected cases. The effectiveness of these agents seems to lie in their ability to block TNF, especially in the treatment of chronic disease.
Adrenal Cortex Hormones↗
Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant.
We performed a phase I/II trial in North America of a recombinant surfactant protein C-based surfactant (Venticute) as treatment for the acute respiratory distress syndrome. Patients were prospectively randomized to receive either standard therapy or standard therapy plus one of two doses of exogenous surfactant given four times over 24 hours. Surfactant administration was well tolerated. No significant treatment benefit was associated with surfactant treatment. Bronchoalveolar lavage of treated patients at 48 hours reflected the presence of exogenous surfactant components, did not show evidence of improved surface tension lowering function, and had interleukin-6 concentrations that were significantly lower than control group values, consistent with an antiinflammatory treatment effect. The presence of exogenous surfactant was not detected in lavage fluid obtained at 120 hours. Future studies might rationally employ larger surfactant doses and a more prolonged dosing schedule.
Bronchoalveolar Lavage Fluid↗