Elyse E. Lower

Efficacy of Dexmethylphenidate for the Treatment of Fatigue After Cancer Chemotherapy: A Randomized Clinical Trial

Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment. Dexmethylphenidate (D-MPH; the D-isomer of methylphenidate) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue. Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale (FACIT-F) total score at Week 8 was the primary outcome measure. One hundred fifty-four patients (predominantly with breast and ovarian cancers) were randomized and treated. Compared with placebo, D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F (P=0.02) and the Clinical Global Impression-Severity scores (P=0.02), without clinically relevant changes in hemoglobin levels. Cognitive function was not significantly improved. There was a higher rate of study drug-related adverse events (AEs) (48 of 76 [63%] vs. 22 of 78 [28%]) and a higher discontinuation rate because of AEs (8 of 76 [11%] vs. 1 of 78 [1.3%]) in D-MPH-treated subjects compared with placebo-treated subjects. The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache, nausea, and dry mouth, and in placebo-treated subjects were headache, diarrhea, and insomnia. D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy. Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered.

Design of A Case Control Etiologic Study of Sarcoidosis (ACCESS)

Sarcoidosis is a chronic granulomatous disorder of unknown cause, characterized by activation of T-lymphocytes and macrophages. A Case Control Etiologic Study of Sarcoidosis (ACCESS) is a multicenter study designed to determine the etiology of sarcoidosis. The study organization includes 10 Clinical Centers, a Clinical Coordinating Center, specialized Core Laboratories, a Central Specimen Repository, and a Project Office at the National Heart, Lung, and Blood Institute. In addition to etiology, ACCESS will examine the socioeconomic status and clinical course of patients with sarcoidosis. We propose to enroll 720 newly diagnosed cases of sarcoidosis and compare them to 720 age, sex, and race matched controls and follow the first 240 cases for two years. Leads to the etiology of sarcoidosis have come from diverse sources: in clinical laboratory investigations, alveolitis has been found to precede granulomatous inflammation; in case control studies, familial aggregation has been identified; and in case reports, recurrence of granulomatous inflammation has been observed after lung transplantation. We describe the rationale for the study design based on genetic, environmental, infectious, and immune dysregulation hypotheses and the methods used for selecting controls. The cause may not prove to be a single, known exposure. Interactions of exposures with genetic predispositions would have important implications for our understanding of immune responses as well as the pathogenesis of sarcoidosis.

Survival in Sarcoidosis-Associated Pulmonary Hypertension: The Importance of Hemodynamic Evaluation

OBJECTIVE Pulmonary hypertension (PH) has been associated with increased mortality in patients with advanced pulmonary sarcoidosis. Sarcoidosis-associated PH may be the result of left ventricular dysfunction (LVD) or isolated pulmonary vasculature abnormality. Our objective was to determine if the cause of PH affects survival in patients with sarcoidosis with persistent dyspnea. METHODS Patients with sarcoidosis with persistent dyspnea despite immunosuppressive therapy underwent right-sided heart catheterization. Patients with a pulmonary artery occluding pressure (PAO) ≥ 15 mm Hg were defined as having LVD. Patients were classified based on hemodynamics as no PH (pulmonary artery mean pressure [PAmean] < 25 mm Hg), PH without LVD (PAmean ≥ 25 mm Hg and PAO < 15 mm Hg), and PH with LVD (PH/LVD) (PAmean ≥ 25 mm Hg and PAO ≥ 15 mm Hg). RESULTS One hundred thirty patients were studied at one institution: 50 (38.5%) patients had PH without LVD, whereas 20 (15.4%) had PH/LVD. All patients had their diagnostic procedure at least 18 months prior to analysis. The hazard ratio (HR) for death in PH without LVD vs no PH was 10.39 (95% CI, 2.99-13.78; P < .0001). The HR for dying for PH without LVD vs PH/LVD was 3.14 (95% CI, 1.01-5.62; P < .05). The presence of stage 4 chest roentgenograms and the need for supplemental oxygen were different between the groups. In a Cox proportional hazards model, independent predictors for survival were stage 4 chest roentgenogram (P < .005) and hemodynamic group (P < .02). CONCLUSION PH without LVD was associated with increased mortality. Proper characterization of patients required hemodynamic evaluation, as 29% of sarcoidosis-associated PH was due to LVD.

The use of low dose methotrexate in refractory sarcoidosis.

Symptomatic sarcoidosis is usually treated with glucocorticoids; however, glucocorticoids are associated with significant morbidity. Because low dose methotrexate has been successful in treating other inflammatory diseases, methotrexate was used in patients with persistent, symptomatic sarcoidosis. Fifteen patients with either progressive advancing disease or severe side effects with prednisone were treated with methotrexate for at least 6 months. In 13 of 14 evaluable cases there was symptomatic improvement. In 12 of 14 patients there was significant improvement in objective parameters, including a greater than 15% increase in the vital capacity (5 patients), improvement in chest roentgenogram (6 patients), or a greater than 50% reduction in skin lesions (4 patients) or liver function tests (2 patients). In five patients the disease relapsed as methotrexate was being withdrawn; all patients responded to reinstitution of the drug.

A clinical approach to the use of methotrexate for sarcoidosis

The management of patients with sarcoidosis has been the subject of many papers in this1 and other journals.2-5 The large number of papers are, in part, because of the difficulty in defining who should be treated for this disease and with what. The most commonly used pharmaceutical class for sarcoidosis has been corticosteroids, both topically and systemically.6 The use of systemic steroids for sarcoidosis was the subject of a trial by the British Thoracic Society1 which concluded that there were some patients who required no treatment and some who would need immediate treatment because of the severity of the disease. In between was a group of patients with persistent disease who appeared to benefit from treatment with corticosteroids. One of the points made was that some patients needed treatment for long periods of time. The term “chronic sarcoidosis” has been used by Dr Geraint James to describe patients with disease for more than two years.7He noted that some features of sarcoidosis such as lupus pernio and neurological disease were associated with a low rate of remission, while other features such as erythema nodosum were associated with a high resolution rate by two years. Several other manifestations of the disease have been associated with chronic disease: bone cysts, cor pulmonale, pulmonary fibrosis,8 and nephrolithiasis.9 Based on the type and duration of symptoms one can classify patients as acute or chronic.10A third group is also evident—namely, those who are refractory to corticosteroid therapy. This includes some neurosarcoidosis patients, patients who develop organ failure, and those who die despite corticosteroid treatment.11 12 Treatment for sarcoidosis is often dependent on the patient’s own manifestation. A patient with anterior uveitis may be a candidate for topical steroids alone, but a patient with neurological disease …

Established and experimental medical therapy of pulmonary sarcoidosis.

The treatment options for pulmonary sarcoidosis have increased over the past 10 years. As new treatments have been introduced, the best way to assess and compare treatments remains unknown. The goal of this review is to discuss the standard treatments for pulmonary sarcoidosis, including glucocorticoids, and cytotoxic agents, such as methotrexate, azathioprine and leflunomide, and compare them to the newer biological agents, such as infliximab and adalimumab. We also discuss some novel treatments which are currently being evaluated. To compare these different regimens, we look at the measures used to assess response. These include pulmonary function, chest imaging, steroid sparing potential and, more recently, improvements in quality of life measures. While there is, as yet, no standard assessment for response, there is a growing consensus that response to treatment may include improvement of one or more of the following: forced vital capacity, chest imaging and steroid sparing. Several drugs used for pulmonary sarcoidosis have demonstrated improvement in one or more of these measures.

Sarcoidosis-associated fatigue

Sarcoidosis-associated fatigue is globally recognised as a disabling symptom. Fatigue has been reported in up to 50–70% of sarcoidosis patients, causing impaired quality of life. The aetiology of this troublesome problem remains elusive and is usually multifactorial. Fatigue can be a consequence of treatment itself, including as a complication of corticosteroid therapy. The diagnosis of sarcoidosis-associated fatigue requires an extensive evaluation to identify and treat potentially reversible causes. Granuloma formation and cytokine release may be involved in its aetiology. However, despite adequate sarcoidosis treatment, many patients continue to experience fatigue. Comorbidities associated with sarcoidosis, including depression, anxiety, hypothyroidism and altered sleep patterns, may all contribute to fatigue. Despite an exhaustive search for treatable clinical causes of fatigue, most patients’ complaints of fatigue are not correlated with clinical parameters of disease activity. Recent studies have demonstrated the effectiveness of various neurostimulants, including methylphenidate, for the treatment of sarcoidosis-associated fatigue. These and other agents may be useful adjuncts for the treatment of sarcoidosis-associated fatigue. Obviously, there is a need for studies evaluating the causes and new therapeutic options of sarcoidosis-associated fatigue. Psychological interventions should also be examined.

Fatigue in sarcoidosis: a systematic review

Purpose of review Several studies have investigated fatigue among sarcoidosis patients. The purpose of this review is to analyze published data on the assessment, prevalence, etiology, and treatment of sarcoidosis-associated fatigue. Recent findings Fatigue was identified as a prominent problem in sarcoidosis, and its presence was frequently associated with impaired quality of life, compared with patients without fatigue. Although the studies with good methodological fatigue assessment found no relationship between clinical parameters and fatigue in sarcoidosis patients, the remaining studies reported associations between fatigue and clinical and psychological parameters. No studies were designed to analyze the etiology of fatigue, but some studies showed that prednisone-treated patients reported more fatigue compared with untreated patients. In addition, only one study focused on a treatment for fatigue, dexmethylphenidate hydrochloride. Several instruments to measure fatigue were used, with the Fatigue Assessment Scale most frequently utilized. Summary This review illustrates the importance of fatigue as an under-recognized complication of sarcoidosis. It further emphasizes the need for longitudinal prospective studies to better define sarcoidosis fatigue, explore its impact on quality of life, define aggravating or alleviating factors and evaluate new potential treatment strategies.

STEROID-SPARING ALTERNATIVE TREATMENTS FOR SARCOIDOSIS

Alternatives to corticosteroids for the treatment of sarcoidosis are reviewed. These include cytotoxic agents such as methotrexate, azathioprine, and cyclophosphamide. In addition, agents such as hydroxychloroquine and cyclosporine are reviewed. The efficacy, toxicity, and timing of these drugs in the management of sarcoidosis is discussed.

Double-Blind, Randomized Trial of Dexmethylphenidate Hydrochloride for the Treatment of Sarcoidosis-Associated Fatigue

BACKGROUND Fatigue is a common complaint in patients with sarcoidosis. We studied the effectiveness of dexmethylphenidate hydrochloride (d-MPH) in treating sarcoidosis-associated fatigue. METHODS This was a double-blind, randomized, placebo-controlled, crossover trial of d-MPH. Patients were seen weekly and completed Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Fatigue Assessment Score (FAS) instruments. After a 1-week wash-in period, patients received either d-MPH or placebo. After 8 weeks, the medications were stopped. Following a 2-week wash-out period, patients were crossed over to 8 weeks of the other treatment. FVC and 6-min walk distance (6MWD) were determined initially and after each treatment arm. RESULTS Ten patients with sarcoidosis were enrolled: 8 women and 5 African Americans. All were receiving systemic sarcoidosis therapy. Significant improvement in fatigue was reported by patients when receiving d-MPH (FACIT-F, p < 0.001; FAS, p < 0.02). FVC was higher at the end of 8 weeks of d-MPH compared to the baseline values (baseline median, 2.38 L; range, 1.17 to 4.53 L; placebo median, 2.41 L; range, 1.50 to 4.65 L; d-MPH median, 2.56 L; range, 1.50 to 4.96 L; p < 0.01). There was no significant difference in the 6MWD (baseline median, 330 m; range, 60 to 460 m; placebo median, 350 m; range, 180 to 460 m; d-MPH median, 390 m; range, 200 to 460 m). d-MPH was well tolerated. CONCLUSIONS Treatment with d-MPH was associated with a significant improvement in sarcoidosis-associated fatigue. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00361387.