Ingrid He Korenromp

Characterization of Chronic Fatigue in Patients With Sarcoidosis in Clinical Remission

BACKGROUND Patients with sarcoidosis frequently complain of fatigue, even when sarcoidosis has come into clinical remission. The primary aim of this study was to assess the severity of fatigue in patients with sarcoidosis in clinical remission and to characterize it according to the international criteria for chronic fatigue syndrome (CFS). Furthermore, we evaluated whether fatigue is associated with depression and anxiety, health status, and patient-reported sleep quality, and we recorded physical activity levels and muscle strength as objective assessments of fatigue. METHODS Data on 75 patients with sarcoidosis in clinical remission were obtained by questionnaires (Checklist Individual Strength [CIS], Symptom Checklist-90, Beck Depression Inventory for primary care, Medical Outcomes Study 36-Item Short-Form Health Survey), standardized interview (CFS criteria), sleep diary, accelerometer, and muscle strength tests. RESULTS Fatigue severity mean score in patients with sarcoidosis in clinical remission was high (CIS fatigue severity 30.5 ± 15.5), and criteria for CFS were met in 47% of fatigued participants. Median time since diagnosis was 9 years. Fatigue was associated with depression (P = .01), anxiety (P = .013), and reduced health status (P < .001). Scores on sleep quality were normal. Physical activity levels were reduced in fatigued participants. Muscle strength, particularly handgrip (P = .006) and quadriceps strength (P < .001), was significantly associated with fatigue. CONCLUSIONS Fatigue in patients with sarcoidosis in clinical remission is a frequent symptom and can be characterized as a severe and long-lasting problem, symptomatically similar to CFS. Psychologic distress and reduced health status are associated with fatigue. Interestingly, we observed significantly reduced physical activity and muscle weakness in fatigued patients.

Anti-TNF therapeutics for the treatment of sarcoidosis.

Sarcoidosis is a systemic disease with an incidence of 1 to 40 per 100 000 persons per year. It predominantly affects people in the age of 20 to 40 years old. Disease course varies from mild self-limiting to chronic debilitating and life-threatening disease. Since the cause of sarcoidosis is unknown, curative therapy is not available. Immunosuppressive drugs may, however, control the symptoms of the disease. The hallmark of sarcoidosis is the formation of granulomas that are most commonly found in lungs and lymph nodes. As TNF plays an important role in both formation and maintenance of these granulomas, as well as in the immune response, anti-TNF biologicals such as infliximab and adalimumab are considered a last resort therapeutic option. Clinical effectiveness, however, varies considerably and data showing which patients would benefit most from this expensive therapy are scarce. This review summarizes current knowledge on anti-TNF therapeutics in sarcoidosis, and describes insights on prediction of response, outcome measures and antibody development.

FDG PET for gauging of sarcoid disease activity.

Fluorodeoxyglucose (FDG), labeled with a positron emitting fluorine-18 ((18)F), is a synthesized glucose analogue and is well known for its application in a wide variety of clinical conditions such as cancer. Visualizing metabolic activity of inflammation is another application of FDG in positron emission tomography (PET). Here, active granulomas appear to have a high affinity for FDG, which is reflected in a high sensitivity of FDG PET imaging. This has led to novel applications of FDG PET in sarcoidosis diagnosis and management. Although chest radiography and high-resolution computed tomography are still the cornerstones of diagnosing pulmonary involvement, FDG PET appears to be superior to both techniques in imaging active sites of disease. FDG PET also correlates well with serum biomarkers such as soluble interleukin-2 receptor in symptomatic patients, and even visualizes active lesions in the context of normal serum biomarkers. Moreover, FDG PET activity in lung parenchyma correlates with decrease of lung function values over time. Also in cardiac involvement in sarcoidosis, FDG PET is a promising technique complementary to magnetic resonance imaging, especially in guiding treatment. New developments, such as applications for quantitative organ-specific measurement, are proceeding and will probably enhance the clinical implementation of FDG PET in sarcoidosis.

Post-inflammatory fatigue in sarcoidosis: Personality profiles, psychological symptoms and stress hormones

OBJECTIVES Chronic fatigue following inflammatory diseases has been well documented. However, little is known about possible risk factors of chronic post-inflammatory fatigue. The aim of this study was to investigate whether chronic post-inflammatory fatigue after clinical remission of the disease sarcoidosis is associated with specific dimensions of personality, psychological symptoms and baseline levels of stress hormones. METHODS Thirty-seven non-fatigued and 33 fatigued patients in clinical remission of sarcoidosis were evaluated with the Temperament and Character Inventory-short form (TCI); the Symptom CheckList-90 (SCL), and the Checklist Individual Strength (CIS). Baseline levels of ACTH and cortisol were measured in plasma. Principal component analysis with orthogonal rotation (varimax) was conducted on all personality, psychological and stress hormone data in order to obtain a smaller set of components. Logistic regression was performed to associate these components with chronic post-inflammatory fatigue. RESULTS Principal component analyses identified 5 components, of which two components were significantly associated with chronic post-inflammatory fatigue. The first component comprised the personality trait Harm Avoidance and all SCL-subscales except Sleep. The second component consisted of baseline levels ACTH and cortisol, and showed an inverse association with chronic post-inflammatory fatigue. The 3 other components, consisting of respectively SCL-Sleep, TCI-Novelty Seeking-Reward Dependence-Self Transcendence, and TCI-Persistence, were not significantly associated with chronic fatigue. CONCLUSION Chronic post-inflammatory fatigue after clinical remission of sarcoidosis is associated with a triad of risk factors: a specific personality profile with profound neurotic characteristics in combination with high levels of psychological distress, and decreased baseline ACTH/cortisol levels.

Changes in disease activity, lung function and quality of life in patients with refractory sarcoidosis after anti-TNF treatment

Objectives: The effect of infliximab therapy in rheumatoid arthritis and Crohns disease has been well documented. However, literature on infliximab therapy in the rare disease sarcoidosis is scarce. The aim of our study is to evaluate change in disease activity and quality of life upon infliximab treatment in patients with refractory sarcoidosis. Research design and methods: Retrospective cohort study of 48 patients who received infliximab treatment at a national referral center for sarcoidosis. The clinical effect of infliximab treatment was analyzed in terms of change in disease activity (18F-FDG PET, serum angiotensin-converting-enzyme [ACE], serum-soluble interleukin-2 receptor [sIL-2R]), lung function (predicted VC, FEV1 and DLCOc), fatigue severity (CIS) and physical functioning (SF-36). Study parameters were assessed before the first dose (week 0) and after the last dose (week 18). Results: We found significant decreases in the serum markers ACE and sIL-2R and in SUVmax on 18F-FDG PET. Furthermore, a significant improvement in fatigue severity and physical functioning scores was observed. In patients with a pulmonary treatment indication, we found significant improvements in percentages of predicted VC (7.6%), FEV1 (7.9%) and DLCOc (3.5%). Conclusions: Infliximab improves PET-scan, serum markers, lung function and quality of life in patients with refractory sarcoidosis.

Is there evidence for anti-TNF drugs in joint involvement in sarcoidosis?

A letter in response to: Banse C, Goeb V. Do not forget the joint involvement of sarcoidosis. Immunotherapy 7(6), 599–600 (2015).

141. Chronic fatigue in patients with sarcoidosis-in-clinical-remission is associated with specific cytokine profiles

The kynurenine pathway (KP) is the main pathway by which tryptophan is metabolised, and KP activation has been implicated in the pathogenesis of depression and neurodegeneration. Indolamine 2,3 dioxygenase (IDO) catalyses the production of kynurenine from tryptophan, and the inflammatory cytokine IFN-gamma is a major inducer of IDO. Kynurenine is in turn metabolised down one of two catabolic pathways either by the enzyme kynurenine 3hydroxylase (KMO) which leads to production of quinolinic acid (neurotoxic), or by kynurenine aminotransferase (KAT II) which yields kynurenic acid (neuroprotective). It is becoming more widely accepted that the kynurenine pathway may link inflammation to depression, and ultimately to neurodegeneration. The objective of this study was to determine if stimulation of BV-2 microglia with IFN-gamma induces expression of key KP enzymes, and if expression of KP enzymes in these cells correlates with their neurotoxic potential. Treatment with IFN-gamma increased IDO and KMO expression, but failed to induce KAT II in BV-2 microglia. Furthermore, conditioned media from IFN-c treated BV-2 microglia induced neurotoxicity in primary cortical neurons. These results suggest that stimulation of BV-2 microglia with IFN-gamma favours the neurotoxic arm of the KP, and future studies will determine if this neurotoxicity is a result of kynurenine metabolites produced by the BV-2 microglia. Supported by EUFP7 MOODINFLAME.