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Purpose of Review: The treatment of sarcoidosis remains uncertain, despite 70 years of study. The conventional approach is to initiate corticosteroids in individuals who require treatment. The position of more aggressive regimes is unknown., Recent Findings: Recent recognition that many patients will require prolonged therapy, and the observation that corticosteroids lead to overt and insidious toxicities, have led to suggestions that steroid-sparing medications be used earlier in the management of sarcoidosis. Individuals with poor prognostic features, designated as 'high-risk' sarcoidosis may, especially benefit from a broader palette of therapeutic options in the initial treatment regimen. An even more aggressive approach, known as 'top-down' or 'hit-hard and early' therapy has emerged in the fields of gastroenterology and rheumatology in the past 15 years, on the premise that highly effective early control of inflammation leads to better outcomes. These regimens typically involve early initiation of biologic therapies., Summary: For certain subpopulations of sarcoidosis patients, 'top-down' therapy could be helpful. Severe pulmonary sarcoidosis, neurosarcoidosis, cardiac sarcoidosis and multiorgan sarcoidosis are phenotypes that may be most relevant for revised therapeutic algorithms. Precision medicine approaches and randomized trials will be necessary to confirm a role for top-down therapy in the routine management of sarcoidosis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

The effect of switching from originator infliximab to biosimilar infliximab in patients with sarcoidosis is unknown. The objective of this study is to investigate the effect of switching from Remicade ® or Inflectra ® to Flixabi ® in patients with severe refractory sarcoidosis. This single center retrospective cohort study was performed at St Antonius Hospital Nieuwegein, The Netherlands. All patients diagnosed with severe refractory sarcoidosis receiving Remicade ® or Inflectra ® switched to Flixabi ® . The primary outcome was infliximab discontinuation within 6 months of switching. Secondary endpoints included adverse events and loss of clinical, functional, or inflammatory response. Out of 86 patients who switched to Flixabi ® , 79 patients had complete data. None of the 79 patients discontinued infliximab during the first 6 months after switching. Five patients reported an adverse event related to Flixabi ® treatment. We found no change from baseline in FVC, FEV1, DLCOc, 6MWT, and infliximab trough levels 26 weeks after switching. An improvement in physical functioning of 7.3 ± 13.4 points ( p = 0.002) with RAND/SF36 and in biomarker sIL-2R (-475.58 ± 1452.39; p = 0.005) was observed. Switching from originator infliximab Remicade ® or biosimilar infliximab Inflectra ® to biosimilar infliximab Flixabi ® did not result in treatment discontinuation or loss of clinical/functional/inflammatory remission.

Sarcoidosis is a heterogeneous disease in terms of presentation, duration, and severity. Due to this heterogeneity, it is difficult to align treatment decisions. Biomarkers have proved to be useful for the diagnosis and prognosis of many diseases, and over the years, many biomarkers have been proposed to facilitate diagnosis, prognosis, and treatment decisions. Unfortunately, the ideal biomarker for sarcoidosis has not yet been discovered. The most commonly used biomarkers are serum and bronchoalveolar lavage biomarkers, but these lack the necessary specificity and sensitivity. In sarcoidosis, therefore, a combination of these biomarkers is often used to establish a proper diagnosis or detect possible progression. Other potential biomarkers include imaging tools and cell signaling pathways. Fluor-18-deoxyglucose positron emission tomography and high-resolution computed tomography have been proven to be more sensitive for the diagnosis and prognosis of both pulmonary and cardiac sarcoidosis than the serum biomarkers ACE and sIL-2R. There is an upcoming role for exploration of signaling pathways in sarcoidosis pathogenesis. The JAK/STAT and mTOR pathways in particular have been investigated because of their role in granuloma formation. The activation of these signaling pathways also proved to be a specific biomarker for the prognosis of sarcoidosis. Furthermore, both imaging and cell signaling biomarkers also enable patients who might benefit from a particular type of treatment to be distinguished from those who will not. In conclusion, the diagnostic and prognostic path of sarcoidosis involves many different types of existing and new biomarker. Research addressing biomarkers and disease pathology is ongoing in order to find the ideal sensitive and specific biomarker for this disease., (Copyright © 2020 Kraaijvanger, Janssen Bonás, Vorselaars and Veltkamp.)

Background: Tumor necrosis factor-alpha (TNF-α) inhibitors are regarded as the third-line therapy in sarcoidosis, the first choice generally being infliximab. To date, data regarding response to adalimumab in sarcoidosis patients intolerant to infliximab are lacking. The objective of this retrospective observational study was to establish if adalimumab could achieve stabilization or improvement of the disease in refractory sarcoidosis patients who developed intolerance to infliximab., Material and Methods: Sarcoidosis patients referred to St Antonius Interstitial Lung Diseases Center of Excellence, Nieuwegein, The Netherlands, between January 2008 and April 2015 who switched from infliximab to adalimumab were included. Changes in organ function, inflammatory biomarker levels, and adverse events were retrieved from medical records., Results: Out of 142 infliximab treated patients, 18 (13%) had to discontinue treatment due to antibody formation or severe adverse events and switched to adalimumab therapy. Organ function improved in 7 patients (39%), was stable in 6 patients (33%), and worsened in 5 patients (28%) after 12 months of treatment or after 6 months if evaluation after 12 months was not available (n = 4). In none of the patients biomarker levels of soluble interleukin-2 receptor (sIL-2R) deteriorated. Median decrease in sIL-2R was 3614 pg/mL. Most reported adverse event was infection (n = 10)., Conclusions: Adalimumab is an effective alternative for patients intolerant to infliximab. The switch to adalimumab achieved clinical improvement in 39% and stabilization in 33% of patients intolerant to infliximab. Further research is needed to develop guidelines on how to use adalimumab for sarcoidosis in terms of dosing regimen., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: In sarcoidosis, the search for disease activity markers that correlate with treatment response is ongoing. The aim of this study was to investigate the pattern of two proposed markers, serum angiotensin-converting enzyme (ACE) and soluble IL-2 receptor (sIL-2R) during methotrexate (MTX) therapy in sarcoidosis patients., Materials and Methods: We analysed 114 sarcoidosis patients who used MTX for six months, consisting of a subgroup of 76 patients with a pulmonary indication for treatment and a subgroup of 38 patients with an extra-pulmonary indication. ACE and sIL-2R serum levels were measured at baseline and after six months of treatment. Correlation coefficients (R) and odds ratios (ORs) were calculated to study the correlation and predictive effect of serum ACE and sIL-2R levels for pulmonary improvement., Results: High baseline levels of ACE correlated significantly with lung function improvement after treatment (R = 0.45, p < 0.0001; stronger in the pulmonary subgroup R 0.57, p < 0.0001). ACE baseline levels >90 U/l predicted a 10% improvement in overall lung function (OR 3.55; CI 1.34-9.38), with the highest prediction level for 10% improvement in DLCO (OR 4.63; CI 1.23-17.4). After six months of MTX, mean ACE decreased with 17.2 U/l (p < 0.0001) and sIL-2R with 1850 pg/ml (p < 0.0001). Decreases in both ACE and sIL-2R correlated with an increase in lung function. The strongest correlation was found with change in DLCO in the pulmonary subgroup (ACE R = 0.63, P < 0.0001; sIL-2R R = 0.56, P < 0.0001)., Conclusion: Baseline and serial serum ACE and sIL-2R levels correlate well with lung function improvement during MTX treatment. Serial measurements of these biomarkers are helpful in monitoring treatment effects in sarcoidosis patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose of Review: Sarcoidosis is a granulomatous disease which affects multiple organs. Its therapeutic management is very challenging due to the heterogeneity in disease manifestation and clinical course, as well as the potential side effects of the immunosuppressive therapy. An overview of presently available second-line and third-line systemic agents is provided., Recent Findings: Because curative treatment is currently not available for sarcoidosis, nonspecific immunosuppression with prednisone remains the first-choice therapy. However, as chronic use of corticosteroids is accompanied with severe adverse events, timely implementation of appropriate steroid-sparing cytotoxic agents is important. Commonly prescribed second-line agents in sarcoidosis are methotrexate, azathioprine, leflunomide and hydroxychloroquine. Nevertheless, the evidence supporting their use is limited. Third-line treatment options, including tumor necrosis factor-alpha inhibitors infliximab and adalimumab and the experimental therapeutic rituximab, are currently reserved for patients refractory to standard therapy., Summary: A better insight into the advantages and disadvantages of second-line and third-line treatment is important. The long-term effects of immunosuppressive agents, the optimal starting and maintenance dosages, and the best interval and discontinuation regimens should be elucidated. Identified associations of polymorphisms with treatment response suggest a step towards personalized medicine. Future research should focus on the role for pharmacogenetic and phenotypic predictors of treatment response and toxicity.

Infliximab is effective as a third-line therapeutic for severe sarcoidosis; however, long-term efficacy is unknown. The aim of this study was to assess the relapse rate after discontinuation of infliximab in sarcoidosis patients and predict relapse by analysis of the activity marker soluble interleukin (IL)-2 receptor (sIL-2R) and maximum standardised uptake value (SUVmax) of (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). In this retrospective cohort study, the proportion of relapse was analysed using the Kaplan-Meier method and predicting factors were studied using Cox regression. 47 sarcoidosis patients who started infliximab therapy were included in the risk analysis. Kaplan-Meier analysis revealed a median time to relapse of 11.1 months and showed that 25% of the cohort relapsed within 4 months. Both mediastinal SUVmax ≥ 6.0 on FDG PET (hazard ratio 3.77, p<0.001) and serum sIL-2R ≥ 4000 pg · mL(-1) (hazard ratio 2.24, p=0.033) at start of therapy predicted relapse. In multivariate analysis, a mediastinal SUVmax ≥ 6.0 at initiation of therapy was an independent predictor of relapse (hazard ratio 4.33, p<0.001). The majority of patients that discontinued infliximab therapy relapsed. High serum sIL-2R and high SUVmax on FDG PET at initiation of therapy were significant predictors of relapse. These results suggest close monitoring of patients in this category when they discontinue infliximab treatment.

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.

Sarcoidosis is a systemic, granulomatous disease that can affect multiple organs and has a variable clinical course. Corticosteroids (e.g. prednisone) remain the mainstay of therapy in sarcoidosis since their first use in this disease in the 1950s. A second-line therapeutic is often added to the treatment regimen in case of intolerable side effects, inefficacy or prolonged use of steroids. Methotrexate is considered by many to be the first choice drug in second-line therapeutics of sarcoidosis. Other often used second-line drugs are azathioprine and leflunomide. No large trials comparing different treatment options have been performed in sarcoidosis. In patients with severe disease who do not respond well to first and second-line therapy, biologicals such as infliximab can be promising. In this review, we provide a complete overview of all currently available therapeutic strategies in sarcoidosis. In addition, the gaps in current literature on sarcoidosis treatment were depicted to underline the importance of research in this mostly empiric field of medicine. Furthermore we highlight future medicine in sarcoidosis with emphasis on the role of personalised medicine.

Background: Three subpopulations of monocytes can be distinguished in human blood: classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++). CD16 expressing monocytes are expanded in patients with sarcoidosis and in various other inflammatory diseases. In sarcoidosis, it is unclear whether either intermediate, nonclassical or both CD16 expressing monocytes are responsible for this increase. Data relating to the monocyte subpopulations is receiving increasing attention, but the expression of TNF receptors on these subpopulations has not been studied thus far. The aim of this study was to determine frequencies of monocyte subpopulations and their expression of TNFR1 and TNFR2 in both sarcoidosis patients and healthy controls. Methods: Peripheral blood cells of sarcoidosis patients and healthy controls were stained for the markers HLA-DR, D14, CD16, CD120a and CD120b. Cells were measured on a FACSCalibur and analyzed with FlowJo. We used Student's t-test and a parametric One-way ANOVA for statistical analysis. Results: Sarcoidosis patients had a significant higher frequency of intermediate monocytes than healthy controls. Significant differences in TNF receptor expression were found between the monocyte subpopulations, both in sarcoidosis patients as well as in healthy controls: intermediates expressed more TNFR1 than classicals and nonclassicals and nonclassicals expressed more TNFR2 than intermediates, whereas intermediates showed higher expression than classicals. Conclusions: In both sarcoidosis patients and healthy controls intermediate monocytes show the highest expression level of TNFR1 among monocyte subpopulations and nonclassical monocytes show the highest expression level of TNFR2. These findings, as wells as the higher frequency of intermediate monocytes in sarcoidosis patients, provide evidence for the existence of two functionally-distinct CD16 expressing monocyte subpopulations. [ABSTRACT FROM AUTHOR]

Introduction. Although the role of TNF-α in tumor development is not fully understood, an increased risk of malignancy with TNF-α-inhibitors, such as infliximab, has been suggested. Case Presentation. We present a 54-year-old nonsmoking female sarcoidosis patient. After seven months of infliximab therapy a T1aN0M0 larynx carcinoma of the right vocal cord was found and excised. Within a year, whilst still on treatment, a second larynx carcinoma of the opposite vocal cord appeared. Discussion. A bilateral vocal cord tumor is rare, especially in a never smoker. Evidence on the role of infliximab in carcinogenesis is inconclusive. To date, there are no follow-up studies evaluating malignancy risk of infliximab therapy in sarcoidosis patients. No studies in other diseases focus on laryngeal carcinomas during infliximab use. We argue that infliximab treatment might have attributed to the rapid progression of vocal cord carcinomas in this patient with an a priori low risk tumor profile. This case illustrates that caution remains warranted in patients with previous malignancies when considering initiation of TNF-α-inhibitors. [ABSTRACT FROM AUTHOR]

Background: 18F-FDG PET/CT has proven to be a reliable tool for therapy monitoring in sarcoidosis. Previous PET studies investigated the SUVmax as a marker for disease activity. Total lung glycolysis (TLuG) is a new tool, quantifying the glycolysis of the entire lung. Since SUVmax represents the maximum activity in only one pixel, we hypothesize that TLuG is a more accurate marker for active pulmonary disease and predictor of response than SUVmax. Methods: In this retrospective cohort study, 27 patients started on infliximab for refractory pulmonary sarcoidosis. Patients received infliximab intravenously monthly at a dose of 5 mg/kg. We performed a lung function test and an 18F-FDG PET/CT before initiation of infliximab and after 6 months of treatment. SUVmax and TLuG were determined in the pre- and post-scan. Change in lung function was correlated with the change in SUVmax and TLuG and was correlated to the initial SUVmax and TLuG to evaluate the predictive value of the initial metabolic activity. Results: ΔSUVmax significantly correlated with ΔFVC (r = − 0.497, p = 0.008) and with ΔFEV1 (r = − 0.467, p = 0.014). Furthermore, ΔTLuG significantly correlated with ΔFVC (r = − 0.430, p = 0.025), ΔFEV1 (r = − 0.532, p = 0.004) and ΔDLCOc (r = − 0.423, p = 0.039). Change in SUVmax and TLuG significantly correlated (r = 0.735, p < 0.001). Initial SUVmax significantly correlated with the change in FVC and DLCOc. In addition, initial TLuG significantly correlated with the change in FEV1 and DLCOc. A SUVmax > 7.5 at initiation of infliximab was predictive for 5% response in FVC, whereas SUVmax > 9.2 was predictive for 5% response in DLCOc. In addition, high TLuG > 4100 at initiation of infliximab was predictive for 5% response in FVC and FEV1 and TLuG > 4500 was predictive for response in DLCOc. Conclusion: SUVmax and TLuG are equal in determining the response to infliximab in pulmonary sarcoidosis patients. Furthermore, SUVmax and TLuG at initiation of infliximab can predict change in lung function after treatment. Since TLuG is a more time-consuming tool, we recommend to use SUVmax of the lung parenchyma for response monitoring in pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]