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Purpose Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. Research Questions Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPF.sup.AF) compared with an untreated cohort (IPF.sup.non-AF)? Is this different for patients with GAP stage I, II, or III. Methods This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPF.sup.AF and IPF.sup.non-AF. This was repeated after stratification for GAP stage. Results In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPF.sup.AF (n = 313) and 2.2 years in IPF.sup.non-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPF.sup.AF (n = 143) and IPF.sup.non-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPF.sup.AF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPF.sup.AF with GAP III was also significantly lower (19.0% vs 65.0%). Conclusion This large real-world study showed a survival benefit in IPF.sup.AF compared with IPF.sup.non-AF. This especially holds true for patients with GAP stage II and III., Author(s): Mark G. J. P. Platenburg [sup.1], Coline H. M. van Moorsel [sup.1] [sup.2], Ivo A. Wiertz [sup.1], Joanne J. van der Vis [sup.1] [sup.3], Adriane D. M. Vorselaars [sup.1] [...]

ABSTRACT: Background and objective: The diagnostic classification of ‘possible idiopathic pulmonary fibrosis (posIPF)’ is characterized by a radiological pattern of inconsistent usual interstitial pneumonia (UIP) on high‐resolution computed tomography (HRCT) scan and a UIP pattern in surgical lung biopsy (SLB). The evidence base to guide treatment for patients with posIPF is lacking; the clinician must choose between observation, treatment with immunomodulatory agents or anti‐fibrotic agents. Methods: To evaluate outcomes of immunomodulatory treatment, a multicentre cohort of 59 posIPF patients treated with prednisone was analysed retrospectively. Prednisone starting dose was 0.5 mg/kg/day and tapered to 0.15 mg/day/kg over 6 months. Outcome measures were forced vital capacity (FVC) and serious adverse events (SAE), defined as death or hospital admissions. Results: The majority of prednisone‐treated posIPF patients were non‐responders (68%) with a decrease in FVC >5% or death within 6 months from baseline; 90% of patients with radiographical presence of honeycombing were non‐responders. In contrast, six out of seven patients with focal desquamative interstitial pneumonia‐like reaction in the SLB who had stopped smoking for <5 years ago were responders to prednisone, demonstrating <5% FVC decline. The mean decline of FVC was 8.7% (95% CI: 3.1–14.3%) before treatment and 20% (95% CI: 9.4–31.1%) after treatment (P = 0.018) in the 32 patients with available FVC data. Twelve SAE occurred within the first 3 months on prednisone (at dosage >0.3 mg/kg/day), including five deaths. Conclusion: Patients with posIPF demonstrated an accelerated FVC decline and a substantial number of SAE on steroid therapy. [ABSTRACT FROM AUTHOR]

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]

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]

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.)

Background: Infliximab, a monoclonal antibody against tumor necrosis factor alpha (TNF-α) is effective third-line therapy in severe sarcoidosis. The originator product of Infliximab, Remicade ® , is expensive, limiting universal access. Recently, a less expensive biosimilar of infliximab, Inflectra ® , has become available, but the efficacy and tolerability has not been studied in sarcoidosis., Methods: In this retrospective cohort study, 29 patients treated with the infliximab biosimilar Inflectra ® , were analysed. Patients received Inflectra ® intravenously monthly at a dose of 5 mg/kg. We measured trough levels before every infusion. Before and after 6 months of induction therapy pulmonary function and disease activity were evaluated using Standardised Uptake Value (SUV) of the 18 F-fluorodeoxyglucose by positron emission tomography ( 18 F-FDG PET), soluble interleukin-2 receptor (sIL-2R), angiotensin converting enzyme (ACE) and health-related quality of life (HRQOL)., Results: In patients with pulmonary sarcoidosis as main treatment indication (n = 15) the predicted FVC improved with 8.1%, p < 0.05. Furthermore, in the whole group HRQoL improved significantly (p < 0.001), whereas SUVmax and sIL-2R significantly reduced (p < 0.001 and p = 0.001 respectively). Hospitalisation due to infections occurred in four patients. None of the patients discontinued Inflectra ® due to side-effects. Furthermore, all patients had detectable trough levels indicating development of neutralizing antibodies., Conclusion: Infliximab biosimilar Inflectra ® seems effective in the treatment of refractory sarcoidosis with a comparable safety profile to the reference product Remicade ® . Inflectra ® can be considered as an alternative and less expensive option for patients with refractory sarcoidosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.)

Inconclusive evidence for the efficacy of infliximab in sarcoidosis hinders the global use of this potentially beneficial drug. To study infliximab efficacy in a clinical setting, we performed a prospective open-label trial in patients refractory to conventional treatment. Patients (n=56) received eight infusions of 5 mg·kg(-1) infliximab. Pulmonary function, disease activity measured by (18)F-fluorodeoxyglucose (FDG) by positron emission tomography (PET) and quality of life were part of the clinical work-up. Infliximab levels were measured before every infusion. After 26 weeks of infliximab treatment, mean improvement in forced vital capacity (FVC) was 6.6% predicted (p=0.0007), whereas in the 6 months before start of treatment, lung function decreased. Maximum standardised uptake value (SUVmax) of pulmonary parenchyma on (18)F-FDG PET decreased by 3.93 (p<0.0001). High SUVmax of pulmonary parenchyma at baseline predicted FVC improvement (R=0.62, p=0.0004). An overall beneficial response was seen in 79% of patients and a partial response was seen in 17% of patients. No correlation between infliximab trough level (mean 18.0 µg·mL(-1)) and initial response was found. In conclusion, infliximab causes significant improvement in FVC in refractory (18)F-FDG PET positive sarcoidosis. Especially in pulmonary disease, high (18)F-FDG PET SUVmax values at treatment initiation predict clinically relevant lung function improvement. These results suggest that inclusion of (18)F-FDG PET is useful in therapeutic decision-making in complex sarcoidosis., (Copyright ©ERS 2015.)

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.