Heleen A. Crommelin

Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis.

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 18F-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 18F-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 18F-FDG PET positive sarcoidosis. Especially in pulmonary disease, high 18F-FDG PET SUVmax values at treatment initiation predict clinically relevant lung function improvement. These results suggest that inclusion of 18F-FDG PET is useful in therapeutic decision-making in complex sarcoidosis. Infliximab is highly effective in refractory 18F-FDG PET positive sarcoidosis patients http://ow.ly/JoxhL

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.

Infliximab therapy balances regulatory T cells, tumour necrosis factor receptor 2 (TNFR2) expression and soluble TNFR2 in sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (Tregs) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. Tregs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on Tregs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of Tregs were significantly higher in patients (n = 54) compared to healthy controls (n = 26; median 6·73 versus 4·36%; P < 0·001) and decreased following therapy (4·95; P < 0·001). Baseline TNFR2 expression on Tregs was increased significantly in patients versus controls (99·4 versus 96·2%; P = 0·031), and also in responders to therapy versus non‐responders (99·6 versus 97·3%; P = 0·012). Furthermore, baseline soluble TNFR2 (sTNFR2) was higher in responders than in non‐responders (mean 174 versus 107 pg/ml; P = 0·015). After treatment, responders showed a significant reduction in sTNFR2 levels in peripheral blood (−44·7 pg/ml; P < 0·001), in contrast to non‐responders (+3·59 pg/ml). Our results demonstrated that Treg frequencies and TNFR2 expression on Tregs are increased in sarcoidosis, followed by a decline during infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non‐responders, making it a potential marker in predicting which patients might benefit from infliximab.

Infliximab therapy balances regulatory T cells, TNFR2 expression and sTNFR2 in sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown aetiology that most commonly affects the lungs. Although elevated levels of regulatory T cells (Tregs) have been reported, the extent to which they play a role in sarcoidosis pathogenesis remains unclear. Tumour necrosis factor (TNF) is thought to be one of the driving forces behind granuloma formation, illustrated by the efficacy of infliximab in severe sarcoidosis. Tregs express TNF receptor 2 (TNFR2) highly. Here, we examined the influence of infliximab therapy on Tregs and (soluble) TNFR2 levels in sarcoidosis, and correlated these with response to therapy. We observed that relative frequencies of Tregs were significantly higher in patients (n = 54) compared to healthy controls (n = 26; median 6·73 versus 4·36%; P < 0·001) and decreased following therapy (4·95; P < 0·001). Baseline TNFR2 expression on Tregs was increased significantly in patients versus controls (99·4 versus 96·2%; P = 0·031), and also in responders to therapy versus non‐responders (99·6 versus 97·3%; P = 0·012). Furthermore, baseline soluble TNFR2 (sTNFR2) was higher in responders than in non‐responders (mean 174 versus 107 pg/ml; P = 0·015). After treatment, responders showed a significant reduction in sTNFR2 levels in peripheral blood (−44·7 pg/ml; P < 0·001), in contrast to non‐responders (+3·59 pg/ml). Our results demonstrated that Treg frequencies and TNFR2 expression on Tregs are increased in sarcoidosis, followed by a decline during infliximab therapy, suggesting a pathophysiological role of this T cell subset. Interestingly, sTNFR2 levels at baseline differed significantly between responders and non‐responders, making it a potential marker in predicting which patients might benefit from infliximab.

Efficacy and safety of infliximab biosimilar Inflectra® in severe sarcoidosis

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 18F-fluorodeoxyglucose by positron emission tomography (18F-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.

Managing FDG PET-positive sarcoidosis: “a riddle wrapped in a mystery inside an enigma”

We read with interest the correspondence from Mohapatra and colleagues regarding our paper “Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis” [1]. We agree with Mohapatra and colleagues that the term refractory sarcoidosis is still under discussion. We defined refractory sarcoidosis in the methods section as “patients with severe sarcoidosis, unresponsive to first- and second-line treatment, or who have experienced severe side-effects from these agents”. Diagnosis of sarcoidosis was made according to American Thoracic Society/European Respiratory Society criteria [2], including biopsy. These criteria also describe exclusion of other differential diagnoses. Using the described definition for refractory sarcoidosis yields a very heterogeneous group of patients, consisting of sarcoidosis patients that need third line immunosuppressive therapies, e.g. biologicals such as infliximab. Considerations in managing FDG PET-positive sarcoidosis with infliximab therapy http://ow.ly/U0qUr

Can intermediate monocytes predict response to infliximab therapy in sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown origin that can cause a variety of symptoms, but most often affects the lungs [1]. Because sarcoidosis is self-limiting in the majority of patients, not all patients require therapy [2]. In case of severe sarcoidosis, first-line therapy consists of prednisone, with methotrexate or azathioprine being the most commonly used second-line options [3]. Infliximab, a monoclonal anti-tumour necrosis factor (TNF) drug, is an effective third-line therapeutic for severe sarcoidosis [4, 5]. Responders to infliximab therapy have more intermediate monocytes at baseline compared with non-responders http://ow.ly/fMLp300oVrO

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).

Infliximab in patients with refractory sarcoidosis: Trough concentrations of infiximab

Aims and Objectives: Inconclusive evidence for the efficacy of infliximab in sarcoidosis hinders the global use of this potentially beneficial drug. In order to study infliximab efficacy in sarcoidosis, we performed an open-label prospective study in clinical setting. We also measured trough concentrations of infliximab during treatment. Methods: A total number of 56 patients received eight infusions of 5 mg/kg infliximab. Pulmonary function tests, disease activity measured by 18F-fluorodeoxyglucose by positron emission tomography (18F-FDG PET) and quality of life were part of the clinical work-up. Infliximab concentration was measured before every infusion. Results: Mean improvement in forced vital capacity (FVC) was 6.6%predicted. Trough levels of infliximab were higher than reported in other treatment indications: mean trough concentration was 18.0 mcg/ml. Results showed a high inter individual variability and a low intra individual variability. No correlation was found between trough concentration and response parameters was found. Most patients (81%) had trough levels that were continuously >3 mcg/ml. Conclusions: In conclusion, infliximab causes significant improvement in FVC in refractory 18F-FDG PET positive sarcoidosis. Trough concentrations of infliximab are high with low intraindividual variability.