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Background: Methotrexate (MTX) is a second line agent for treatment of sarcoidosis. Its long term safety and efficacy in sarcoidosis remains unclear., Methods: This was a retrospective review of patients seen at the University of Cincinnati Sarcoidosis Clinic over a six year period. For each visit, complete blood count, liver function testing, and dosing and outcome of MTX was noted. For efficacy, we compared the outcome of therapy of a matching subgroup of patients treated with either MTX or infliximab for one year and results scored as improved, stable, or worse based on response of the target organ., Results: Over six years, 1606 sarcoidosis patients were seen with a total of 13,576 clinical visits. During the study period, 607 patients (38% of total) were receiving MTX and had available blood work. Moderate elevation of alanine aminotransferase (ALT) (>3 times upper limit normal) was seen in nine (1.6%) patients. White blood count of <1500 cells per cu mm was seen in one patient. At six months, over half of the 44 patients initiated on infliximab and with at least six months of follow-up were better, while only 23% of the 44 of a matched subset of MTX treated patients were better (Chi square=10.566, p=0.0143). At the 12 month assessment, the infliximab treated patients were still more likely to be better than those treated with MTX (Chi square=10.033, p=0.0183). Only 23% of those treated with MTX were worse at twelve months., Conclusion: In our study, MTX therapy was associated with very few hepatic or hematologic complications. MTX was less likely than infliximab to improve clinical status. However, only 20% were worse after one year of MTX. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (3): e2020001) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

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.

Background: In severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment, the third-line tumor necrosis factor-alpha (TNF-α) inhibitors infliximab and adalimumab might be an alternative. However, appropriate studies to guide the clinician are lacking. The aim of this study was to establish practical recommendations for the use of TNF-α inhibitors in the management of refractory sarcoidosis patients., Methods: Based on a literature search and the opinion of sarcoidosis experts worldwide, the recommendations were established. Studies conducted in sarcoidosis were supplemented with data obtained from relevant studies in other inflammatory diseases. A Delphi method of polling, using an online survey addressing 12 clinical questions, was performed amongst 20 of the world's leading sarcoidologists to investigate consensus in case of inadequate data to determine an objective answer., Results: Of the 256 papers found, 101 were included. Randomized controlled trial studies about the use of TNF-α inhibitors in sarcoidosis are limited. Ninety-five percent (19 of 20) of the sarcoidologists contacted, completed the questionnaire (Europe 68%, North America 32%). Nine recommendations were formulated concerning general aspects of TNF-α inhibitor use; Specific sarcoidosis related items, including indications, starting and maintenance dosage, interval of treatment, treatment duration, and discontinuation regimen of infliximab and adalimumab, were addressed., Conclusion: Based on earlier studies and consensus amongst world's leading sarcoidologists, practical recommendations for the use of TNF-α inhibitors in sarcoidosis were established. These recommendations, with emphasis on indications, dosage and discontinuation regimens, have been developed to support the clinician in the management of refractory sarcoidosis patients.

Responsiveness to tumour necrosis factor (TNF) inhibitors has been associated with the TNF-α G-308A polymorphism in rheumatoid arthritis. The aim of this study was to examine the association between the presence of this polymorphism and the response to TNF inhibitors in patients with refractory sarcoidosis. Patients (n=111) who started TNF-inhibitor treatment (76 infliximab, 35 adalimumab) were followed for at least 1 year. The main symptoms in these patients were fatigue (n=100, 90.1%), small fibre neuropathy (n=91, 82.0%), pulmonary involvement (n=69, 62.2%), and/or uveitis (n=31, 27.9%). Patients were additionally genotyped for the presence of the TNF-α G-308A polymorphism. Treatment response was assessed using clinical outcome measures and questionnaires. Three-quarters (n=83, 74.8%) of the patients responded well. Of the patients without the variant A-allele 93.6% (73 out of 78, p<0.001) improved, while 30.3% (10 out of 33) of variant A-allele carriers responded favourably to TNF inhibitors. For patients with the GG-genotype, the probability of improving compared with remaining stable or deteriorating was three times higher (risk ratio 3.09, 95% CI 1.84-5.20). Sarcoidosis patients without the TNF-α -308A variant allele (GG-genotype) had a three-fold higher response to TNF inhibitors (adalimumab or infliximab). Further research is needed to evaluate the value of genotyping for the TNF-α G-308A polymorphism in order to tailor TNF-inhibitor treatment., (©ERS 2014.)

Purpose of Review: Sarcoidosis is a systemic disease characterized by the formation of granulomas in various organs, mainly lungs and lymphatic system. Joint, muscle, and bone involvement is also rather common. Recent studies on its pathogenesis and therapeutic management are reviewed here., Recent Findings: The pathogenesis of sarcoidosis is not fully elucidated. An exaggerated granulomatous reaction after exposure to unidentified antigens in genetically susceptible individuals evokes a clinical situation which we call sarcoidosis. No firm guidelines exist on whether, when, and how treatment should be started. Treatment is dependent on the presentation and the distribution, extensiveness and severity of sarcoidosis. Treatment of Löfgren's triad-related symptoms starts with NSAIDs; in other more extensive manifestations of sarcoidosis, the initiating dosage of glucocorticosteroids is approximately 20 mg daily. In terms of evidence-based treatment for sarcoidosis, only a few randomized controlled trials have been done. There is no cure for chronic sarcoidosis, and treatment only changes the granulomatous process and its clinical consequences., Summary: Identified associations of certain polymorphisms with severity of the disease and treatment response suggest future research questions as well as finding the cause(s) of sarcoidosis, and the elucidation of relevant biomarkers and new efficient treatments. Between 20 and 70% of patients need systemic therapy. The increased awareness of long-term side-effects of glucocorticosteroids and the emergence of new drugs have changed the treatment of sarcoidosis. Alternative or additional options to corticosteroids should be assessed.

Background: Sarcoidosis is characterized by a wide range of disease manifestations. In the management and follow-up of sarcoidosis patients, knowledge of extent of disease, activity and severity is crucial. Objectives The aim of this study was to assess the extent, distribution and consistency of inflammatory organ involvement using 18F-FDG PET/CT (PET) in sarcoidosis patients with persistent disabling symptoms., Methods: Retrospectively, sarcoidosis patients who underwent a PET between 2005 and 2011 (n=158) were included. Clinical data were gathered from medical records and PET scans were evaluated. Positive findings were classified as thoracic and/or extrathoracic. RESULTS :Of the studied PET positive sarcoidosis patients (n=118/158; 75%), 93% had intrathoracic activity (79% mediastinal and 64% pulmonary activity, respectively) and 75% displayed extrathoracic activity (mainly peripheral lymph nodes, bone/bone marrow, and spleen). Hepatic positivity was always accompanied by splenic activity, whereas the majority of patients with parotid gland, splenic or bone/bone marrow activity showed lymph node activity. A substantial number of patients with PET positive pulmonary findings (86%) had signs of respiratory functional impairment. No obvious association between hepatic, splenic or bone/bone marrow activity and their corresponding laboratory abnormalities suggestive of specific organ involvement, was found., Conclusions: The majority of studied patients appeared to have PET positive findings (75%), of which a high proportion (75%) displayed extrathoracic activity. Hence, PET can be especially useful in the assessment of extent, distribution and consistency of inflammatory activity in sarcoidosis to provide an explanation for persistent disabling symptoms and/or to provide a suitable location for biopsy.

Unlabelled: Muscle atrophy is a common problem in many chronic inflammatory diseases. It may occur as part of a generalized wasting process (cachexia) or be hidden due to preservation of fatmass (sarcopenia, sarcopenic obesity)., Objectives: The aim of this study was to assess the prevalence of cachexia and muscle atrophy in sarcoidosis and their association with disease activity and severity., Methods: A cross-sectional study was performed in 423 sarcoidosis patients. Fat-free mass was assessed as an indirect measure of muscle mass by bioelectrical impedance analysis. Patients were stratified based on body mass index (BMI) and fat-free mass index (FFMI).Muscle atrophy was defined as FFMI <15 kg/m2 for women and <17 kg/m2 for men corresponding to <10th percentile of current reference values; cachexia as BMI <20 combined with muscle atrophy.Multivariate linear regression models were used to adjust for potential confounders., Results: Of the patients examined, 58% were categorized as overweight (37%) or obese (21%), whereas 7% were underweight.Muscle atrophy was present in 25% and cachexia in 5%. Patients with muscle atrophy showed significantly worse lung function (DLCO, FEV1, FVC, all p-values <0.01) and impaired exercise capacity (VO2max, p<0.001). The associations were most pronounced in patients with cachexia. Associations remained significant after adjustment for potential confounders., Conclusions: Muscle atrophy was present in 25% of sarcoidosis patients and was associated with more severe pulmonary disease. Prospective studies with longitudinal design are needed to assess the association between muscle atrophy and disease severity in sarcoidosis.

Purpose of Review: Although glucocorticosteroids are considered the first-line treatment in sarcoidosis, refractory cases require alternatives, such as methotrexate (MTX). The aim of this study was to develop, on behalf of the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG), multinational evidence-based recommendations for the use of MTX in sarcoidosis for routine clinical practice., Recent Findings: A systematic literature search was conducted and combined with the opinions of sarcoidosis experts worldwide to formulate the recommendations. An online survey concerning 10 clinical questions was sent through the WASOG newsletter to sarcoidosis experts. Agreement about the recommendations amongst the world's leading sarcoidologists was evaluated. A total of 237 articles were identified, 43 of which were included. Randomized controlled trial evidence supporting the use of MTX in sarcoidosis was limited. Forty-five per cent (113 of 250) of the sarcoidosis experts contacted completed the survey (Europe 55%, North America 26% and Asia 12%). Ten recommendations were formulated concerning the indications for use, starting dose, folic acid, work-up, contraindications, monitoring, administration options in case of adverse gastrointestinal effects, hepatotoxicity, long-term safety and use during pregnancy and breast feeding., Summary: Ten multinational evidence-based recommendations for the use of MTX in sarcoidosis were developed, which are supported by the world's foremost sarcoidosis experts.

Purpose of Review: Surveillance of hepatic involvement in sarcoidosis has not been standardized. Therefore, management of hepatic involvement is a clinical challenge. This review analyses published data on the pharmacological treatment of hepatic sarcoidosis., Recent Findings: Only 5-30% of patients with hepatic sarcoidosis display symptoms. Occasionally, it has a rapid progressive course with serious complications, stressing an appropriate and carefully timed therapeutic approach. Because symptomatic hepatic sarcoidosis is uncommon, therapeutic studies are scarce. Answers to the questions when to initiate which treatment are lacking. Case reports describe beneficial effects of prednisone and the augmentation of cytotoxic and anti-tumor necrotic factor-α (TNF-α) therapy. However, because of small sample sizes, no meaningful conclusions could be drawn. In symptomatic hepatic sarcoidosis patients, it is recommended to start to treat the sarcoidosis with prednisone, preceded by ursodeoxycholic acid when signs of cholestasis are present. In refractory cases or when prednisone weaning is impossible, cytotoxic drugs or anti-TNF-α therapy should be considered., Summary: This review illustrates the importance of an appropriate therapeutic approach of sarcoidosis patients with hepatic involvement. It emphasizes the need for future studies to evaluate treatment options to avoid disease progression and hepatic complications.