Advertisement

Role of anti-tumor necrosis factor-alpha agents in treatment of sarcoidosis: A meta-analysis

Published:December 14, 2022DOI:https://doi.org/10.1016/j.ejim.2022.12.003

      Highlights

      • Anti-TNF-α therapy is effective in both pulmonary and extrapulmonary sarcoidosis.
      • Anti-TNF-α therapy has higher efficacy in extrapulmonary compared to pulmonary sarcoidosis (75% vs. 70%).
      • Treatment with Infliximab and Adalimumab show the highest efficacy in sarcoidosis.

      Abstract

      Importance

      Anti-tumor necrosis factor-alpha agent (anti-TNF-α) is considered an effective third-line therapy for refractory sarcoidosis,studies observing the efficacy of anti-TNF-α agents show conflicting results.

      Objective

      We performed an up-to-date systemic meta-analysis to determine effectiveness and further elucidate the role of anti-TNF-α in the treatment of sarcoidosis.

      Data sources

      A systematic search was carried out in PubMed/Medline, EMBASE, and Cochrane Library for studies reporting the therapeutic effects of anti-TNF drugs on patients with pulmonary and extra-pulmonary sarcoidosis, published up to April 10, 2022. The study was registered in the international prospective register of systematic reviews (PROSPERO) under ID: CRD42022364614.

      Study selection

      Clinical trials written reporting the therapeutic effects of anti-TNF drugs on patients with pulmonary and extra-pulmonary sarcoidosis were included.

      Data extraction and synthesis

      Statistical analyses were performed with Comprehensive Meta-Analysis software, and the random-effects model was used. The combined overall treatment success was determined for patients with pulmonary and extrapulmonary sarcoidosis.

      Main outcomes and measures

      Overall treatment success rate wasdefined as no disease progression or improvement in symptoms.

      Results

      Eight clinical trial articles were included in the meta-analysis; four used Infliximab, two Etanercept, one Adalimumab, and one Ustekinumab and Golimumab. The mean age of participants was 48.5 years. The duration of drug therapy ranged from 14 to 45 weeks. We found a combined overall treatment success rate, defined as no disease progression or improvement in symptoms, of 69.9% (95% CI 35.0-90.9, I2: 70%) in the pulmonary sarcoidosis group and 74.5% (95% CI 36.3-93.7, I2: 90%) in the extrapulmonary sarcoidosis group. There was no evidence of publication bias in either group.

      Conclusion and relevance

      Treatment of refractory sarcoidosis with anti-TNF-α agents was effective in both pulmonary and extrapulmonary sarcoidosis, with a slightly higher efficacy seen in extrapulmonary sarcoidosis. Further randomized controlled trials should be conducted to determine the effects of anti-TNF-α agents as a part of the management strategy of sarcoidosis. Patients with pulmonary sarcoidosis should be studied separately from patients with extrapulmonary sarcoidosis to adjust for confounding results.

      Abbreviations:

      TNF-α (Tumor necrosis factor-alpha)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Gerke AK
        • Hunninghake G.
        The immunology of sarcoidosis.
        Clin Chest Med. 2008; 29: 379-390
        • Patterson KC
        • Hogarth K
        • Husain AN
        • Sperling AI
        • Niewold TB.
        The clinical and immunologic features of pulmonary fibrosis in sarcoidosis.
        Transl Res. 2012; 160: 321-331
        • Broos CE
        • van Nimwegen M
        • Hoogsteden HC
        • Hendriks RW
        • Kool M
        • van den Blink B
        Granuloma formation in pulmonary sarcoidosis.
        Front Immunol. 2013; 4: 437
        • Fehrenbach H
        • Zissel G
        • Goldmann T
        • Tschernig T
        • Vollmer E
        • Pabst R
        • et al.
        Alveolar macrophages are the main source for tumour necrosis factor-alpha in patients with sarcoidosis.
        Eur Respir J. 2003; 21: 421-428
        • Statement on sarcoidosis
        Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.
        Am J Respir Crit Care Med. 1999; 160: 736-755
        • Jain R
        • Yadav D
        • Puranik N
        • Guleria R
        • Jin J-O
        Sarcoidosis: causes, diagnosis, clinical features, and treatments.
        J Clin Med. 2020; 9: 1081
        • Judson MA.
        The diagnosis of sarcoidosis.
        Clin Chest Med. 2008; 29: 415-427
        • Valeyre D
        • Prasse A
        • Nunes H
        • Uzunhan Y
        • Brillet PY
        • Sarcoidosis Müller-Quernheim J.
        Lancet. 2014; 383: 1155-1167
        • Baughman RP
        • Nunes H
        • Sweiss NJ
        Lower EE. Established and experimental medical therapy of pulmonary sarcoidosis.
        Eur Respir J. 2013; 41: 1424-1438
        • Baughman RP
        • Costabel U
        • du Bois RM.
        Treatment of sarcoidosis.
        Clin Chest Med. 2008; 29 (ix-x): 533-548
        • Valeyre D
        • Jeny F
        • Nunes H
        Current medical therapy for sarcoidosis.
        Semin Respir Crit Care Med. 2017; 38: 523-531
        • Baughman RP
        • Lower EE.
        Infliximab for refractory sarcoidosis.
        Sarcoidosis Vasc Diffuse Lung Dis. 2001; 18: 70-74
        • Yee AM
        • Pochapin MB.
        Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy.
        Ann Intern Med. 2001; 135: 27-31
        • Baughman RP
        • Lower EE
        • Drent M.
        Inhibitors of tumor necrosis factor (TNF) in sarcoidosis: who, what, and how to use them.
        Sarcoidosis Vasc Diffuse Lung Dis. 2008; 25: 76-89
        • Brito-Zerón P
        • Pérez-Alvarez R
        • Pallarés L
        • Retamozo S
        • Baughman RP
        • Ramos-Casals M.
        Sarcoidosis: an update on current pharmacotherapy options and future directions.
        Expert Opin Pharmacother. 2016; 17: 2431-2448
        • Page MJ
        • McKenzie JE
        • Bossuyt PM
        • Boutron I
        • Hoffmann TC
        • Mulrow CD
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        Int J Surg. 2021; 88105906
        • Higgins JP
        • Altman DG
        • Gøtzsche PC
        • Jüni P
        • Moher D
        • Oxman AD
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; : 343
        • Higgins JP
        • Thompson SG.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Begg CB
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; : 1088-1101
        • Baughman RP
        • Lower EE
        • Bradley DA
        • Raymond LA
        • Kaufman A.
        Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial.
        Chest. 2005; 128: 1062-1067
        • Judson MA
        • Baughman RP
        • Costabel U
        • Drent M
        • Gibson KF
        • Raghu G
        • et al.
        Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.
        Eur Respir J. 2014; 44: 1296-1307
        • Judson MA
        • Baughman RP
        • Costabel U
        • Flavin S
        • Lo KH
        • Kavuru MS
        • et al.
        Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial.
        Eur Respir J. 2008; 31: 1189-1196
        • Kullberg S
        • Rivera N
        • Abo Al Hayja M
        • Grunewald J
        • Eklund A
        Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.
        Clin Exp Immunol. 2020; 201: 85-93
        • Pariser RJ
        • Paul J
        • Hirano S
        • Torosky C
        • Smith M.
        A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis.
        J Am Acad Dermatol. 2013; 68: 765-773
        • Saleh S
        • Ghodsian S
        • Yakimova V
        • Henderson J
        • Sharma OP
        Effectiveness of infliximab in treating selected patients with sarcoidosis.
        Respir Med. 2006; 100: 2053-2059
        • Sweiss NJ
        • Noth I
        • Mirsaeidi M
        • Zhang W
        • Naureckas ET
        • Hogarth DK
        • et al.
        Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis.
        Sarcoidosis Vasc Diffuse Lung Dis. 2014; 31: 46
        • Utz JP
        • Limper AH
        • Kalra S
        • Specks U
        • Scott JP
        • Vuk-Pavlovic Z
        • et al.
        Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis.
        Chest. 2003; 124: 177-185
        • Baughman RP
        • Valeyre D
        • Korsten P
        • Mathioudakis AG
        • Wuyts WA
        • Wells A
        • et al.
        ERS clinical practice guidelines on treatment of sarcoidosis.
        Eur Respir J. 2021; 58
        • Baughman RP
        • Drent M
        • Kavuru M
        • Judson MA
        • Costabel U
        • du Bois R
        • et al.
        Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
        Am J Respir Crit Care Med. 2006; 174: 795-802
        • Rossman MD
        • Newman LS
        • Baughman RP
        • Teirstein A
        • Weinberger SE
        • Miller Jr., W
        • et al.
        A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis.
        Sarcoidosis Vasc Diffuse Lung Dis. 2006; 23: 201-208
        • Vorselaars AD
        • Crommelin HA
        • Deneer VH
        • Meek B
        • Claessen AM
        • Keijsers RG
        • et al.
        Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis.
        Eur Respir J. 2015; 46: 175-185
        • Adler BL
        • Wang CJ
        • Bui T-L
        • Schilperoort HM
        • Armstrong AW.
        Anti-tumor necrosis factor agents in sarcoidosis: a systematic review of efficacy and safety.
        in: Seminars in arthritis and rheumatism. Elsevier, 2019: 1093-1104
        • Sakkat A
        • Cox G
        • Khalidi N
        • Larche M
        • Beattie K
        • Renzoni EA
        • et al.
        Infliximab therapy in refractory sarcoidosis: a multicenter real-world analysis.
        Respir Res. 2022; 23: 1-9
        • Sinokrot O
        • Pan S
        • Reyentovich A
        • Addrizzo-Harris D.
        Efficacy of infliximab therapy in cardiac sarcoidosis: a single center case series. B39 GRANULOMATOUS ILDs.
        American Thoracic Society, 2019 (A3064-A)
        • Tracey D
        • Klareskog L
        • Sasso EH
        • Salfeld JG
        • Tak PP.
        Tumor necrosis factor antagonist mechanisms of action: a comprehensive review.
        Pharmacol Ther. 2008; 117: 244-279
        • Varfolomeev EE
        • Ashkenazi A.
        Tumor necrosis factor: an apoptosis JuNKie?.
        Cell. 2004; 116: 491-497
        • Bazzoni F
        • Beutler B.
        The tumor necrosis factor ligand and receptor families.
        N Engl J Med. 1996; 334: 1717-1725
        • Kast RE
        • Altschuler EL.
        Anti-apoptosis function of TNF-alpha in chronic lymphocytic leukemia: lessons from Crohn's disease and the therapeutic potential of bupropion to lower TNF-alpha.
        Arch Immunol Ther Exp (Warsz). 2005; 53: 143-147
        • Kaneko H
        • Yamada H
        • Mizuno S
        • Udagawa T
        • Kazumi Y
        • Sekikawa K
        • et al.
        Role of tumor necrosis factor-alpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice.
        Lab Invest. 1999; 79: 379-386
        • Kasahara K
        • Kobayashi K
        • Shikama Y
        • Yoneya I
        • Kaga S
        • Hashimoto M
        • et al.
        The role monokines in granuloma formation in mice: The ability of interleukin 1 and tumor necrosis factor-α to induce lung granulomas.
        Clin Immunol Immunopathol. 1989; 51: 419-425
        • Starshinova AA
        • Malkova AM
        • Basantsova NY
        • Zinchenko YS
        • Kudryavtsev IV
        • Ershov GA
        • et al.
        Sarcoidosis as an autoimmune disease.
        Front Immunol. 2020; 10: 2933
        • Ziegenhagen MW
        • Schrum S
        • Zissel G
        • Zipfel PF
        • Schlaak M
        • Müller-Quernheim J.
        Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis.
        J Investig Med. 1998; 46: 223-231
        • Baughman RP
        • Strohofer S
        • Buchsbaum J
        • Lower E.
        Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis.
        J Lab Clin Med. 1990; 115: 36-42
        • Dai H
        • Guzman J
        • Chen B
        Costabel U. Production of soluble tumor necrosis factor receptors and tumor necrosis factor-α by alveolar macrophages in sarcoidosis and extrinsic allergic alveolitis.
        Chest. 2005; 127: 251-256
        • Ziegenhagen MW
        • Rothe ME
        • Zissel G
        • Müller-Quernheim J.
        Exaggerated TNFalpha release of alveolar macrophages in corticosteroid resistant sarcoidosis.
        Sarcoidosis Vasc Diffuse Lung Dis. 2002; 19: 185-190
        • Crommelin HA
        • Vorselaars AD
        • Van Moorsel CH
        • Korenromp IH
        • Deneer VH
        • Grutters JC.
        Anti-TNF therapeutics for the treatment of sarcoidosis.
        Immunotherapy. 2014; 6: 1127-1143
        • Kullberg S
        • Rivera NV
        • Abo Al Hayja M
        • Grunewald J
        • Eklund A
        Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.
        Clin Exp Immunol. 2020; 201: 85-93
        • Song GG
        • Kim J-H
        • Lee YH.
        Associations between TNF-α− 308 a/G and lymphotoxin-α+ 252 a/G polymorphisms and susceptibility to sarcoidosis: a meta-analysis.
        Mol Biol Rep. 2014; 41: 259-267
        • Wijnen P
        • Nelemans P
        • Verschakelen J
        • Bekers O
        • Voorter C
        • Drent M.
        The role of tumor necrosis factor alpha G-308A polymorphisms in the course of pulmonary sarcoidosis.
        Tissue Antigens. 2010; 75: 262-268
        • Wijnen PA
        • Cremers JP
        • Nelemans PJ
        • Erckens RJ
        • Hoitsma E
        • Jansen TL
        • et al.
        Association of the TNF-α G-308A polymorphism with TNF-inhibitor response in sarcoidosis.
        Eur Respir J. 2014; 43: 1730-1739