The clinical application of biological products is increasingly extensive, bringing good therapeutic effects for patients with a variety of immune diseases. We searched the Science Citation Index Expanded (SCI-E) database in the Web of Science Core Collection (WOSCC) and selected the highly cited papers based on biological products. The literature was analyzed based on journals, countries/regions, institutions, authors, and keywords, using VOSviewer, SCImago Graphica, and CiteSpace software to generate knowledge maps and identify hotspots and trends. The 193 highly cited papers appeared in 124 journals from 59 different countries/regions. Nature Reviews Rheumatology published most of the articles, while Nature Reviews Drug Discovery had the highest number of citations. The United States had the highest number of publications, and the top institution and author was the University of California San Diego and Fabbrocini, Gabriella. The top 5 co-occurrence keywords included drug delivery, double blind, in vitro, monoclonal antibody, and in vivo. Biological products are important adjunctive therapies for the treatment of immune-mediated inflammatory diseases. Lowering the nanotoxicity of biological products, reducing adverse events due to immunogenicity, therapeutic drug monitoring (TDM) the efficacy of biological products, and producing new substances with intrinsic antimicrobial activity may be the focus and trends for future biological products research.

1. Rader RA. defining biopharmaceutical. Nature Biotechnology. 2008; 26(7): 743-751. doi: 10.1038/nbt0708-743

2. Blumenthal G. US Food and Drug Administration. J Thorac Oncol. 2019; 14(10): S37-S.

3. McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetin‐associated pure red cell aplasia: past, present, and future considerations. Transfusion. 2008; 48(8): 1754-1762. doi: 10.1111/j.1537-2995.2008.01749.x

4. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Annals of the Rheumatic Diseases. 2022; 82(1): 3-18. doi: 10.1136/ard-2022-223356

5. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Annals of the Rheumatic Diseases. 2019; 78(6): 736-745. doi: 10.1136/annrheumdis-2019-215089

6. Perren TJ, Swart AM, Pfisterer J, et al. A Phase 3 Trial of Bevacizumab in Ovarian Cancer. New England Journal of Medicine. 2011; 365(26): 2484-2496. doi: 10.1056/nejmoa1103799

7. Bronckers IMGJ, Paller AS, West DP, et al. A Comparison of Psoriasis Severity in Pediatric Patients Treated with Methotrexate vs Biologic Agents. JAMA Dermatology. 2020; 156(4): 384. doi: 10.1001/jamadermatol.2019.4835

8. Higgins CH. Biological products. Canadian Medical Association Journal. 1912; 2: 114-20.

9. Barzman M, Bàrberi P, Birch ANE, et al. Eight principles of integrated pest management. Agronomy for Sustainable Development. 2015; 35(4): 1199-1215. doi: 10.1007/s13593-015-0327-9

10. Isakoff MS, Bielack SS, Meltzer P, et al. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. Journal of Clinical Oncology. 2015; 33(27): 3029-3035. doi: 10.1200/jco.2014.59.4895

11. Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis. JAMA. 2018; 320(13): 1360. doi: 10.1001/jama.2018.13103

12. Capitanio U, Montorsi F. Renal cancer. Lancet. 2016; 387(10021): 894-906. doi: 10.1016/S0140-6736(15)00046-X

13. Marur S, Forastiere AA. Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment. Mayo Clinic Proceedings. 2016; 91(3): 386-396. doi: 10.1016/j.mayocp.2015.12.017

14. van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nature Reviews Rheumatology. 2013; 9(3): 164-172. doi: 10.1038/nrrheum.2013.4

15. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Annals of the Rheumatic Diseases. 2017; 77(2): 175-187. doi: 10.1136/annrheumdis-2017-211555

16. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. Journal of the American Academy of Dermatology. 2019; 80(4): 1029-1072. doi: 10.1016/j.jaad.2018.11.057

17. Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Annals of the Rheumatic Diseases. 2019; 79(1): 19-30. doi: 10.1136/annrheumdis-2019-215672

18. Jacob JM, Karthik C, Saratale RG, et al. Biological approaches to tackle heavy metal pollution: A survey of literature. Journal of Environmental Management. 2018; 217: 56-70. doi: 10.1016/j.jenvman.2018.03.077

19. Gu Y, Yu L, Mou J, et al. Research Strategies to Develop Environmentally Friendly Marine Antifouling Coatings. Marine Drugs. 2020; 18(7): 371. doi: 10.3390/md18070371

20. Thapa Magar K, Boafo GF, Li X, et al. Liposome-based delivery of biological drugs. Chinese Chemical Letters. 2022; 33(2): 587-596. doi: 10.1016/j.cclet.2021.08.020

21. Hauser AS, Attwood MM, Rask-Andersen M, et al. Trends in GPCR drug discovery: new agents, targets and indications. Nature Reviews Drug Discovery. 2017; 16(12): 829-842. doi: 10.1038/nrd.2017.178

22. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & Rheumatology. 2015; 68(1): 1-26. doi: 10.1002/art.39480

23. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nature Reviews Drug Discovery. 2014; 13(9): 655-672. doi: 10.1038/nrd4363

24. Fraenkel L, Bathon JM, England BR, et al. American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care & Research. 2021; 73(7): 924-939. doi: 10.1002/acr.24596

25. Papamichael K, Cheifetz AS, Melmed GY, et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients with Inflammatory Bowel Diseases. Clinical Gastroenterology and Hepatology. 2019; 17(9): 1655-1668. doi: 10.1016/j.cgh.2019.03.037

26. Solitano V, Facciorusso A, Jess T, et al. Comparative Risk of Serious Infections with Biologic Agents and Oral Small Molecules in Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Clinical Gastroenterology and Hepatology. 2023; 21(4): 907-921.e2. doi: 10.1016/j.cgh.2022.07.032

27. Megna M, Camela E, Battista T, et al. Efficacy and safety of biologics and small molecules for psoriasis in pediatric and geriatric populations. Part II: focus on elderly patients. Expert Opinion on Drug Safety. 2023; 22(1): 43-58. doi: 10.1080/14740338.2023.2173171

28. Megna M, Camela E, Battista T, et al. Efficacy and safety of biologics and small molecules for psoriasis in pediatric and geriatric populations. Part I: focus on pediatric patients. Expert Opinion on Drug Safety. 2023; 22(1): 25-41. doi: 10.1080/14740338.2023.2173170

29. Martora F, Megna M, Battista T, et al. Adalimumab, Ustekinumab, and Secukinumab in the Management of Hidradenitis Suppurativa: A Review of the Real-Life Experience. Clinical, Cosmetic and Investigational Dermatology. 2023; 16: 135-148. doi: 10.2147/ccid.s391356

30. Megna M, Potestio L, Ruggiero A, et al. Risankizumab treatment in psoriasis patients who failed anti‐IL17: A 52‐week real‐life study. Dermatologic Therapy. 2022; 35(7). doi: 10.1111/dth.15524

31. Patra JK, Das G, Fraceto LF, et al. Nano based drug delivery systems: recent developments and future prospects. Journal of Nanobiotechnology. 2018; 16(1). doi: 10.1186/s12951-018-0392-8

32. Scioli Montoto S, Muraca G, Ruiz ME. Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical Aspects. Frontiers in Molecular Biosciences. 2020; 7. doi: 10.3389/fmolb.2020.587997

33. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated with Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology. 2020; 158(1): 189-199. doi: 10.1053/j.gastro.2019.09.041

34. Levy-Clarke G, Jabs DA, Read RW, et al. Expert Panel Recommendations for the Use of Anti–Tumor Necrosis Factor Biologic Agents in Patients with Ocular Inflammatory Disorders. Ophthalmology. 2014; 121(3): 785-796.e3. doi: 10.1016/j.ophtha.2013.09.048

35. Sandborn WJ, Panés J, D’Haens GR, et al. Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials. Clinical Gastroenterology and Hepatology. 2019; 17(8): 1541-1550. doi: 10.1016/j.cgh.2018.11.035

36. St.Clair EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: Results from ATTRACT, a multicenter, randomized, double‐blind, placebo‐controlled trial. Arthritis & Rheumatism. 2002; 46(6): 1451-1459. doi: 10.1002/art.10302

37. Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut. 2014; 64(10): 1539-1545. doi: 10.1136/gutjnl-2014-307883

38. Adedokun OJ, Sandborn WJ, Feagan BG, et al. Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients with Ulcerative Colitis. Gastroenterology. 2014; 147(6): 1296-1307.e5. doi: 10.1053/j.gastro.2014.08.035

39. Ma C, Battat R, Jairath V, et al. Advances in Therapeutic Drug Monitoring for Small-Molecule and Biologic Therapies in Inflammatory Bowel Disease. Current Treatment Options in Gastroenterology. 2019; 17(1): 127-145. doi: 10.1007/s11938-019-00222-9

40. Papamichael K, Vogelzang EH, Lambert J, et al. Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases. Expert Review of Clinical Immunology. 2019; 15(8): 837-848. doi: 10.1080/1744666x.2019.1630273

41. Medina F, Plasencia C, Goupille P, et al. Current Practice for Therapeutic Drug Monitoring of Biopharmaceuticals in Rheumatoid Arthritis. Therapeutic Drug Monitoring. 2017; 39(4): 364-369. doi: 10.1097/ftd.0000000000000421

42. Nagase H, Suzukawa M, Oishi K, et al. Biologics for severe asthma: The real-world evidence, effectiveness of switching, and prediction factors for the efficacy. Allergology International. 2023; 72(1): 11-23. doi: 10.1016/j.alit.2022.11.008

43. Khan N, Mahmud N. Effectiveness of SARS-CoV-2 Vaccination in a Veterans Affairs Cohort of Patients with Inflammatory Bowel Disease with Diverse Exposure to Immunosuppressive Medications. Gastroenterology. 2021; 161(3): 827-836. doi: 10.1053/j.gastro.2021.05.044

44. Gagliardi A, Giuliano E, Venkateswararao E, et al. Biodegradable Polymeric Nanoparticles for Drug Delivery to Solid Tumors. Frontiers in Pharmacology. 2021; 12. doi: 10.3389/fphar.2021.601626

45. Pettinari C, Pettinari R, Di Nicola C, et al. Antimicrobial MOFs. Coordination Chemistry Reviews. 2021; 446: 214121. doi: 10.1016/j.ccr.2021.214121

46. Castellano JM, Ramos-Romero S, Perona JS. Oleanolic Acid: Extraction, Characterization and Biological Activity. Nutrients. 2022; 14(3): 623. doi: 10.3390/nu14030623

47. Azadeh H, Alizadeh-Navaei R, Rezaiemanesh A, et al. Immune-related adverse events (irAEs) in ankylosing spondylitis (AS) patients treated with interleukin (IL)-17 inhibitors: a systematic review and meta-analysis. Inflammopharmacology. 2022; 30(2): 435-451. doi: 10.1007/s10787-022-00933-z

48. Kozma GT, Shimizu T, Ishida T, et al. Anti-PEG antibodies: Properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Advanced Drug Delivery Reviews. 2020; 154-155: 163-175. doi: 10.1016/j.addr.2020.07.024

49. Rathore AS, Nikita S, Thakur G, et al. Artificial intelligence and machine learning applications in biopharmaceutical manufacturing. Trends in Biotechnology. 2023; 41(4): 497-510. doi: 10.1016/j.tibtech.2022.08.007