Therapy of immunoglonuline IgG4 related disease (IgG4-RD)

Czech version

Authors: Zdeněk Adam ¹; Milan Dastych ²; Aleš Čermák ³; Martina Doubková ⁴; Šárka Skorkovská ⁵; Luděk Pour ¹; Zdeněk Řehák ⁶; Renata Koukalová ⁶; Zuzana Adamová ⁷; Martin Štork ¹; Marta Krejčí ¹; Ivanna Boichuk ¹; Zdeněk Král ¹
Authors‘ workplace: Interní hematologická a onkologická klinika LF MU a FN Brno ¹; Interní gastroenterologická klinika LF MU a FN Brno ²; Urologická klinika LF MU a FN Brno ³; Klinika nemocí plicních a tuberkulózy LF MU a FN Brno ⁴; Oční klinika LF MU a FN Brno ⁵; Oddělení nukleární medicíny, Masarykův onkologický ústav Brno ⁶; Oddělení chirurgie nemocnice Frýdek Místek a Chirurgické oddělení Vsetínské nemocnice ⁷
Published in: Vnitř Lék 2022; 68(E-6): 15-22
Category: Review Articles
doi: https://doi.org/10.36290/vnl.2022.086

Overview

Immunoglobulin IgG4 related disease (IgG4-RD) is a heterogeneous disorder with multi-organ involvement recognised as a separate entity at the beginning of this century only. Evolving therapy is reviewed in this paper. Glucocorticoids are first choice drug but long administration of glucocorticoids is connected with many adverse effects. In case of combination glucocorticoids and immunosuppressive agents lower doses of glucocorticoids are needed, the response rate is higher and therapy is better tolerated. Rituximab is drug, that is possible use as monotherapy or in combination with glucocorticoids and immunosuppressive drugs. Only one study compared two immunosuporessive drugs, mycophenolate mofetil and cyclophosphamide. The response rated was similar but remissions were longer after glucocorticoids with cyclophosphamide then glucocorticoids with mycofenolat mofetil. No other comparative study of combination of various imunossupressive drugs with glucocorticoids was published. Rituximab has high number (90 %) of response rate in monotherapy, but can be used in combination with glucocorticoids and immunosuppressives. Rituximab is now preferred and recommended for maintenance therapy administered in 6-month interval. In case of advanced disease, we prefer therefore combination of rituximab, cyclofosphamide and dexamethasone for initial therapy followed by maintenance with rituximab in 6 months interval. There are two new drugs under investigation abatacept and dupilimab with promising results. Although we have very intensive therapies for good results of therapy early diagnosis before irreversible fibrotic changes in IgG4-RD involved organs is still needed.

Keywords:

sirolimus – IgG4-related disease; glucocorticoids; immunosuppressive agents; rituximab – takrolimus – dupilimab – abetacept

Sources

1. Fathala A. Multimodalities Imaging of Immunoglobulin 4-related Cardiovascular Disorders. Curr Cardiol Rev. 2019;15(3):224-229. doi: 10.2174/1573403X15666190117101607.

2. Mitamura K, Arai‑Okuda H, YamamotoY et al. Disease activity and response to therapy monitored by [¹⁸F]FDG PET/CT using volume‑based indices in IgG4-related disease. EJNMMI Res. 2020 Dec 9;10(1):153. doi: 10.1186/s13550-020-00743-w.

3. Vankadari K, Mittal BR, Kumar R et al. Isolated Involvement of Prostate Gland by Immunoglobulin G4-Related Disease Diagnosed With the Help of FDG PET/CT. Clin Nucl Med. 2019 Sep;44(9):e537-e539. doi: 10.1097/RLU.0000000000002689.

4. Martinez‑Pimienta G, Noriega‑Álvarez E, Simó‑Perdigó M. Study of systemic disease IgG4. Usefulness of 2-[18 F]-fluoro-2-deoxy‑D‑glucose -positron emission tomography/computed tomography for staging, selection of biopsy site, evaluation of treatment response and follow‑up. Eur J Rheumatol. 2017;4(3):222-225. doi: 10.5152/eurjrheum.2017.16118.

5. Luo Y, Pan Q, Yang H et al. Fibroblast Activation Protein- Targeted PET/CT with 68Ga‑FAPI for Imaging IgG4-Related Disease: Comparison to 18F‑FDG PET/ CT. J Nucl Med. 2021;62(2):266-271. doi: 10.2967/jnumed.120.244723.

6. Pan Q, Luo Y, Zhang W. Recurrent Immunoglobulin G4-Related Disease Shown on 18 F‑FDG and 68Ga‑FAPI PET/CT. Clin Nucl Med. 2020;45(4):312-313. doi: 10.1097/ RLU.0000000000002919. PMID: 31977476.

7. Khosroshahi A, Wallace ZS, Crowe JL et al. Second International Symposium on IgG- 4-Related Disease. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease.Arthritis Rheumatol. 2015;67(7):1688-99. doi: 10.1002/art.39132.

8. Abraham M, Khosroshahi A. Diagnostic and treatment workup for IgG4-related disease. Expert Rev Clin Immunol. 2017;13(9):867-875. doi:10.1080/1744666X.2017.1354698.)

9. Löhr JM, Beuers U, Vujasinovic M. UEG guideline working group.European Guideline on IgG4-related digestive disease – UEG and SGF evidence‑based recommendations. United European Gastroenterol J. 2020;8(6):637-666. doi: 10.1177/2050640620934911. Epub 2020 Jun 18.

10. Moussiegt A, Müller R, Ebbo M et al for French IgG4-RD Study Group. IgG4-related disease and hypereosinophilic syndrome: Overlapping phenotypes. Autoimmun Rev. 2021 Sep;20(9):102889. doi:10.1016/j.autrev.2021.102889. Epub 2021 Jul 5.

11. Masaki Y, Matsui S, Saeki T et al. A multi‑ center phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease. Mod Rheumatol. 2017;27(5):849–854.

12. Masamune A, Nishimori I, Kikuta K, et al. Randomised controlled trial of long‑term maintenance corticosteroid therapy in patients with autoimmune pancreatitis. Gut. 2017;66(3):487–494.

13. Hart PA, Topazian MD, Witzig TE et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62(11):1607– 1615.

14. Yoshikawa M, Muro Y, Ogawa‑Momohar, M.A. case with overlapping features of IgG4-related autoimmune pancreatitis, Sjögren’s syndrome and anti‑aminoacyl‑tRNA synthetase syndrome. Mod Rheumatol Case Rep. 2021 Jan;5(1):82-86. doi: 10.1080/24725625.2020.1816675.,

15. Wang L, Zhang P, Wang M et al. Failure of remission induction by glucocorticoids alone or in combination with immunosuppressive agents in IgG4-related disease: a prospective study of 215 patients. Arthritis Res Ther2018; 20:65. doi:10.1186/s13075-018-1567- 2 pmid:29636109

16. Omar D, Chen Y, Cong Y, Dong L. Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta‑nalysis[ Oxford]. Rheumatology (Oxford)2019;kez380. doi:10.1093/rheumatology/kez380

17. Bektaş M, Ağargün BF, Torun ES et al. Pure Red Cell Aplasia in IgG4-Related Disease: Successful Treatment With Cyclosporine. J Clin Rheumatol. 2020 Dec 14. doi: 10.1097/ RHU.0000000000001666. Epub ahead of print.

18. Yunyun F, Yu C, Panpan Z et al. Efficacy of cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids. Sci Rep. 2017;7(1):6195-6198.

19. Yunyun F, Yu P, Panpan Z et al. Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial. Rheumatology( Oxford). 2019;58(1):52-60. doi: 10.1093/rheumatology/key227.

20. Drobysheva A, Fuller J, Pfeifer CM, Rakheja D. Orbital Granulomatosis With Polyangiitis Mimicking IgG4-Related Disease in a 12-Year‑Old Male. Int J Surg Pathol. 2018 Aug;26(5):453- 458. doi: 10.1177/1066896917754252.

21. Luo X, Peng Y, Zhang P et al. Comparison of the Effects of yclophosphamide and Mycophenolate Mofetil Treatment Against Immunoglobulin G4-Related Disease: A Retrospective Cohort Study. Front Med (Lausanne). 2020 Jul 7;7:253. doi: 10.3389/fmed.2020.00253.

22. Yamamoto M. B cell targeted therapy for immunoglobulin G4-related disease. Immunol Med. 2021 Feb 14:1-7. doi: 10.1080/25785826.2021.1886630.

23. Khosroshahi A, Bloch DB, Deshpande V et al. JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum 2010;62(6):1755-1762.

24. Khosroshahi A, Carruthers MN, Deshpande V et al. Rituximab for the treatment of IgG- 4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91(1):57- 66.

25. Carruthers MN, Topazian MD, Khosroshahi A et al. Rituximab for IgG4-related disease: a prospective, open‑ label trial. Ann Rheum, DiS. 2015;74(6):1171–1177.

26. Ebbo M, Grados A, Samson M, et al. Long‑term efficacy and safety of rituximab in Ig- G4-related disease: Data from a French nationwide study of thirty‑three patients. PLoS One 2017;12(9):e0183844. Published online 2017 Sep 15. doi: 10.1371/journal.pone.0183844

27. Backhus J, Neumann C, Perkhofer L et al. A Follow‑Up Study of a European IgG4-Related Disease Cohort Treated with Rituximab. J Clin Med. 2021;10(6):1329. doi: 10.3390/ jcm10061329.

28. Gu WJ, Zhang Q, Zhu J et. al. Rituximab was used to treat recurrent IgG4-related hypophysitis with ophthalmopathy as the initial presentation: A case report and literature review. Medicine (Baltimore) 2017;96(24):e6934.

29. Shao SAN, Chia‑der LIN, Sheng‑ta TSAI et al. Immunoglobulin G4-Related Disease Presented as Recurrent Otitis Media and Mixed Hearing Loss Treated With cyclophosphamide and Rituximab: Arch Rheumatol. 2019;34 (2):233–237.

30. Wu A, Andrew NH, Tsirbas A et al. Rituximab for the treatment of IgG4-related orbital disease: experience from five cases. Eye (Lond) 2015;29 (1):122-128.

31. Aouidad I, Schneider P, Zmuda M et al. IgG4-Related Disease With Orbital Pseudotumors Treated With Rituximab Combined With Palpebral Surgery. JAMA Dermatol 2017; 153(3):355-356.

32. Berta AI, Agaimy A, Braun JM, et al. Bilateral Orbital IgG4-Related Disease with Systemic and Corneal Involvement Showing an Excellent Response to Steroid and Rituximab Therapy: Report of a Case with 11 Years Follow‑Up. Orbit 2015;34(5): 299-301.

33. Caso F, Fiocco U, Costa L et al. Successful use of rituximab in a young patient with immunoglobulin G4-related disease and refractory scleritis. Joint Bone Spine. 2014; 81(2):190-192.

34. Chen TS, Figueira E, Lau OC et al. Successful „medical“ orbital decompression with adjunctive rituximab for severe visual loss in IgG4-related orbital inflammatory disease with orbital myositis. Ophthal Plast Reconstr Surg. 2014;30(5):e122-125.

35. Savino G, Battendieri R, Siniscalco A et al. Intraorbital injection of Rituximab in idiopathic orbital inflammatory syndrome: case reports. Rheumatol Int. 2015;35(1): 183-188.,

36. Della‑Torre E, Campochiaro C, Cassione EB et al. Intrathecal rituximab for IgG4-related hypertrophic pachymeningitis. J Neurol Neurosurg Psychiatry2018; 89: 441-444. doi:10.1136/ jnnp-2017-316519 pmid:28819060

37. Mageau A, Shor N, Fisselier M, et al. Rituximab for corticosteroid‑resistant relapsing Ig- G4-related intracranial pachymeningitis: report of two cases. Pract Neurol. 2018;18(2):159- 161. doi: 10.1136/practneurol-2017-001826.

38. Gu WJ, Zhang Q, Zhu J, et. al. Rituximab was used to treat recurrent IgG4-related hypophysitis with ophthalmopathy as the initial presentation: A case report and literature review. Medicine (Baltimore) 2017: 96(24 :e6934.)

39. Bullock DR, Miller BS, Clark HB, Hobday PM. Rituximab treatment for isolated IgG4-related hypophysitis in a teenage female. Endocrinol Diabetes Metab Case Rep. 2018;2018:18- 0135. doi: 10.1530/EDM-18-0135. Epub 2018 Dec 28.

40. Boharoon H, Tomlinson J, Limback‑Stanic C et al. A Case Series of Patients with Isolated IgG4-related Hypophysitis Treated with Rituximab. J Endocr Soc. 2020 Apr 21;4(6):bvaa048. doi: 10.1210/jendso/bvaa048.

41. Mammen SV, Gordon MB. Succesful use of rituximab in case of Riedel thyreoiditis A resistant to treatment with prednisone and tamoxifem. AACE Clin Case Rep. 2019 Apr 25;5(3):e218-e221. doi: 10.4158/ACCR-2018-0352.

42. Jalilian C, Prince HM, McCormack C et al. IgG4-related disease with cutaneous manifestations treated with rituximab: case report and literature review. Australas J Dermatol. 2014;55 (2):132-136.

43. Pomponio G, Olivari D, Mattioli M et al. Sustained clinical response after single course of rituximab as first‑ line monotherapy in adult‑onset asthma and periocular xanthogranulomas syndrome associated with IgG4-related disease: A case report. Medicine (Baltimore). 2018;97(26):e11143. doi: 10.1097/MD.0000000000011143

44. Mochizuki H, Kato M, Higuchi T et al. Overlap of IgG4-related Disease and Multicentric Castleman’s Disease in a Patient with Skin Lesions. Intern Med 2017;56 (9):1095-1099.

45. McMahon BA, Novick T, Scheel PJ et al. Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis: Case Report and Review of the Literature. Medicine (Baltimore) 2015;94 (32) e1366.

46. Quattrocchio G, Barreca A, Demarchi A et al. IgG4-related kidney disease: the effects of a Rituximab‑based immunosuppressive therapy. Oncotarget. 2018;9(30):21337–21347. doi: 10.18632/oncotarget.25095.

47. Eroglu E, Sipahioglu MH, Senel S et al. Successful treatment of tubulointerstitial nephritis in immunoglobulin G4-related disease with rituximab: A case report. World J Clin Cases. 2019;7(16):2309-2315. doi:

48. Lanzillotta M, Della‑Torre E, Wallace ZS et al. Efficacy and safety of rituximab for IgG- 4-related pancreato‑biliary disease: A systematic review and meta‑analysis. Pancreatology. 2021 Oct;21(7):1395-1401. doi:10.1016/j.pan.2021. 06. 009. Epub 2021 Jul 3. PMID: 34244040.

49. Gillispie MC, Thomas RD, Hennon TR. Successful treatment of IgG-4 related sclerosing disease with rituximab: a novel case report. Clin Exp Rheumatol 2015;33 (4):549-550.

50. Nikolic S, Panic N, Hintikka ES et al. Efficacy and safety of rituximab in autoimmune pancreatitis type 1: our experiences and systematic review of the literature. Scand J Gastroenterol. 2021;56(11):1355-1362. doi: 10.1080/00365521.2021.1963837. Epub 2021 Aug 19.

51. Terumi Kamisawa, Takahiro Nakazawa, Susumu Tazuma, et al. Clinical practice guidelines for IgG4-related sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2019 Jan; 26(1): 9–42.

52. Peisen F, Thaiss WM, Ekert K et al. Retroperitoneal Fibrosis and its Differential Diagnoses: The Role of Radiological Imaging. Rofo. 2020;192(10):929-936. doi: 10.1055/a-1181-9205. Epub 2020 Jul 22. PMID:32698236.

53. Kawano M, Saeki T, Nakashima H. IgG4-related kidney disease and retroperitoneal fibrosis: An update. Mod Rheumatol. 2019;29(2):231-239. doi:10.1080/14397595.2018.15543 21. Epub 2019 Jan 8.

54. Forestier A, Buob D, Mirault T et al. No specific imaging pattern can help differentiate IgG4-related disease from idiopathic retroperitoneal fibrosis: 18 histologically proven cases. Clin Exp Rheumatol. 2018;36(3):371-375.

55. Raglianti V, Rossi GM, Vaglio A. Idiopathic retroperitoneal fibrosis: an update for nephrologists. Nephrol Dial Transplant. 2021;36(10):1773-1781.doi: 10.1093/ndt/gfaa083.

56. Wallwork R, Wallace Z, Perugino C et al. Rituximab for idiopathic and IgG4-related retroperitoneal fibrosis. Medicine (Baltimore). 2018;97(42):e12631. doi: 10.1097/ MD.0000000000012631.

57. Boyeva V, Alabsi H, Seidman MA et al. Use of rituximab in idiopathic retroperitoneal fibrosis. BMC Rheumatol. 2020;4:40. doi: 10.1186/s41927-020-00140-9. PMID: 32775962;

58. Almeqdadi M, Al‑Dulaimi M, Perepletchikov A, et al. Rituximab for retroperitoneal fibrosis due to IgG4-related disease: A case report and literature review. Clin Nephrol Case Stud. 2018 Apr 27;6:4-10. doi 10.5414/CNCS109321

59. Hamdan A, Moeen Z, Tariq H et al. An Interesting Case of Immunoglobulin G4-Related Retroperitoneal Fibrosis Treated With Rituximab. Cureus. 2021 Sep 13;13(9):e17940. doi:10.7759/cureus.17940.

60. Rossi GM, Rocco R, Accorsi Buttini E et al. Idiopathic retroperitoneal fibrosis and its overlap with IgG4-related disease. A. Intern Emerg Med. 2017;12:287–299.

61. Kermani TA, Crowson CS, Achenbach SJ. Idiopathic retroperitoneal fibrosis: a retrospective review of clinical presentation, treatment, and outcomes. Mayo Clin Proc. 2011;86:297–303.

62. Marcolongo R, Tavolini IM, Laveder F et al. Immunosuppressive therapy for idiopathic retroperitoneal fibrosis: a retrospective analysis of 26 cases. Am J Med. 2004;116:194–197

63. Scheel PJ, Feeley N, Sozio SM Combined prednisone and mycophenolate mofetil treatment for retroperitoneal fibrosis: a case series. Ann Intern Med. 2011;154:31–36.

64. Marzano A, Trapani A, Leone N et al. Treatment of idiopathic retroperitoneal fibrosis using cyclosporin. Ann Rheum, DiS. 2001;60:427–428.

65. Fenaroli P, Maritati F, Vaglio A. Into Clinical Practice: Diagnosis and Therapy of Retroperitoneal Fibrosis. Curr Rheumatol Rep. 2021 Feb 10;23(3):18. doi: 10.1007/s11926-020- 00966-9. PMID: 33569638.

66. Nikiphorou E, Galloway J, Fragoulis GE. Overview of IgG4-related aortitis and periaortitis. A decade since their first description. Autoimmun Rev. 2020 Dec;19(12):102694. doi: 10.1016/j.autrev.2020.102694.

67. Marvisi C, Accorsi Buttini E, Vaglio A. Aortitis and periaortitis: The puzzling spectrum of inflammatory aortic diseases. Presse Med. 2020 Apr;49(1):104018. doi: 10.1016/j. lpm.2020.104018.

68. Shinoda K, Taki H, Sugiyama T. Recurrence of IgG4-related disease following treatment with rituximab. Mod Rheumatol. 2013; 23 (6): 1226-1230.

69. Wallace ZS, Mattoo H, Mahajan VS et al. Predictors of disease relapse in IgG4-related disease following rituximab. Rheumatology (Oxford) 2016; 55 (6): 1000-1008

70. Campochiaro C, Della‑Torre E, Lanzillotta M et al. Long‑term efficacy of maintenance therapy with Rituximab for IgG4-related disease. Eur J Intern Med 2019; S0953- 6205(19)30467-4. doi:10.1016/j.ejim.2019. 12. 029

71. Majumder S, Mohapatra S, Lennon RJ et al. Rituximab Maintenance Therapy Reduces Rate of Relapse of Pancreaticobiliary Immunoglobulin G4-related Disease. Clin Gastroenterol Hepatol. 2018;16(12):1947-1953. doi: 10.1016/j.cgh.2018. 02. 049.

72. Yamamoto M, Awakawa T, Takahashi H. Is rituximab effective for IgG4-related disease in the long term? Experience of cases treated with rituximab for 4 years. Ann Rheum, DiS. 2015; 74 (8):e46.

73. Della‑Torre E, Lanzillotta M, Campochiaro C et al. Efficacy and safety of rituximab biosimilar (CT‑P10) in IgG4-related disease: an observational prospective open‑ label cohort study. Eur J Intern Med. 2021 Feb;84:63-67. doi: 10.1016/j.ejim.2020. 12. 006.

74. Khan ML, Colby TV, Viggiano RW, Fonseca R. Treatment with bortezomib of a patient having hyper IgG4 disease. Clin Lymphoma Myeloma Leuk. 2010; 10(3):217-219.

75. Jalaj S, Dunbar K, Campbell A et al. Treatment of Pediatric IgG4-Related Orbital Disease With TNF‑ α Inhibitor. Plast Reconstr Surg. 2018 Jan/Feb;34(1):e10-e12.

76. Poo SX, Pepper RJ, Onwordi L et al. Sirolimus use in patients with subglottic stenosis in the context of granulomatosis with polyangiitis (GPA), suspected GPA, and immunoglobulin G₄-related disease. Scand J Rheumatol. 2021;50(1):52-57. doi:10.10 80/03009742.2020.1777324.

77. Takanashi S, Kaneko Y, Takeuchi T. Effectiveness of takrolimus on IgG4-related disease. Mod Rheumatol. 2019;29(5):892-894. doi:10.1080/14397595.2018.1532560.

78. Peng L, Zhang P, Zhang X, et al. Clinical features of immunoglobulin G4-related disease with central nervous system involvement: an analysis of 15 cases. Clin Exp Rheumatol. 2020;38(4):626-632. Epub 2020 Feb 14. P

79. Yamamoto M, Takahashi H, Takano K et al. Efficacy of abatacept for IgG4-relateddisease over 8 months. Ann Rheum, DiS. 2016;75(8):1576-8. doi:10.1136/annrheumdis-2016-209368.

80. Lanzillotta M, Fernàndez‑Codina A, Culver E et al. Emerging therapy options for Ig- G4-related disease.Expert Rev Clin Immunol. 2021 May;17(5):471-483. doi:10.1080/17446 66X.2021.1902310.

81. Della‑Torre E, Lanzillotta M, Yacoub MR. Dupilumab as a potential steroid‑sparing treatment for IgG4-related disease. Ann Rheum, DiS. 2020 Jan14: annrheumdis-2020-216945. doi: 10.1136/annrheumdis-2020-216945. Epub ahead of print.

82. Yamamoto M, Yoshikawa N, Tanaka H. Efficacy of dupilumab reveals therapeutic target for IgG4-related disease: simultaneous control of inflammation and fibrosis. Ann Rheum, DiS. 2020 Feb 7:annrheumdis-2020-217076. doi: 10.1136/annrheumdis-2020-217076. Epub ahead of print.

83. Simpson RS, Lau SKC, Lee JK. Dupilumab as a novel steroid‑sparing treatment for IgG4-related disease. Ann Rheum, DiS. 2020 Apr;79(4):549-550. doi 10.1136/annrheumdis- 2019-216368. Epub 2019 Dec 19. PMID: 31857343.

84. Hoy SM. Dupilumab: A Review in Chronic Rhinosinusitis with Nasal Polyps. Drugs. 2020 May;80(7):711-717. doi: 10.1007/s40265-020-01298-9. PMID: 32240527

85. Chovancová Z. IgG4 podřída imunoglobulinů a s ní související patologické stavy aneb jak účinně imitovat nádorové onemocnění. Klinická onkologie, přijato do tisku.

86. Chovancová Z. Immunosenescence - the sunset over the immune system. Vnitř. Lék.2020;66(6):353-358.

Labels

Diabetology Endocrinology Internal medicine

Evaluation of medication errors in the hospital environment

Clinical experience with the use of newer antibiotics in internal medicine

New onset of diabetes mellitus and weight loss as a manifestation of pancreatic cancer

EFIM Academy

European Summer School of Internal Medicine (12.–18. 6. 2022, El Escorial, Madrid, Španělsko)

Article was published in

Internal Medicine

2022 Issue E-6