nach oben

Erschienen in:

01.06.2018 | Pediatric Rheumatology (S Ozen, Section Editor)

Therapeutic Approaches to Type I Interferonopathies

verfasst von: Marc Bienias, Normi Brück, Constanze Griep, Christine Wolf, Stefanie Kretschmer, Barbara Kind, Victoria Tüngler, Reinhard Berner, Min Ae Lee-Kirsch

Erschienen in: Current Rheumatology Reports | Ausgabe 6/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

To review recent scientific advances and therapeutic approaches in the expanding field of type I interferonopathies.

Summary

Type I interferonopathies represent a genetically and phenotypically heterogenous group of disorders of the innate immune system caused by constitutive activation of antiviral type I interferon (IFN). Clinically, type I interferonopathies are characterized by autoinflammation and varying degrees of autoimmunity or immunodeficiency. The elucidation of the underlying genetic causes has revealed novel cell-intrinsic mechanisms that protect the organism against inappropriate immune recognition of self nucleic acids by cytosolic nucleic acid sensors. The type I IFN system is subject to a tight and complex regulation. Disturbances of its checks and balances can spark an unwanted immune response causing uncontrolled type I IFN signaling. Novel mechanistic insight into pathways that control the type I IFN system is providing opportunities for targeted therapeutic approaches by repurposing drugs such as Janus kinase inhibitors or reverse transcriptase inhibitors.

Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18:832–42.CrossRefPubMed

• Schlee M, Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol. 2016;16:566–80. Excellent and comprehensive review on nucleic acid-sensing mechanisms. CrossRefPubMed

Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14:36–49.CrossRefPubMedPubMedCentral

Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91–8.CrossRefPubMed

Lee-Kirsch MA. The type I interferonopathies. Annu Rev Med. 2017;68:297–315.CrossRefPubMed

Rodero MP, Tesser A, Bartok E, Rice GI, Della Mina E, Depp M, et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat Commun. 2017;8:2176.CrossRefPubMedPubMedCentral

Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15:49–54.CrossRefPubMed

Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GMA, Gornall HL, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A:296–312.CrossRefPubMed

Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum. 2010;62:1469–77.CrossRefPubMed

10.

Ramantani G, Hausler M, Niggemann P, Wessling B, Guttmann H, Mull M, et al. Aicardi-Goutieres syndrome and systemic lupus erythematosus (SLE) in a 12-year-old boy with SAMHD1 mutations. J Child Neurol. 2011;26:1425–8.CrossRefPubMed

11.

Cuadrado E, Vanderver A, Brown KJ, Sandza A, Takanohashi A, Jansen MH, et al. Aicardi–Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies. Ann Rheum Dis. 2014;74:1931–9. https://doi.org/10.1136/annrheumdis-2014-205396.CrossRefPubMed

12.

Rice GI, Forte GM, Szynkiewicz M, Chase DS, Aeby A, Abdel-Hamid MS, et al. Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. 2013;12:1159–69.CrossRefPubMedPubMedCentral

13.

Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet. 2006;38:917–20.CrossRefPubMed

14.

Crow YJ, Leitch A, Hayward BE, Garner A, Parmar R, Griffith E, et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat Genet. 2006;38:910–6.CrossRefPubMed

15.

Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41:829–32.CrossRefPubMedPubMedCentral

16.

Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, et al. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet. 2012;44:1243–8.CrossRefPubMedPubMedCentral

17.

Rice GI, Del Toro DY, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46:503–9.CrossRefPubMedPubMedCentral

18.

Yang YG, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007;131:873–86.CrossRefPubMed

19.

•• Wolf C, Rapp A, Berndt N, Staroske W, Schuster M, Dobrick-Mattheuer M, et al. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat Commun. 2016;7:11752. This study demonstrates that TREX1 is a cytosolic tail-anchored DNase lining the outer nuclear membrane to degrade self DNA leaking from the nucleus into the cytosol. CrossRefPubMedPubMedCentral

20.

•• Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134:587–98. This paper demonstrates that self DNA derived from reverse-transcribed retroelements accumulates in TREX1-deficient mice. CrossRefPubMedPubMedCentral

21.

Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol. 2014;192:5993–7.CrossRefPubMed

22.

Gray EE, Treuting PM, Woodward JJ, Stetson DB. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutieres syndrome. J Immunol. 2015;195:1939–43.CrossRefPubMedPubMedCentral

23.

Reijns MA, Rabe B, Rigby RE, Mill P, Astell KR, Lettice LA, et al. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell. 2012;149:1008–22.CrossRefPubMedPubMedCentral

24.

Hiller B, Achleitner M, Glage S, Naumann R, Behrendt R, Roers A. Mammalian RNase H2 removes ribonucleotides from DNA to maintain genome integrity. J Exp Med. 2012;209:1419–26.CrossRefPubMedPubMedCentral

25.

Sparks JL, Chon H, Cerritelli SM, Kunkel TA, Johansson E, Crouch RJ, et al. RNase H2-initiated ribonucleotide excision repair. Mol Cell. 2012;47:980–6.CrossRefPubMedPubMedCentral

26.

Kind B, Muster B, Staroske W, Herce HD, Sachse R, Rapp A, et al. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome. Hum Mol Genet. 2014;23:5950–60.CrossRefPubMed

27.

Gunther C, Kind B, Reijns MA, Berndt N, Martinez-Bueno M, Wolf C, et al. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest. 2015;125:413–24.CrossRefPubMed

28.

Mackenzie KJ, Carroll P, Lettice L, Tarnauskaitė Ž, Reddy K, Dix F, et al. Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J. 2016;35:831–44.CrossRefPubMedPubMedCentral

29.

Pokatayev V, Hasin N, Chon H, Cerritelli SM, Sakhuja K, Ward JM, et al. RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J Exp Med. 2016;213:329–36.CrossRefPubMedPubMedCentral

30.

Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature. 2011;480:379–82.CrossRefPubMed

31.

Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol. 2012;13:223–8.CrossRefPubMedPubMedCentral

32.

Tungler V, Staroske W, Kind B, Dobrick M, Kretschmer S, Schmidt F, et al. Single-stranded nucleic acids promote SAMHD1 complex formation. J Mol Med (Berl). 2013;91:759–70.CrossRef

33.

Beloglazova N, Flick R, Tchigvintsev A, Brown G, Popovic A, Nocek B, et al. Nuclease activity of the human SAMHD1 protein implicated in the Aicardi-Goutieres syndrome and HIV-1 restriction. J Biol Chem. 2013;288:8101–10.CrossRefPubMedPubMedCentral

34.

Ryoo J, Choi J, Oh C, Kim S, Seo M, Kim SY, et al. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 2014;20:936–41.CrossRefPubMedPubMedCentral

35.

Kretschmer S, Wolf C, Konig N, Staroske W, Guck J, Hausler M, et al. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 2014;

36.

Clifford R, Louis T, Robbe P, Ackroyd S, Burns A, Timbs AT, et al. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood. 2014;123:1021–31.CrossRefPubMedPubMedCentral

37.

Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. 2015;349:1115–20.CrossRefPubMedPubMedCentral

38.

Lee-Kirsch MA, Gong M, Schulz H, Ruschendorf F, Stein A, Pfeiffer C, et al. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet. 2006;79:731–7.CrossRefPubMedPubMedCentral

39.

Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80:811–5.CrossRefPubMedPubMedCentral

40.

Lee-Kirsch MA, Chowdhury D, Harvey S, Gong M, Senenko L, Engel K, et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med. 2007;85:531–7.CrossRefPubMed

41.

Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, Crow YJ. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus. Am J Med Genet A. 2011;155A:235–7.CrossRefPubMed

42.

•• König N, Fiehn C, Wolf C, Schuster M, Cura Costa E, Tüngler V, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2016; First description, together with reference [52••], of clinical efficacy of JAK inhibition in type I IFN-mediated autoinflammation.

43.

•• Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18. First description of TMEM173 mutations in patients with severe autoinflammation, acral vasculitis, and pulmonary disease. This study also demonstrates suppression of type I IFN activation in patient cells in vitro. CrossRefPubMedPubMedCentral

44.

Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124:5516–20.CrossRefPubMedPubMedCentral

45.

Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, et al. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet. 2010;87:866–72.CrossRefPubMedPubMedCentral

46.

Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012;64:895–907.CrossRefPubMedPubMedCentral

47.

Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125:4196–211.CrossRefPubMedPubMedCentral

48.

O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28.CrossRefPubMedPubMedCentral

49.

Assi R, Verstovsek S, Daver N. “JAK-ing” up the treatment of primary myelofibrosis: building better combination strategies. Curr Opin Hematol. 2017;24:115–24.CrossRefPubMed

50.

Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, von Bubnoff N. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10:391–402.CrossRefPubMed

51.

Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960–77.CrossRefPubMed

52.

•• Frémond M-L, Rodero MP, Jeremiah N, Belot A, Jeziorski E, Duffy D, et al. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016;138:1752–5. See annotation for reference [42••]. CrossRefPubMed

53.

Seo J, Kang J-A, Suh DI, Park E-B, Lee C-R, Choi SA, et al. Tofacitinib relieves symptoms of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173. J Allergy Clin Immunol. 2017;139:1396–1399.e12.CrossRefPubMed

54.

Tüngler V, König N, Günther C, Engel K, Fiehn C, Smitka M, et al. Response to: “JAK inhibition in STING-associated interferonopathy” by Crow et al. Ann Rheum Dis. 2016;75:e76.CrossRefPubMed

55.

Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;pii: 98814. https://doi.org/10.1172/JCI98814. [Epub ahead of print]

56.

Kim H, Brooks KM, Tang CC, Wakim P, Blake M, Brooks SR, et al. Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients. Clin Pharmacol Ther. 2017;

57.

Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol. 2010;11:1005–13.CrossRefPubMedPubMedCentral

58.

Kassiotis G, Stoye JP. Immune responses to endogenous retroelements: taking the bad with the good. Nat Rev Immunol. 2016;16:207–19.CrossRefPubMed

59.

• Beck-Engeser GB, Eilat D, Wabl M. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology. 2011;8:91. First description of a therapeutic effect of antiretroviral therapy with RT inhibitors in TREX1-deficient mice. CrossRefPubMedPubMedCentral

60.

•• Thomas CA, Tejwani L, Trujillo CA, Negraes PD, Herai RH, Mesci P, et al. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell. 2017;21:319–331.e8. This study demonstrates enhanced LINE-retroelement activity in human reprogrammed neurons from AGS patients with TREX1 deficiency. CrossRefPubMedPubMedCentral

61.

Ballana E, Esté JA. SAMHD1: at the crossroads of cell proliferation, immune responses, and virus restriction. Trends Microbiol. 2015;23:680–92.CrossRefPubMed

62.

Ahmad S, Mu X, Yang F, Greenwald E, Park JW, Jacob E, et al. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell. 2018;172:797–810.e13.CrossRefPubMed

63.

•• Achleitner M, Kleefisch M, Hennig A, Peschke K, Polikarpova A, Oertel R, et al. Lack of Trex1 causes systemic autoimmunity despite the presence of antiretroviral drugs. J Immunol Baltim. 2017;199:2261–9. This study demonstrates a lack of therapeutic effect of antiretroviral treatment with RT inhibitors in TREX1-deficient mice. CrossRef

64.

Reverse Transcriptase Inhibitors in AGS - Full Text View - ClinicalTrials.gov [Internet]. [cited 2018 Feb 18]. Available from: https://clinicaltrials.gov/ct2/show/NCT02363452.

65.

Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39:1065–7.CrossRefPubMed

66.

Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 2011;12:270–9.CrossRefPubMedPubMedCentral

67.

An J, Briggs TA, Dumax-Vorzet A, Alarcón-Riquelme ME, Belot A, Beresford M, et al. Tartrate-resistant acid phosphatase deficiency in the predisposition to systemic lupus erythematosus. Arthritis Rheumatol. 2017 69(1):131–142. https://doi.org/10.1002/art.39810

68.

Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:1909–16.CrossRefPubMedPubMedCentral

69.

Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol Hoboken NJ. 2017;69:376–86.CrossRef

70.

Frémond M-L, Uggenti C, Van Eyck L, Melki I, Bondet V, Kitabayashi N, et al. Brief report: blockade of TANK-binding kinase 1/IKKɛ inhibits mutant stimulator of interferon genes (STING)-mediated inflammatory responses in human peripheral blood mononuclear cells. Arthritis Rheumatol Hoboken NJ. 2017;69:1495–501.CrossRef

71.

Peschke K, Achleitner M, Frenzel K, Gerbaulet A, Ada SR, Zeller N, et al. Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity. J Immunol. 2016;197:2157–66.CrossRefPubMed

Titel: Therapeutic Approaches to Type I Interferonopathies
verfasst von: Marc Bienias
Normi Brück
Constanze Griep
Christine Wolf
Stefanie Kretschmer
Barbara Kind
Victoria Tüngler
Reinhard Berner
Min Ae Lee-Kirsch
Publikationsdatum: 01.06.2018
Verlag: Springer US
Erschienen in: Current Rheumatology Reports / Ausgabe 6/2018
Print ISSN: 1523-3774
Elektronische ISSN: 1534-6307
DOI: https://doi.org/10.1007/s11926-018-0743-3

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

27.05.2024 Blut im Stuhl Nachrichten

Immunchemischer Stuhltest positiv, Koloskopie negativ – in solchen Fällen kann die Blutungsquelle auch weiter proximal sitzen. Ein Forschungsteam hat nachgesehen, wie häufig und in welchen Lokalisationen das der Fall ist.

GLP-1-Agonisten können Fortschreiten diabetischer Retinopathie begünstigen

24.05.2024 Diabetische Retinopathie Nachrichten

Möglicherweise hängt es von der Art der Diabetesmedikamente ab, wie hoch das Risiko der Betroffenen ist, dass sich sehkraftgefährdende Komplikationen verschlimmern.

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

ADT zur Radiatio nach Prostatektomie: Wenn, dann wohl länger

24.05.2024 Prostatakarzinom Nachrichten

Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Purpose of Review

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2018

Gender Differences in Axial Spondyloarthritis: Women Are Not So Lucky

Therapy for CPPD: Options and Evidence

Current Options and Emerging Biomaterials for Periprosthetic Joint Infection