This document discusses biological therapies for rheumatic diseases. It provides a historical overview of biological therapies and reviews various cytokine inhibitors including tumor necrosis factor (TNF) inhibitors, interleukin inhibitors, T-cell and B-cell directed therapies. It summarizes several TNF inhibitors including infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol. The document also reviews strategies for using biologics in rheumatoid arthritis and considerations for special patient populations.

1. Samar Tharwat Radwan
Lecturer of Internal Medicine
(Rheumatology & Immunology)
Mansoura University
BIOLOGICAL THERAPY IN RHEUMATIC DISEASES

2. OVERVIEW OF BIOLOGIC THERAPIES

3. HISTORICAL REVIEW
• The technology for producing monoclonal antibodies:1975
• Oncology and transplantation medicine

4. A NOBEL PRIZE FOR ANTI-TNF?
Sir Ravinda Maini and Sir Marc Feldman
Should be rewarded with a Nobel Prize
Many other world-class scientific prizes

5. Professor Bruce Beutler: etanercept
Nobel Prize 2011 for the discovery of Toll-like receptors

7. BIOLOGIC VERSUS SYNTHETIC DMARDS
1. Biologics can be effective where conventional DMARDs have failed.
2. Biologics, and specifically the anti-TNF biologics, can have a very rapid onset of action: same day.
3. Radiographic efficacy of the anti-TNF agents exceeded expectations.
4. Anti-TNF agents, and biologics in general, are surprisingly well tolerated and relatively safe.
5. Biologics have a well-defined and specific mechanism of action

8. CYTOKINE INHIBITORS

9. • Tumor necrosis factor inhibitors
• Interleukin-6 inhibitors
• Interleukin-1 inhibitors
• IL-17 inhibition
• IL-12/23 inhibition

10. TUMOR NECROSIS FACTOR INHIBITORS
The pathophysiology of rheumatoid arthritis depicted as a cascade, in which TNF is upstream from IL-1, IL-6, and IL-8

12. INFLIXIMAB
• 5 mg/kg with or without MTX, at 0, 2, and 6 weeks, then every 8 weeks
• Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn disease, and
ulcerative colitis
• S.E: severe infusion reactions
anti-infliximab monoclonal antibodies

13. ADALIMUMAB (HUMIRA)
• Subcutaneous 40 mg every other week
• RA, JIA, PsA, AS, nr-axSpA, Crohn’s disease, psoriasis.
• MTX
• No adjustment of dosing for body weight or size, nor for age or metabolic status
(except advanced renal failure)

14. ETANERCEPT (ENBREL)
• MTX
• 50 mg SC weekly or 25 mg twice weekly
• JIA,RA, PsA, and AS.
• Not effective for ulcerative colitis

15. GOLIMUMAB (SIMPONI)
• RA
• long dosing interval
• 50 mg subcutaneously once a month
• Intravenous golimumab (Simponi Aria)

16. CERTOLIZUMAB PEGOL (CIMZIA)
• linked to polyethyleneglycol (PEG) for greater stability & a longer half-life
• RA
• Various DMARDs
• Higher risks for infection
• Single bi-weekly subcutaneous 200 mg injection or as 2injections given /4weeks

17. EFFICACY OF TUMOR NECROSIS FACTOR
INHIBITORS
• Rheumatoid Arthritis
• Psoriatic Arthritis (PsA)
• Ankylosing Spondylitis
• Other Considerations:
Treatment in Other Autoimmune Conditions:Crohn’s,JIA, psoriasis, idiopathic and
spondyloarthropathy-related anterior uveitis, sarcoidosis, Sjِ gren’s syndrome, Behçet’s
disease, inflammatory myopathies, and various types of vasculitis, SLE

18. CARDIOVASCULAR RISK AND LIPID PROFILE

19. MONITORING
tuberculosis infection HBV complete blood count

20. VACCINATIONS
• It is preferred to have all recommended vaccinations before initiating treatment
• Live vaccines with TNF inhibitors is not recommended

21. TOXICITY
Infusion and Injection
Site Reactions
Antigenicity Infection Malignancy
Autoimmune
Disorders.
Demyelinating
Syndromes
Congestive Heart
Failure

22. INTERLEUKIN-6 INHIBITORS
TOCILIZUMAB (ACTEMRA)
• SE: Infections, tuberculosis
Cancer
Elevated transaminases
Cytopenias: leukopenia, neutropenia, thrombocytopenia
Elevations of cholesterol
‘Masking’ of the acute phase response
• Dosing: 4 or 8 mg/kg given at 4-week intervals
subcutaneous 162 mg given once weekly
Other interleukin-6 antagonists: sarilumab, sirukumab, Olokizumab, clazakizumab

23. INTERLEUKIN-1 INHIBITORS
• Kineret ,Canakinumab, Rilonacept
• Approved for the treatment of RA, but results in practice were disappointing (slower, daily
subcutaneous injections, cutaneous reactions, less effective)
• Cryopyrin-associated inflammatory syndromes
• Improved efficacy
• High incidence of severe infections

24. T-CELL DIRECTED THERAPY

25. T-CELL DIRECTED THERAPY

26. T-CELL DIRECTED THERAPY
Abatacept (Orencia)
• Monotherapy or combined with MTX
• IV 500, 750, or 1000 mg based on body weight, given every 4 weeks.
• SC at 125 mg weekly
High rate of severe infections

27. B-CELL DIRECTED THERAPY

28. B-CELL DIRECTED THERAPY
• Professor Jonathan Edwards proposed that IgG-
rheumatoid factors play a central role in the
pathophysiology of rheumatoid arthritis
• Hypothesized that B-cell depletion would be
effective

29. RITUXIMAB
• Non-hodgkin lymphoma
• off-label of many autoimmune diseases
• (ANCA)-associated vasculitis, SLE, multiple sclerosis
• SE:infusion reactions
progressive multifocal leukoencephalopathy
• 500 or 1000 mg given intravenously twice with two weeks in between
• 6-monthly repeat courses
• Monotherapy or combination with DMARDs

30. RITUXIMAB
Combination of rituximab with leflunomide may be even more effective than the MTX combination

31. NOVEL BIOLOGICS AND SMALL MOLECULES
WITH BIOLOGIC-LIKE EFFECTS
Novel Biologics
Interleukin-12/23 antagonist
Interleukin-17 antagonists
Granulocyte-macrophage colony-stimulating factor antagonist
Antirheumatic Medications With Biologic-like Properties

32. IL-12/23 BLOCKADE
Ustekinumab
• Psoriasis and psoriatic arthritis
• It is administered every 12 weeks by subcutaneous injection after several loading doses

33. IL-17 INHIBITION
Secukinumab
• Psoriasis ,PsA ,AS, uveitis
• 150 mg SC at weeks 0, 1, 2, 3, and 4 and q4wk thereafter
• Ixekizumab: Psoriasis ,PsA

34. GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR ANTAGONIST
Mavrilimumab
• Immunoregulatory functions

35. JANUS KINASE INHIBITORS
• Tofacitinib: 5mg dose orally twice daily
• SE: Infections
Hepatic transaminase elevations
Increases in cholesterol
• Baricitinib

36. STRATEGIES FOR THE OPTIMAL USE OF BIOLOGIC
AGENTS IN RHEUMATOID ARTHRITIS

37. • Established and refractory disease : dramatic response

38. ECONOMIC CONSEQUENCES

39. • Patient who had failed numerous DMARDs and had highly active disease
• Pattient who had failed methotrexate (MTX) and at least one other DMARDs
Which Patients The Biologics Should Be Used?

40. What Treatment To Choose For The Patient Who Has
Failed MTX?

41. Triple therapy was as good as (‘non-inferior to’) anti-TNF therapy

42. Treatment Of The Patients With Newly Diagnosed
Methotrexate-naive Rheumatoid Arthritis

49. Induction-maintenance Strategies In Rheumatoid Arthritis

50. SWITCHING AFTER FAILING ONE BIOLOGIC

52. HEAD-TO-HEAD COMPARATIVE STUDIES OF
BIOLOGIC AGENTS

53. abatacept achieved similar ACR responses as infliximab
the responses and the adverse events were similar
tocilizumab was shown to be superior to adalimumab

54. Personalized Therapy
How Should We Choose The Right Treatment For Each Patient?

55. Trial-and-error
Biomarker Panels
VectraDA Ultrasound
fluorescent optical
imaging

56. Considerations For Special Patient Populations
Pregnant Pediatric Elderly

57. BIOLOGICS IN PREGNANCY
Teratogenicity
Infection
Disease
Activity

59. BIOLOGICS IN PEDIATRIC PATIENTS
Commonly Used Medications in Juvenile Idiopathic Arthritis

60. A relatively high prevalence of lymphoma in children and adolescents treated with anti-TNF agents
JIA itself is associated with an elevated risk for malignancies

61. BIOLOGICS IN ELDERLY PATIENTS
comorbidities treatments osteopenia joint damage sarcopenia complications
The elderly respond equally well, and donot have
more side effects, to treatment with adalimumab,
etanercept, infliximab, rituximab, or tocilizumab

62. BIOLOGICS IN PSORIATIC ARTHRITIS

63. • without severe
PsA /psoriasis
• prefer an oral drug
• contraindications
to TNFi treatment

65. UNDIFFERENTIATED SPONDYLOARTHRITIS
In patients with axial involvement or severe manifestations despite conventional treatment,
TNF inhibitors should be considered

66. SYSTEMIC LUPUS ERYTHEMATOSUS

67. SJOGREN'S SYNDROME
• Infliximab and etanercept
• Rituximab
• Belimumab and abatacept

68. SYSEMIC SCLEROSIS
• B cell–targeted immunotherapy:Rituximab
• TNF inhibitors:Etanercept,Infliximab

70. BIOSIMILARS VERSUS BIOLOGICS