Handbook of Biologics for Rheumatological Disorders

Handbook of Biologics for Rheumatological Disorders
	Preface
	Contents
	About the Editors
	1: A Historical Introduction to the Biological Response Modifier Drugs: The ‘Biologicals’
		1.1	 Introduction
		1.2	 Historical Background
		1.3	 Basic Requirements for Producing Monoclonal Antibodies (MABS) for Therapeutic Use
			1.3.1	 Discovery of Tissue Culture Technique for Studying Biological Systems
			1.3.2	 Identifying the Key Pathogenic Molecule in RA; Study of the Synovial Tissue and its Molecules in Cell Cultures
				1.3.2.1	 Early Studies on Synovial Tissue from RA Patients in Tissue Culture
				1.3.2.2	 The Saga of the Discovery of Tumour Necrosis Factor-α (TNF-α) and its Cloning
				1.3.2.3	 Discovery of TNF-α as the Key Molecule in the Pathogenesis of Synovitis in a Patient with RA
				1.3.2.4	 Identifying and Isolating a Single Antibody-Producing Cell for Producing Monoclonal Antibody: Jerne’s ‘Haemolytic Plaque Technique’ Using Soft Agar-Gel
				1.3.2.5	 Hybridoma Technology and the Commercial Production of mAbs
				1.3.2.6	 TNF-α, Jan Vilček and the Monoclonal Anti-TNF-α
				1.3.2.7	 Maini and Feldmann’s First Use of Anti-TNF-α in Human Disease: Rheumatoid Arthritis
		1.4	 Conclusion
		References
	2: Biologics in Rheumatoid Arthritis
		2.1	 Introduction
		2.2	 What Are Biologic DMARDs (bDMARDs)?
		2.3	 What Are the Types of Biologic DMARDs?
		2.4	 What Do bDMARDs Target?
		2.5	 When to Initiate Biologics in RA?
		2.6	 How to Initiate Biologics in RA?
		2.7	 What Do Biologics Achieve in RA?
		2.8	 Place of Biologics in the Treatment Matrix of RA
		2.9	 Efficacy of Biologics
		2.10	 What Is Switching of Biologics?
		2.11	 Which Biologic for Whom?
		2.12	 Immunogenicity with Biologics
		2.13	 Biologics and Safety Issues
		2.14	 Biologics in Pregnancy and Breastfeeding
		2.15	 Biologics Versus Targeted Synthetic DMARDs
		2.16	 Bio-Originators and Biosimilars
		2.17	 Future Prospects
		Further Reading
	3: Biologics in Spondyloarthritis
		3.1	 Introduction
		3.2	 Overarching Principles for Use of Biologicals in Spondyloarthritis
		3.3	 Biological Agents Approved for Spondyloarthritis
			3.3.1	 Infliximab in Spondyloarthritis
			3.3.2	 Etanercept in Spondyloarthritis
			3.3.3	 Adalimumab in Spondyloarthritis
			3.3.4	 Certolizumab Pegol in Spondyloarthritis
			3.3.5	 Golimumab in Spondyloarthritis
			3.3.6	 Secukinumab and Ixekizumabin Spondyloarthritis
			3.3.7	 Ustekinumab in Spondyloarthritis
		3.4	 Biologics in Various Spondyloarthritides
			3.4.1	 Axial Spondyloarthritis
			3.4.2	 Non-psoriatic Peripheral Spondyloarthritis
			3.4.3	 Psoriatic Arthritis
		3.5	 Extraarticular Manifestations and Choice of Biologicals in SpA
		3.6	 Summary
		References
	4: Biologics in Psoriatic Arthritis
		4.1	 Introduction
		4.2	 Tumor Necrosis Factor Inhibitors (TNFi)
			4.2.1	 Approved TNFi in the Treatment of PsA
			4.2.2	 Effectiveness of TNFi on PsA Domains
			4.2.3	 Persistence of Treatment with TNFi in PsA Patients
			4.2.4	 Adverse Events with TNFi in Patients with PsA
			4.2.5	 Dose Reduction and Withdrawal of TNFi in PsA
		4.3	 Interleukin-17 (IL-17) Inhibitors
			4.3.1	 IL-17 Inhibitors in the Treatment of Psoriatic Disease
			4.3.2	 Efficacy of IL-17 Inhibitors in Psoriatic Arthritis
				4.3.2.1	 Peripheral Joint Outcome
				4.3.2.2	 Axial PsA Outcome
				4.3.2.3	 Enthesitis and Dactylitis Outcome
				4.3.2.4	 Persistence of Treatment with IL-17 Inhibitors in Patients with PsA
				4.3.2.5	 Safety of IL-17 Inhibitors in Patients with PsA
		4.4	 IL-23 Inhibitors
		4.5	 Interleukin-12/Interleukin-23p40 Inhibitor
			4.5.1	 Effectiveness of UST on Axial PsA, Enthesitis, and Dactylitis
			4.5.2	 Persistence of Treatment with UST in PsA Patients
			4.5.3	 Safety of UST in PsA Patients
		4.6	 Interleukin-23p19 Inhibitors
			4.6.1	 Efficacy of Guselkumab for Peripheral Joint Outcomes in Active PsA
			4.6.2	 Guselkumab in Axial PsA
			4.6.3	 Efficacy in Enthesitis and Dactylitis
			4.6.4	 Safety of Guselkumab in PsA Patients
		4.7	 Co-Stimulation Blockade in PsA
		4.8	 Small Molecules in PsA
		4.9	 Targeting the JAK/STAT Pathway: The JAK Inhibitors
			4.9.1	 Tofacitinib (TOFA)
				4.9.1.1	 Efficacy of TOFA on Peripheral and Axial Arthritis
				4.9.1.2	 Efficacy of TOFA on Enthesitis and Dactylitis
				4.9.1.3	 Tolerability and Safety Profile of TOFA in Psoriatic Arthritis
			4.9.2	 Upadacitinib (UPA)
				4.9.2.1	 Efficacy of UPA on Peripheral and Axial Arthritis
				4.9.2.2	 Efficacy of UPA on Enthesitis and Dactylitis
				4.9.2.3	 Safety of UPA in PsA
		4.10	 Phosphodiesterase-4 (PDE4) Inhibitor: Apremilast
			4.10.1	 Efficacy of APR on Peripheral Arthritis
			4.10.2	 Efficacy of APR on Enthesitis and Dactylitis
			4.10.3	 Persistence and Safety of APR in Patients with PsA
		4.11	 Positioning of Targeted DMARDs in the Recommendations for PsA
		4.12	 Conclusion
		References
	5: Biologics in Gout
		5.1	 Introduction
		5.2	 Urate Lowering Drugs
			5.2.1	 Pegloticase
			5.2.2	 Rasburicase
		5.3	 Anti-IL1 Agents
			5.3.1	 Anakinra
			5.3.2	 Rilonacept
			5.3.3	 Canakinumab
		5.4	 Summary
		References
	6: Biologics in Systemic Lupus Erythematosus (SLE)
		6.1	 Introduction
		6.2	 Unmet Needs in the Management of SLE
		6.3	 Points of Intervention in the Immunological Pathways of SLE (Fig. 6.1)
		6.4	 Biological Therapies for SLE
			6.4.1	 Targeting B Cell Growth and Survival Factors
			6.4.2	 Belimumab
			6.4.3	 Tabalumab
			6.4.4	 Blisibimod
			6.4.5	 Atacicept
			6.4.6	 Targeting B Cell Surface Molecules
				6.4.6.1	 Rituximab
				6.4.6.2	 Ocrelizumab
				6.4.6.3	 Obinutuzumab
				6.4.6.4	 Epratuzumab
				6.4.6.5	 Daratumumab
			6.4.7	 Targeting Co-Stimulatory Molecules
				6.4.7.1	 Abatacept
				6.4.7.2	 Dapirolizumab
			6.4.8	 Combination/Sequential Biological Therapies
			6.4.9	 Targeting Cytokines
				6.4.9.1	 IL-6
				6.4.9.2	 Type I Interferons (IFNs)
				6.4.9.3	 Rontalizumab
				6.4.9.4	 Sifalimumab
				6.4.9.5	 Anifrolumab
				6.4.9.6	 Interferon-α-Kinoid (IFN-K)
				6.4.9.7	 IL-12/23
			6.4.10	 Targeting Intracellular Pathways
				6.4.10.1	 JAK Inhibition and Other Small Molecules
				6.4.10.2	 Other Biological Agents and New Molecules
		6.5	 Conclusions
		References
	7: Biologics in Sjogren’s Syndrome
		7.1	Introduction
		7.2	 Rationale for Biologics in Sjogren’s Syndrome
		7.3	 Rituximab
		7.4	 Belimumab
		7.5	 Abatacept
		7.6	 Anti-CD40 and Anti-CD40 Ligand
		7.7	 Epratuzumab
		7.8	 Anti-TNF Therapy
		7.9	 JAK and BTK Inhibitors
		7.10	 Tocilizumab
		7.11	 Novel Biologics and New Molecules
		7.12	 Conclusion
		References
	8: Biologics in Systemic Sclerosis
		8.1	Introduction
		8.2	 Rationale for Biologics in Systemic Sclerosis
		8.3	 Abatacept
		8.4	 Brentuximab Vedotin
		8.5	 Belimumab
		8.6	 Inebilizumab
		8.7	 Rituximab
		8.8	 Rilonacept
		8.9	 Romilkimab
		8.10	 Tocilizumab
		8.11	 Tofacitinib
		8.12	 Intravenous Immunoglobulin
		8.13	 Clinical Practice
		8.14	 Summary
		References
	9: Biologics in Idiopathic Inflammatory Myopathies
		9.1	Introduction
		9.2	 Rituximab (Anti-CD 20)
		9.3	 Abatacept (CTLA-4 Agonist)
		9.4	 Intravenous or Subcutaneous Immunoglobulin (IVIg/SCIg)
		9.5	 Sifalimumab
		9.6	 Other Biologics
		9.7	 Conclusion
		References
	10: Biologics in ANCA-Associated Vasculitides
		10.1	 Initial Management
		10.2	 Remission Induction
			10.2.1	 The History
		10.3	 The Introduction of Biological Drug in AAV
		10.4	 Rituximab in AAV
		10.5	 Remission Maintenance
		10.6	 Other Biological Drugs in AAV
		10.7	 Conclusion
		References
	11: Biologics in Behcet’s syndrome
		11.1	Introduction
		11.2	 Immune Dysfunction and Therapeutic Targets in Behcet’s Syndrome
		11.3	 EULAR 2018 Update of Guidelines for Management of Behcet’s Syndrome
		11.4	 Indications of Biologic Therapies in Behcet’s Syndrome
		11.5	 Conclusion
		References
	12: Biologics in Takayasu’s Arteritis
		12.1	 Introduction
		12.2	 Case Scenario
		12.3	 Discussion
		12.4	 STEP 1: Initial Assessment and Diagnosis
		12.5	 Step 2: Initiating Corticosteroids and Immunosuppression
		12.6	 Case Scenario
		12.7	 Step 3: Assessment of Disease Activity at Follow up
		12.8	 Case Scenario
		12.9	 Step 4: Step up to Biological Agents
		12.10	 Step 5: Experimental Therapy and Logistic Considerations
		12.11	 Case Scenario Completion
		Suggested Further Reading
	13: Biologics in Interstitial Lung Diseases in Rheumatological Disorders
		13.1	 Introduction
		13.2	 Tumor Necrosis Factor Inhibitors
		13.3	 Anti-B-Cell Agents
		13.4	 Abatacept
		13.5	 Other bDMARDs
		13.6	 Idiopathic Pulmonary Fibrosis
		13.7	 Conclusion
		References
	14: Biologics in Osteoporosis
		14.1	 Introduction
		14.2	 Therapeutic Options: Current and New
		14.3	 Teriparatide
		14.4	 Abaloparatide
		14.5	 Denosumab
			14.5.1	 Newer Therapies
		14.6	 Sclerostin
		14.7	 Romosozumab
		14.8	 Summary
		References
	15: Biologics in Osteoarthritis
		15.1	 Introduction
			15.1.1	 Biologics Targeting Pain Pathways
			15.1.2	 Stopping Degeneration
		15.2	 IL-1 Countering Monoclonals
			15.2.1	 Monoclonals Targeting IL1β Molecule
			15.2.2	 Drugs Acting on IL1 Receptor
			15.2.3	 Anti TNF Therapies
			15.2.4	 Targeting Cartilage Breakdown
			15.2.5	 Biologicals with Disease Modifying Properties in Osteoarthritis or Growth Factors
		15.3	 Summary
		References
	16: Biologics in Juvenile Idiopathic Arthritis
		16.1	 Introduction
		16.2	 Interference with Cytokines
			16.2.1	 Soluble TNF Receptor Fusion Protein
				16.2.1.1	 Etanercept
			16.2.2	 Monoclonal Anti-TNF Antibody
				16.2.2.1	 Adalimumab
				16.2.2.2	 Infliximab
			16.2.3	 Inhibition of Interleukin-1
				16.2.3.1	 Anakinra
				16.2.3.2	 Rilonacept
				16.2.3.3	 Canakinumab
		16.3	 Inhibition of Interleukin-6
			16.3.1	 Tocilizumab
		16.4	 Inhibition of T-cell Co-stimulation
			16.4.1	 Abatacept
		16.5	 B-cell Depletion
		16.6	 Treatment Guidelines for Juvenile Idiopathic Arthritis
		16.7	 Conclusion
		References
	17: Biologics in Pediatric Connective Tissue Disorders
		17.1	 Introduction
		17.2	 Biologics in SLE
		17.3	 Biologics in JDM
		17.4	 Biologics in Pediatric Vasculitis
			17.4.1	 Takayasu Arteritis
			17.4.2	 Kawasaki Disease
			17.4.3	 DADA2 Deficiency and PAN
			17.4.4	 ANCA Vasculitis (AAV)
			17.4.5	 IgA Vasculitis
		17.5	 Conclusions
		References
	18: JAK Inhibitors in Rheumatic Disease
		18.1	Introduction
		18.2	 The JAK/STAT Pathway
		18.3	 Evaluation of Efficacy of JAKinibs in RA Clinical Trials
		18.4	 JAKinibs in PsA
			18.4.1	 Tofacitinib
			18.4.2	 Upadacitinib
		18.5	 Giant Cell Arteritis
		18.6	 Safety of JAKinibs
			18.6.1	 Infections
			18.6.2	 Malignancies
			18.6.3	 Gastrointestinal Perforation
			18.6.4	 Deep Vein Thrombosis and Pulmonary Embolus
			18.6.5	 Laboratory Abnormalities
		18.7	 Newer JAKinibs (Table 18.4)
			18.7.1	 Filgotinib
			18.7.2	 Peficitinib
			18.7.3	 Decernotinib
		18.8	 Conclusion
		References
	19: Biologics in Rheumatic Diseases in the Presence of Infection
		19.1	 Introduction
		19.2	 Latent TB Infection
			19.2.1	 Non-anti-TNF Biologics
			19.2.2	 Screening for Latent TB
			19.2.3	 Treatment
				19.2.3.1	 One of the Following Treatment Regimens can be Chosen for LTBI
		19.3	 HBV and HCV Infection
		19.4	 Hepatitis B
			19.4.1	 Natural Course
			19.4.2	 HBV Reactivation
			19.4.3	 Screening Recommendations
			19.4.4	 In HBsAg Positive Patients
			19.4.5	 In HBsAg Negative, anti-HBC Positive Subjects (Occult HBV Infection)
		19.5	 Hepatitis C
			19.5.1	 Natural Course
			19.5.2	 Screening Recommendations
		19.6	 HIV Infection
		19.7	 Other Infections
		19.8	 Conclusion
		References
	20: Biologics in Rheumatologic Conditions with Malignancy
		20.1	 Introduction
		20.2	 Rheumatic Diseases and Cancer: A Possible Link
		20.3	 The Possible Association Between Biologics and Malignancy
			20.3.1	 Rheumatoid Arthritis (RA)
				20.3.1.1	 Lymphoma in RA
				20.3.1.2	 Breast Cancer in RA
				20.3.1.3	 Lung Cancer in RA
				20.3.1.4	 Other Cancers in RA
		20.4	 Conclusions
			20.4.1	 Ankylosing Spondylitis (AS)
			20.4.2	 Primary Sjogren’s Syndrome
			20.4.3	 Scleroderma
			20.4.4	 Myositis
			20.4.5	 Psoriasis
			20.4.6	 Systemic Lupus Erythematosus (SLE)
			20.4.7	 Vasculitis
		20.5	 Summary
		References
	21: Biologics in Uveitis
		21.1	 Introduction
		21.2	 Conventional Treatment for Noninfectious Uveitis
		21.3	 Systemic Biologic Therapy for Noninfectious Uveitis
			21.3.1	 Tumor Necrosis Factor Inhibitors (TNFi)
				21.3.1.1	 Infliximab (Remicade®, Janssen Biotech, Inc) [6, 10, 24]
				21.3.1.2	 Adalimumab (Humira®, AbbVie Inc) [8, 16, 27, 28]
				21.3.1.3	 Golimumab (Simponi®, Janssen Biotech, Inc) [30]
				21.3.1.4	 Certolizumab (Cimzia®, UBC, Inc) [18, 21]
				21.3.1.5	 Etanercept (Enbrel®, Immunex Corporation) [7, 23]
			21.3.2	 Lymphocyte Inhibitors and Lympho-Cytotoxic Medications
				21.3.2.1	 Rituximab (Rituxan®, Genentech, Inc) [11, 25, 26]
				21.3.2.2	 Abatacept (Orencia®, Bristol-Myers Squibb Company) [2, 29]
				21.3.2.3	 Alemtuzumab (Lemtrada®, Genzyme Corporation) [4, 20, 32]
			21.3.3	 Interleukin (IL) Inhibitors
				21.3.3.1	 Anakinra (Kineret®, Swedish Orphan Biovitrum AB [Publ]) and Canakinumab (Ilaris®, Novartis) [5]
				21.3.3.2	 Gevokizumab (XOMA 052, XOMA Corporation)
				21.3.3.3	 Tocilizumab (Actemra®, Genentech, Inc) [14, 19, 22, 31]
				21.3.3.4	 Secukinumab (Cosentyx®, Novartis) [3, 12]
				21.3.3.5	 Ustekinumab (Stelara®, Janssen Biotech, Inc)
			21.3.4	 Janus Kinase (JAK) and Tyrosine Kinase (TYK) Inhibitors
				21.3.4.1	 Tofacitinib (Xeljanz®, Pfizer) [13, 17]
				21.3.4.2	 Filgotinib (GLPG0634, Galapagos NV/Gilead)
				21.3.4.3	 Baricitinib (Olumiant®, Eli Lilly and Company) [15]
			21.3.5	 Interferons (IFN) [1, 9]
		21.4	 Special Consideration
			21.4.1	 Vedolizumab (Entyvio®, Takeda)
		References
	22: Biologics in Sarcoidosis
		22.1	 Introduction
		22.2	 Immunopathogenesis
		22.3	 Management
			22.3.1	 Glucocorticoids
			22.3.2	 Methotrexate
			22.3.3	 Azathioprine
			22.3.4	 Leflunomide
			22.3.5	 Mycophenolate
			22.3.6	 Antimalarial Agents
			22.3.7	 Biological Therapy
				22.3.7.1	 Infliximab
				22.3.7.2	 Etanercept
				22.3.7.3	 Adalimumab
				22.3.7.4	 Non Targeted TNF Inhibitors
				22.3.7.5	 Cytotoxic T-lymphocyte Associated Blockade
				22.3.7.6	 IL-12/IL-23P40 and Th17 Pathways
				22.3.7.7	 Other Therapies
				22.3.7.8	 Novel Therapeutics
		References
	23: Biologics in IgG4-Related Disease
		23.1	 Case Vignette
		23.2	 Introduction
		23.3	 Biologics
		23.4	 Understanding the Targets of Biological Therapies in IgG4-RD
		23.5	 Screening Before Starting Biologics
		23.6	 Use of Biological Agents in IgG4 RD
			23.6.1	 B Cell-Targeted Therapies
				23.6.1.1	 Rituximab
				23.6.1.2	 Dose Protocol
				23.6.1.3	 Use of Rituximab in IgG4 RD
				23.6.1.4	 Side Effects
			23.6.2	 Other Therapies Targeting B Cells
				23.6.2.1	 XmAb5871
				23.6.2.2	 Bortezomib
				23.6.2.3	 Inebilizumab
			23.6.3	 T Cells Targeted Therapy
				23.6.3.1	 Abatacept
			23.6.4	 B and T Cells Targeted Therapy
				23.6.4.1	 Elotuzumab
			23.6.5	 Cytokine Inhibitors
				23.6.5.1	 Infliximab
				23.6.5.2	 Dupilimab
			23.6.6	 Other Possible Cytokine Targets
				23.6.6.1	 IL6 Inhibitor Tocilizumab
				23.6.6.2	 Anakinra and Canakinumab
			23.6.7	 Other Targets
				23.6.7.1	 Omalizumab
				23.6.7.2	 Eculizumab and Simtuzumab
		23.7	 Conclusion
		References
	24: Biosimilars in Rheumatology
		24.1	 Introduction
		24.2	 Biomimics and Biocopies
		24.3	 Development of Biosimilars
		24.4	 Evaluation of Proposed Biosimilars
		24.5	 Regulations for Biosimilars
		24.6	 Switching, Substitution, Interchangeability, and Extrapolation
		24.7	 Clinical Experience with Biosimilars
			24.7.1	 Biosimilars of Infliximab
			24.7.2	 Biosimilars of Etanercept
			24.7.3	 Biosimilars of Adalimumab and Rituximab
		24.8	 Biosimilars in Other Fields
		24.9	 Challenges
		24.10	 Summary
		References
	25: Off-Label Use of Biologics in Rheumatological Disorders
		25.1	 Introduction
		25.2	 Commonly Used Biological DMARDs in Rheumatic Diseases
			25.2.1	 Tocilizumab
				25.2.1.1	 Takayasu Arteritis (TA)
				25.2.1.2	 Adult-Onset Still Disease (AOSD)
				25.2.1.3	 Systemic Sclerosis (SSc)
				25.2.1.4	 Behcet’s Disease (BD)
				25.2.1.5	 Polymyalgia Rheumatica (PMR)
			25.2.2	 Rituximab
				25.2.2.1	 Systemic Lupus Erythematosus (SLE)
				25.2.2.2	 Systemic Sclerosis (SSc)
				25.2.2.3	 Sjogren Syndrome (SS)
				25.2.2.4	 Idiopathic Inflammatory Myositis (IIM)
			25.2.3	 Anti-TNF α Agents
				25.2.3.1	 Sarcoidosis
				25.2.3.2	 Uveitis in Rheumatic Diseases
				25.2.3.3	 Behcet’s Disease (BD)
				25.2.3.4	 Kawasaki Disease (KD)
			25.2.4	 Anti IL-1 Agents
			25.2.5	 Anti IL-17 Agents
		25.3	 Conclusion
		References
	26: Biologics and Ethical Issues in Rheumatology
		26.1	 Introduction: Ethical Issues in Rheumatology
		26.2	 Biologics/Biosimilars and their Cost-Effectiveness
		26.3	 Patient-Related Ethical Issues
			26.3.1	 Control Arms and Healthy Controls
			26.3.2	 Treatment Naïve and Treated Patients
			26.3.3	 Beneficence and Non-Maleficence
			26.3.4	 Patient Autonomy
			26.3.5	 Distribution of Justice
		26.4	 Physician-Related Issues
			26.4.1	 Physician–Pharmaceutical Industry Relations
			26.4.2	 Conflict of Interest
			26.4.3	 Medical Education and Bias
		26.5	 Industry-Related Issues
			26.5.1	 Fair Control Trials
			26.5.2	 Publication Biases
		26.6	 Future and Conclusion
		References
	27: Patient Consent for Biologics
		27.1	 Introduction
		27.2	 Consent
		27.3	 Consent for Biologics
			27.3.1	 Indications
			27.3.2	 Toxicity and Pre-Treatment Screening
				27.3.2.1	 Infection Risk
				27.3.2.2	 Pre-Treatment Counselling and Screening
			27.3.3	 Mode of Administration and Cost
		27.4	 Conclusion
		References