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