- •Sjögren’s Syndrome
- •Foreword
- •Contents
- •Contributors
- •1.1 Primary Sjögren’s Syndrome
- •1.1.1 Diagnostic Criteria
- •1.1.2 Incidence
- •1.1.3 Prevalence
- •References
- •2.1 Introduction
- •2.2 Genetic Epidemiology of SS
- •2.3 Key Concepts in Genetics, Transcriptomics, and Proteomics
- •2.4 Candidate Genes and SS Pathogenesis
- •2.5 Gene Expression Studies in SS
- •2.6 Protein Expression Studies in SS
- •2.7 Future Directions
- •References
- •3.1 Introduction
- •3.2 Characteristics of Autoimmune Lesions
- •3.3 Epithelial Cells as Key Regulators of Autoimmune Responses
- •3.4 Tissue Injury and Repair
- •3.4.1 Functional Impairment of Glands and Autonomic Nervous System Involvement
- •3.4.2 Extracellular Matrix and Tissue Damage
- •3.5 Pathogenetic Factors
- •3.5.1 Genetic Predisposition
- •3.5.2 Environmental Factors
- •3.5.3 Hormonal
- •3.6 Conclusions/Summary
- •References
- •4.1 Hepatitis C Virus
- •4.2 Hepatitis B Virus
- •4.5 Coxsackieviruses
- •4.6 Herpes Viruses
- •4.7 Human Parvovirus B19
- •4.8 Conclusion
- •References
- •5.1 The Role of T Cells in SjS
- •5.2 The Role of B Cells in SjS
- •5.2.1 The Impact of B Cell Cytokines
- •5.2.2 Ontogeny of B Lymphocytes
- •5.2.3 Subpopulations of B Cells
- •5.2.4 B Cell Monoclonal Expansion
- •5.3 B Cells Are Not Dispensable
- •5.3.1 B Cell Chemokines and Antibody Production
- •5.3.2 Peculiarities of B Cell Products: Cytokines and IgA Autoantibodies
- •5.3.3 Intrinsic Abnormalities of B Cells in Primary SjS
- •5.4 Conclusion
- •References
- •6.1 Introduction
- •6.3 Objective Determination of Salivary Flow
- •6.4 Etiology of Xerostomia
- •6.5 Orofacial Manifestations in SS
- •6.5.1 Salivary Involvement
- •6.5.2 Neurological Involvement
- •6.6 Sialochemical Changes in SS
- •6.7 Hyposalivation: Clinical Features and Complications
- •6.7.1 Clinical Features
- •6.7.2 Examination
- •6.7.3 Clinical Signs of Hyposalivation
- •6.7.4 Effect of Hyposalivation on Quality of Life
- •6.7.5 Management of Hyposalivation
- •6.7.6 Chronic Complications of Hyposalivation
- •Box 6.1: Chronic Complications of Hyposalivation
- •6.7.6.1 Dental Caries
- •Box 6.2: Strategies for Reducing Dental Caries in Patients with Sjögren’s Syndrome
- •6.7.6.2 Periodontal Health
- •6.7.6.3 Oral Functional Impairments
- •6.7.6.4 Oral Infections
- •Box 6.3: Factors Predisposing to Oral Candidiasis
- •6.7.6.6 Angular Stomatitis
- •6.7.6.7 Candidiasis
- •6.7.6.8 Bacterial Sialadenitis
- •6.7.6.9 Oral Ulceration
- •6.8 Salivary Gland Enlargement
- •6.8.1 Box 6.5: Non-Salivary Causes of Salivary Gland Enlargement
- •6.9 Salivary Swelling in SS
- •References
- •Key Websites (Accessed Dec 19, 2009)
- •7.1 Sjögren’s Syndrome: A Disease of the Lacrimal Functional Unit
- •7.2 Components of the Lacrimal Functional Unit
- •7.3 Lacrimal Gland
- •7.4 Conjunctiva
- •7.5 Cornea
- •7.6 Meibomian Glands and Eyelids
- •7.7 Neural Innervation
- •7.8 Mechanisms of Dysfunction
- •7.8.1 Lacrimal Gland
- •7.8.2 Ocular Surface
- •7.9 Diagnosis of Ocular Involvement in Sjögren’s Syndrome
- •7.10 Treatment of LFU Dysfunction
- •References
- •8.1 Introduction
- •8.2 Otologic Manifestations
- •8.3 Sinus and Nasal Manifestations
- •8.4 Laryngopharyngeal and Tracheal Manifestations
- •References
- •9.1 Epidemiology of Fatigue
- •9.2 Assessing Fatigue
- •9.4 Relationship of Fatigue to Cognitive Symptoms and to Depression
- •9.5 Fatigue Viewed From the Physiological Perspective: Relationships Between Fatigue, Sleep Quality, and Neuroendocrine Function
- •9.6 Relationship Between Fibromyalgia and SS
- •9.7 Management of Pain and Fatigue
- •9.8 Summary
- •References
- •10.1 Introduction
- •10.2 Arthralgias and Arthritis
- •10.3 Arthritis: Patterns of Expression
- •10.4 Differential Diagnosis: RA, SLE, and Other Arthropathies
- •References
- •11.1 Introduction
- •11.2 Epidemiology
- •11.3 Skin Changes Encountered in Primary SjS
- •11.3.1 Pruritus
- •11.3.2 Annular Erythema of SjS
- •11.3.3 Eyelid Dermatitis
- •11.3.4 Panniculitis
- •11.3.5 Primary Nodular Cutaneous Amyloidosis
- •11.3.6 B Cell Lymphoma
- •11.4 Skin Changes Encountered in Secondary SjS
- •11.4.1 Skin Changes Associated with Lupus Erythematosus
- •References
- •12.1 Introduction
- •12.2 Epidemiology
- •12.3 Histopathology
- •12.4 Laboratory Findings
- •12.5 Pathogenesis
- •12.6 Clinical Findings
- •12.7 Skin
- •12.8 Peripheral and Central Nervous System
- •12.9 Other Organs
- •12.10 Vasculitis and Mortality
- •12.11 Treatment
- •References
- •13.1 Introduction
- •13.2 Pericarditis
- •13.3 Myocarditis
- •13.4 Valvular Abnormalities
- •13.5 Diastolic Dysfunction
- •13.6 Atrioventricular Block
- •13.7 Subclinical Atherosclerosis
- •13.8 Pulmonary Arterial Hypertension
- •13.9 Autonomic Cardiovascular Dysfunction
- •13.10 Therapeutic Management
- •13.11 Conclusion
- •References
- •14.1 Introduction
- •14.2 Airway Disease
- •14.2.1 Overview
- •14.2.2 Pathology
- •14.2.3 Imaging Studies
- •14.3 Interstitial Lung Disease
- •14.3.1 Overview
- •14.3.2 Pathology
- •14.3.4 Usual Interstitial Pneumonia
- •14.3.5 Follicular Bronchiolitis
- •14.3.6 Lymphocytic Interstitial Pneumonia
- •14.3.7 Cryptogenic Organizing Pneumonia
- •14.3.8 Clinical Features
- •14.3.9 Imaging Studies
- •14.4 Pleuritis
- •14.5 Diagnosis and Management
- •References
- •15.1 Evaluation of the Sjögren’s Syndrome and Raynaud’s Phenomenon
- •15.2 Management of Raynaud’s Phenomenon
- •15.2.1 Vasodilator Therapy
- •15.2.2 Calcium Channel Blockers
- •15.2.3 Adrenergic Blockers
- •15.2.4 Nitrates
- •15.2.5 Phosphodiesterase Inhibitors
- •15.2.6 Prostacyclins
- •15.2.7 Other Agents
- •15.3 Surgical Options
- •15.3.1 Sympathectomies
- •15.3.2 Management of Critical Digital Ischemia
- •References
- •16.1 Dysphagia
- •16.3 Chronic Gastritis
- •16.5 Association with Celiac Disease
- •16.6 Intestinal Vasculitis
- •16.7 Other Intestinal Diseases
- •16.8 Conclusion
- •References
- •17.1 Introduction
- •17.2 Primary Biliary Cirrhosis (PBC)
- •17.2.2 Similarities, Differences, and Overlap Among SS and PBC
- •17.2.3 Epithelium Involvement
- •17.2.4 Animal Models
- •17.2.5 Histology and Serology
- •17.3 Autoimmune Hepatitis (AIH)
- •17.4 Hepatitis C Virus (HCV) Infection and Sicca Syndrome
- •17.5 Algorithm for the Diagnosis of Liver Involvement in SS
- •References
- •18.1 Introduction
- •18.3 Involvement of the Pancreas in SjS
- •18.3.1 Clinical Presentation
- •18.3.2 Autoantibodies
- •18.3.3 Pancreatic Enzymes
- •18.3.4 Pathology
- •18.3.5 Imaging Studies of the Pancreas
- •18.4 Autoimmune Pancreatitis
- •18.4.1 Introduction
- •18.4.2 Clinical Features
- •18.4.3 Imaging
- •18.4.4 Serology
- •18.4.5 Pathology
- •18.4.6 Diagnostic Criteria
- •18.5.1 Introduction
- •18.5.2 Nomenclature
- •18.5.3 Clinical Manifestations
- •18.5.4 Serological Issues
- •18.5.5 Pathology
- •18.5.6 Diagnostic Criteria
- •18.6 Conclusions
- •References
- •19.1 Introduction
- •19.2 Interstitial Nephritis in Primary Sjögren’s Syndrome
- •19.2.1 Historical Aspects
- •19.2.2 Clinical Features
- •19.2.3 Histology
- •19.2.4 Pathogenesis
- •19.2.5 Differential Diagnosis
- •19.2.6 Treatment
- •19.3 Glomerulonephritis in Primary Sjögren’s Syndrome
- •19.3.1 Historical Aspects
- •19.3.2 Clinical Features
- •19.3.3 Histology
- •19.3.4 Pathogenesis
- •19.3.5 Differential Diagnosis
- •19.3.6 Treatment
- •19.4 Painful Bladder Syndrome/Interstitial Cystitis and Primary Sjögren’s Syndrome
- •19.4.1 Historical Aspects
- •19.4.2 Clinical, Cytoscopic, and Histologic Features
- •19.4.3 Pathogenesis and Association with Sjögren’s Syndrome
- •19.4.4 Differential Diagnosis
- •19.4.5 Treatment
- •References
- •20.2 Cerebral Lesions
- •20.3 Differential Diagnosis with Multiple Sclerosis, Neuromyelitis Optica, and Antiphospholipid Syndrome
- •20.4 Cranial Nerve Involvement
- •20.5 Diagnostic Algorithm of SS Patient with CNS Lesions, Myelitis, Meningitis
- •References
- •21.3 Sensorimotor Demyelinating Polyneuropathy (CIDP)
- •21.4 Multiple Mononeuropathy or Mononeuritis Multiplex
- •21.5 Sensory Ataxic Neuronopathy
- •21.6 Small Fiber Painful Sensory Neuropathy
- •21.7 Restless Leg Syndrome
- •References
- •22.1 Introduction
- •22.2 Pathogenesis of Autonomic Dysfunction in pSS
- •22.3 Diagnostic Tests
- •22.4 Parasympathetic and Sympathetic Disorders
- •22.4.1 Secretomotor Disorder
- •22.4.2 Urinary Disorder
- •22.4.3 Gastrointestinal Disorder
- •22.4.4 Pupillomotor Disorder
- •22.4.5 Orthostatic Intolerance
- •22.4.6 Vasomotor Disorder
- •22.5 Diagnostic Algorithm of pSS Patient with Autonomic Dysfunction
- •22.6 Treatment
- •References
- •23.1 Introduction
- •23.5 Prolactin and Sjögren Syndrome
- •23.7 Perspectives of Hormonal Treatment on Sjögren Syndrome
- •23.8 Conclusions
- •References
- •24.1 Introduction
- •24.2 Gynecological Manifestations in Sjögren’s Syndrome
- •24.3.1 Epidemiology and Clinical Features of NLS and Congenital Heart Block (CHB)
- •24.3.2 Maternal and Fetal Outcomes in NLS
- •24.3.3 Diagnosis
- •24.3.4 Risk Factors
- •24.3.5 Pathogenesis of Congenital Heart Block
- •References
- •25.1 Introduction
- •25.2 Serum Proteins
- •25.2.1 Acute Phase Reactants
- •25.2.2 Gammaglobulins
- •25.2.2.1 Polyclonal Hypergammaglobulinemia
- •25.2.2.3 Circulating Monoclonal Immunoglobulins
- •25.3 Hematological Abnormalities
- •25.3.1 Normocytic Anemia
- •25.3.2 Autoimmune Hemolytic Anemia
- •25.3.3 Aplastic Anemia
- •25.3.4 Pure Red Cell Aplasia
- •25.3.5 Myelodysplasia
- •25.3.6 Pernicious Anemia
- •25.3.7 Leukopenia
- •25.3.8 Lymphopenia
- •25.3.9 Neutropenia
- •25.3.10 Eosinophilia
- •25.3.11 Thrombocytopenia
- •25.4 Conclusions
- •References
- •26.2 Questionnaires
- •26.3 Ocular Tests
- •26.3.1 Schirmer Test
- •26.3.2 Vital Dyes
- •26.3.3 Rose Bengal
- •26.3.4 Fluorescein
- •26.3.5 Lissamine Green
- •26.3.7 Tear Osmolarity
- •26.3.8 Tear Meniscus
- •26.3.9 Tear Proteins
- •26.3.10 Ferning Test
- •26.3.11 Ocular Cytology
- •26.4 Oral Tests
- •26.4.1 Wafer Test
- •26.4.2 Whole Saliva Flow Collection
- •26.4.3 Saxon Test
- •26.4.5 Impression Cytology
- •26.5 Conclusion
- •References
- •27.1 Salivary Scintigraphy
- •27.2 Sialography
- •27.3 Ultrasound
- •27.4 Tomography
- •27.5 Magnetic Resonance
- •27.6 Salivary Gland Biopsy
- •27.6.1 Labial Gland Biopsy
- •27.6.2 Daniels’ Technique
- •27.6.3 Punch Biopsy
- •27.6.4 Major Salivary Gland Biopsy
- •27.6.5 Lacrimal Gland Biopsy
- •27.6.6 Focus Score
- •27.7 Is There an Alternative to Labial Salivary Gland Biopsy?
- •References
- •28.1 Antinuclear Antibodies
- •28.3 Antibodies Against Nonnuclear Antigens
- •28.7 Antiphospholipid Antibodies
- •28.9 Anticentromere Antibodies
- •28.12 Rheumatoid Factor and Cryoglobulins
- •28.13 Complement
- •28.14 Conclusion
- •References
- •29.1 Introduction
- •29.2 Historical Overview and Sets of Criteria
- •29.3 Preliminary European Criteria
- •References
- •30.1 Introduction
- •30.2 Clinical and Serological Peculiarities of Sjögren’s Syndrome
- •30.3 Assessment of Disease Activity or Damage in Systemic Autoimmune Diseases
- •30.4 Methodological Procedures to Develop Disease Status Criteria
- •30.5 Development of Disease Status Indices for Sjögren’s Syndrome
- •30.5.1 The Italian Approach
- •30.5.2 The British Approach
- •30.5.3 The EULAR Initiative
- •References
- •31.1 Introduction
- •31.3 Other Generic QoL/HRQoL Measures
- •31.6 Predictors of QoL and HRQoL (WHOQoL) in PSS
- •31.7 Therapeutic Interventions
- •31.8 Conclusions and Summary
- •References
- •32.1 Introduction
- •32.2 SS Associated with Systemic Lupus Erythematosus (SLE)
- •32.3 SS Associated with Rheumatoid Arthritis (RA)
- •32.5 SS Associated with Other Systemic Autoimmune Diseases
- •32.5.1 Mixed Connective Tissue Disease
- •32.5.2 Systemic Vasculitis
- •32.5.3 Antiphospholipid Syndrome (APS)
- •32.5.4 Sarcoidosis
- •32.6.1 SS Associated with Autoimmune Thyroiditis
- •32.6.2 SS Associated with Autoimmune Liver Disease
- •32.6.3 Association of SS with Coeliac Disease
- •32.7 Conclusions
- •References
- •33.1 Introduction
- •33.2 Methodological Considerations
- •33.3 Primary Sjögren’s Syndrome and Lymphoma
- •33.3.1 Risk Levels
- •33.3.2 Lymphoma Subtypes
- •33.4 Prediction of Lymphoma
- •33.4.1 Can We Tell Who Will Develop Lymphoma and When This May Occur?
- •33.4.2 Established Risk Factors
- •33.4.3 Recently Proposed Newer Risk Factors
- •33.5 Pathogenetic Mechanisms
- •33.6 Medication and Risk of Lymphoma in SS
- •33.7 Associated Sjögren’s Syndrome and Lymphoma
- •33.8 Other Cancers in SS
- •33.9 Conclusion
- •References
- •34.1 Introduction
- •34.2 Mortality and Causes of Death in pSS
- •34.4 Conclusions
- •References
- •35.1 Introduction
- •35.2 General Considerations
- •35.3.1 Keratoconjunctivitis Sicca
- •35.3.2 Xerostomia
- •35.3.3 Systemic Dryness
- •35.3.4 Extraglandular Manifestations
- •35.4 Diagnosis
- •35.4.2 Diagnostic Methods
- •35.4.2.1 Keratoconjunctivitis Sicca
- •35.4.2.2 Xerostomia
- •35.4.2.3 Salivary Gland Biopsy
- •35.4.2.4 Immunological Tests
- •35.4.2.5 Other Laboratory Findings
- •35.5 Comorbidities and Occupational Disability
- •35.6 Treatment
- •35.6.1 Keratoconjunctivitis Sicca
- •35.6.2 Xerostomia
- •35.6.3 Management of Extraglandular Features
- •35.7 When to Refer to a Specialist
- •References
- •36.1 Background
- •36.2 General Approach to Dry Mouth
- •36.3 Additional Dental Needs of the SjS Patient
- •36.3.1 Background
- •36.4 Particular Oral Needs of the SjS Patient to Be Assessed by the Rheumatologist
- •36.5 Use of Secretagogues
- •36.5.1 Other Cholinergic Agonists
- •36.5.2 Additional Topical Treatments
- •36.5.3 Systemic Therapy
- •36.6 Oral Candidiasis
- •36.7 Treatment and Management of Cutaneous Manifestations
- •36.7.1 Treatment of Dry Skin in SjS Is Similar to Managing Xerosis in Other Conditions
- •36.7.2 Vaginal Dryness
- •36.7.3 Special Precautions at the Time of Surgery
- •References
- •37.1 Introduction
- •37.2 Marginal Zone (MZ) Lymphomas
- •37.2.1 Extranodal Marginal Zone Lymphomas of MALT Type
- •37.2.2 Therapeutic Approaches of MALT Lymphomas
- •37.2.4 Managing NMZL
- •37.3.1 Histology and General Considerations
- •37.3.2 Treatment of DLBCL
- •37.4 Conclusions
- •References
- •38.1 Introduction
- •38.2 Antimalarials
- •38.4 Glucocorticoids
- •38.5 Azathioprine
- •38.6 Cyclophosphamide
- •38.7 Methotrexate
- •38.8 Cyclosporine
- •38.9 Conclusion
- •References
- •39.3 Mycophenolic Acid
- •39.4 Mizoribine
- •39.5 Rebamipide
- •39.6 Diquafosol
- •39.7 Cladribine
- •39.8 Fingolimod
- •References
- •40.1.2.1 Serum BAFF in SS
- •40.1.3 BAFF Is Secreted by Resident Cells of Target Organs of Autoimmunity
- •40.2 Rituximab in SS
- •40.2.1 The Different Studies Assessing Rituximab in SS
- •40.2.2 Safety of Rituximab
- •40.2.3 Increase of BAFF After Rituximab Therapy
- •40.3.1 Epratuzumab
- •40.4 Conclusion
- •References
- •41.1 Introduction
- •41.2 Cytokine Targeted Therapies
- •41.2.2 Etanercept
- •41.2.3 Interferon Alpha
- •41.2.4 Emerging Anticytokine Therapies
- •41.3 T Cell Targeted Therapies
- •41.3.1 Efalizumab
- •41.3.2 Alefacept
- •41.3.3 Abatacept
- •41.4 Conclusion
- •References
- •42.1 Introduction
- •42.2 Progression and Disease Activity in SjS
- •42.2.1 Saliva
- •42.2.2 Serum
- •42.2.3 Labial or Parotid Tissue
- •42.3 Molecular Targets for Potential Therapeutic Interventions
- •42.3.1 Interferons
- •42.3.2 Cytokines
- •42.3.3 B Cell Activating Factors
- •42.3.4 B and T Cell Receptors
- •42.3.4.1 Rituximab
- •42.3.4.2 Epratuzumab
- •42.3.4.3 Abatacept
- •42.4 Gene Therapy
- •42.5 Stem Cell Therapy
- •42.6 Conclusion
- •References
- •Index
40 B-Cell-Targeted Therapies in Sjögren’s Syndrome |
581 |
shown to have higher serum concentrations of BAFF compared to those without those antibodies. These findings have been confirmed in other studies [18–20].
40.1.3 BAFF Is Secreted by Resident Cells of Target Organs of Autoimmunity
The first report by Groom et al. in 2002 showed the presence of BAFF within the lymphocytic salivary infiltrate that is characteristic of primary SS. Lavie et al. subsequently demonstrated that both the T-cells of the infiltrate and the epithelial cells could express BAFF [21]. Deridon et al. suggested that the B-cells of the infiltrate that are the target of BAFF and express the different receptors could also express the ligand, leading to an autocrine pathway way for BAFF secretion and activation of B-cells [22].
Several groups have demonstrated that salivary epithelial cells express and secrete BAFF, both in patients with SS and in healthy subjects [22, 23]. This expression is increased by stimulation with type 1 or type 2 interferon (IFN) [23]. Salivary epithelial cells from patients with SS seem to be more susceptible to the effects of type 1 INF.
SLE and SS share many characteristics, including the presence of an IFN signature in both peripheral blood mononuclear cells and target organs of the respective diseases (e.g., the salivary glands in SS and the kidneys in SLE) [24–26]. It has been shown that stimulation of salivary epithelial cells by poly(I:C) or infection of the cells by reovirus, a double-stranded RNA virus, induces BAFF secretion by salivary epithelial cells [27]. Thus, BAFF is a possible bridge between innate and adaptive immunity in SS.
40.1.4 Increase of BAFF Could Explain the Lack of Efficacy of TNF Inhibition in SS
Two randomized controlled trials, one with infliximab [28] and one with etanercept [29], demonstrated the lack of efficacy of TNF inhibition in SS. Primary SS patients in the etanercept group but not in the placebo group experienced an increase in type 1 IFN levels and BAFF secretion following etanercept administration, possibly explaining the failure of the anti-TNF strategy [30].
40.2Rituximab in SS
40.2.1The Different Studies Assessing Rituximab in SS
Rituximab, a monoclonal anti-CD20 antibody, is approved for the treatment of rheumatoid arthritis that is refractory to TNF inhibition. Targeting B-cells also appears to be a promising treatment strategy in SS. The use of rituximab to treat lymphomas complicating SS has been the subject of case reports [31–38] as well as three case series [39–41] (Table 40.1). In two of these case series [39, 41], the
Table 40.1 Open and controlled studies of rituximab in primary Sjögren’s syndrome
|
|
|
|
|
|
Efficacy for |
Efficacy for |
Decrease in |
|
|
Type of |
Number of |
Indications |
Efficacy for |
Efficacy for |
objective |
subjective |
RF and of |
Infusion |
Reference |
study |
patients |
of RTX |
systemic features |
fatigue |
dryness |
dryness |
IgG |
reactions |
|
|
|
|
|
|
|
|
|
|
Pijpe 2005 |
Open |
15 |
Lymphoma |
Yesa: 3/7 (43%) |
No |
No |
No |
Yes (RF) |
3 SSR, 2 IRR |
[39] |
|
|
(7/15) |
|
|
|
|
|
|
|
|
|
Early SS |
NM |
Yes |
Yes if residual |
Yes if residual |
No (IgG) |
|
|
|
|
(2.3 years) |
|
|
salivary |
salivary |
|
|
|
|
|
(8/15) |
|
|
flow |
flow |
|
|
Seror 2007 |
Open |
16 |
Lymphoma |
Yesa: 4/5 (80%) |
NM |
No: 2/16 (18%) |
No: 5/16 |
Yes (both) |
2 SSR, 2 IRR |
[40] |
|
|
(5/16) |
|
|
|
(36%) |
|
|
|
|
|
Systemic |
Yes: 9/11 (82%) |
|
|
|
|
|
|
|
|
features |
|
|
|
|
|
|
|
|
|
(9.5 years) |
|
|
|
|
|
|
|
|
|
(11/16) |
|
|
|
|
|
|
Devauchelle |
Open |
16 |
SS (13.3 years) |
1/2 (interstitial |
Yes |
No |
Yes |
No (except |
2 IRR |
2007 [41] |
|
|
|
pneumonitis) |
|
|
|
IgA RF) |
|
Dass 2008 |
RCT |
17 (8 on |
SS (7.7 years) |
NR |
Yes in the RTX |
No |
No |
Yes (RF) |
1 SSR, 2 IRR |
[42] |
|
RTX) |
Anti-SSA + |
|
group |
|
|
No (IgG) |
|
|
|
|
|
P<0.001 |
|
|
|
||
|
|
|
|
|
|
|
|
||
|
|
|
|
|
|
|
|
|
|
Meijer 2010 |
RCT |
30 (20 on |
Early SS |
Yes |
Yes |
Yes |
Yes |
Yes (both) |
1 SSR |
[43] |
|
RTX) |
(5.5 years) |
|
|
|
|
|
|
|
|
|
RF + Anti- |
P = 0.03 |
P=0.023 (RTX |
P = 0.038(RTX |
P<0.05 (RTX |
P < 0.05 |
|
|
|
|
SSA + resid- |
(RTX vs |
vs placebo) |
vs placebo) |
vs placebo) |
(RTX vs |
|
|
|
|
ual salivary |
placebo) |
|
|
|
placebo) |
|
|
|
|
flow |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
IRR infusion-related reaction, NR not relevant, NM not mentioned, RCT randomized controlled trial, SSR serum sickness-like reaction aEfficacy on lymphoma
582
Mariette .X
40 B-Cell-Targeted Therapies in Sjögren’s Syndrome |
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efficacy of rituximab appeared to be restricted to patients with early disease. The third open study focused on patients with extraglandular complications of SS, because B-cell hyperactivity is more pronounced in this category of patients [40]. Rituximab appeared to have a strong impact on the systemic features of SS in that study, e.g., the parotidomegaly, synovitis, and cryoglobulinemic vasculitis. However, patients experienced no improvement in either subjective assessments or objective measurements of their sicca symptoms.
The first randomized, controlled trial of rituximab in SS included only 17 patients without any systemic complications [42]. Fatigue, assessed by a visual analogic scale (VAS), was the primary end-point. Fatigue improved significantly in the rituximab group and not in the placebo group (50% improvement versus 20%, respectively).
Another randomized, controlled trial demonstrated efficacy of RTX on stimulated salivary flow, the primary end-point, as well as on systemic complications, symptoms of oral and ocular dryness, and fatigue [43]. A significant decrease in rheumatoid factor level was also observed. Two larger randomized trials are now under way, one in France and one in the UK.
40.2.2Safety of Rituximab
Serum sickness appears to be a common complication of rituximab in SS. Up to 15% of SS patients treated with rituximab present with a serum sickness-like disease 3–7 days after rituximab infusion (fever, arthralgia, and purpura). Cases of serum sickness have also been described in open studies of rituximab in lupus. The higher frequency of serum sickness disease in SS may be due to hypergammaglobulinemia, which is much more common in SS and SLE than in RA. This complication is benign in most cases but serves as a contraindication to further treatment with rituximab.
The risk of severe infections is a potential issue with rituximab, as with other biologic agents. In RA, the rate of severe infections has been reported to be approximately 2.3/100 patients-years in clinical trials [44] and approximately 5.0/100 patient-years in patients followed in registries [45]. In RA, low serum IgG level, which is rare in SS, is a risk factor of severe infections [45]. Some cases of progressive multifocal leukoencephalopathy (PML) have been described in patients with autoimmune diseases treated with rituximab, but not in any SS patient to date [46]. Assessments of the role of rituximab in causing PML is challenging because most patients reported to date have received intensive immunosuppression with other medications before receiving rituximab.
40.2.3Increase of BAFF After Rituximab Therapy
Serum BAFF levels increase after rituximab. This has been demonstrated in RA [47, 48], SLE, and SS [49, 50]. The increase has been attributed in part to the disappearance of B-cells in the peripheral blood and the consequent failure of BAFF to bind
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to its receptor. Two independent studies have also shown that a true homeostatic feedback mechanism exists, characterized by increased BAFF mRNA expression in monocytes following the administration of rituximab [48, 49]. In theory, the increase in BAFF after rituximab could favor the stimulation of new autoimmune B-cells. Another potential biologic target in SS, therefore, is BAFF itself, with inhibition of BAFF via a targeted monoclonal antibody or another strategy. The implications of depleting B-cells and inhibiting BAFF simultaneously remain unclear at the present time. However, targeted BAFF inhibition strategies are in advanced stages of testing in SLE (see below).
40.3Other B-Cell-Targeted Therapies
40.3.1Epratuzumab
Epratuzumab, an anti-CD22 monoclonal antibody, has been studied in an openlabel trial of 15 patients [51]. This anti-B-cell antibody leads to only partial B-cell depletion (50% in blood). In this open study, improvements of dryness, fatigue, and pain VAS were observed. Moreover, salivary flow appeared to improve in patients with early disease. A controlled trial is now necessary to confirm these data.
40.3.2BAFF-Targeted Therapy
BAFF is clearly implicated in pathogenesis of SLE and SS. The role of APRIL is less clear, but APRIL could play an important role in the local stimulation of B-cells within the synovium of RA patients. Thus, neutralizing BAFF or APRIL is an appealing approach to the treatment of human autoimmune disease. Two different drugs are currently under development (Fig. 40.1):
•Belimumab is a monoclonal anti-BAFF antibody which targets only BAFF.
•Atacicept is a TACI-Fc molecule that targets both BAFF and APRIL.
Two large phase 2 studies (400–500 patients each) of belimumab have been reported. In RA, the results are rather disappointing with around 30% ACR 20 response in all belimumab groups versus 15% in the placebo group [52]. This may be explained by the fact that, as indicated above, B-cell activation in RA may not be driven only by BAFF. In SLE, the results are more encouraging. Although the primary end-point (decrease of SLEDAI of more than three points) was not achieved in the whole study including 449 patients, the analysis restricted to the 70% of patients with antinuclear antibodies or anti ds-DNA antibodies showed a significant effect of belimumab for decreasing activity of the disease measured by SLEDAI and anti ds-DNA antibody level [53]. Thus, two phase 3 studies including each more