Preface

Connective tissue diseases (CTDs) constitute a heterogenous group of systemic autoimmune disorders and related conditions, characterized by rheumatic manifestations, production of myriad autoantibodies, and varied immune-mediated organ injury. Included in this category are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma (systemic sclerosis; SSc), polymyositis/ dermatomyositis (PM/DM), systemic vasculitides, and Sjögren's syndrome (SS), among others. During the past few decades, a great paradigm shift has occurred in the realm of therapeutics due to advances in our understanding of disease etiopathology. Robust emerging evidence on the precise role of the innate and adaptive immune systems and their contributions to initiation and development of CTDs has facilitated our understanding of disease, generating great interest in immunotherapy including numerous biologics. To achieve the best outcomes for patients, timely and accurate evaluation has become fundamental and, as such, advanced diagnostic and assessment modalities have also been developed, and have had a revolutionary impact in precise characterization of the disease conditions in CTDs.

*Connective Tissue Disease: Current State of the Art* consists of five chapters that combine systematic reviews, investigations and original clinical studies; comprehensive rheumatologic perspectives on RA, lupus and the other arthritides such as spondyloarthritis; new concepts of diagnostic modalities; and clinical implications of physical therapy. In Chapter 1, which serves as an introductory chapter and which has original material, we start with a comprehensive overview of the recent and revolutionary paradigm shift in RA, the most common of the CTDs, emphasizing the urgent need for diagnostic precision. This leads us to the introduction of our proposed "diagnostic criteria for early RA with MRI findings." Chapter 2 discusses lupus, the most typical of the systemic autoimmune disease in its ability to cause widespread inflammation and tissue damage in affected organs including skin, joints, brain, lungs, kidneys, and blood vessels. The authors provide intriguing dermatologic perspectives based on their studies with dermoscopy and histopathology. Chapter 3 elegantly demonstrates recent advances in nail fold capillaroscopy, a modality that is extremely important today in the evaluation of patients with Raynaud's phenomenon and systemic sclerosis (SSc) spectrum diseases. Considering that vasculature changes by functional and structural alterations of the microcirculation play a central role in the pathogenesis of CTDs, this methodology gives new impetus for improvement of precision evaluation of disease in daily practice. Chapter 4 covers the disease concept of spondyloarthritis (SpA) in which several subtypes can be distinguished, including ankylosing spondylitis (AS), psoriatic arthritis (PsA), SpA related to inflammatory bowel disease (IBD-SpA), reactive arthritis (ReA), and undifferentiated SpA (uSpA). Chapter 5 appraises the increasing importance of physical activity and exercise training in the clinical course of CTDs, explaining the benefits of exercise on physical limitations and fatigue in these diseases, with both short- and long-term effectiveness.

Written by expert clinical and research scientists who are directly involved in patient care and CTD research, this book covers a broad spectrum of interests and provide a deep understanding of this category of diseases for rheumatologists, physician

scientists, researchers, and students. I would like to extend my heartfelt appreciation to all the authors for their time and effort in providing their best, and Ms. Sara Debeuc at IntechOpen for her diligent editorial assistance. Additionally, I am grateful to Hideharu Sugimoto, MD, my old colleague, a radiology expert at Jichi Medical University School of Medicine, for fruitful long-term collaborations and discussions. Finally, I would like to convey special thanks to Professor Gautam A. Deshpande, MD, at the Department of General Medicine, Juntendo University, for his sapient advice and vital support throughout the process of compilation. His encouragement made it possible to achieve the goal.

**Akira Takeda, MD, PhD**

**Chapter 1**

**Abstract**

Growing Need for Diagnostic

for Early Diagnosis

diagnostic needs in the early treatment of RA.

**1. Introduction**

*Akira Takeda and Hideharu Sugimoto*

Precision in Rheumatoid Arthritis:

The recent and revolutionary paradigm shift involving novel therapeutics for the treatment of rheumatoid arthritis (RA) has called for changes in the early diagnosis of RA. Physicians now need to diagnose RA earlier, and with greater accuracy, in order to initiate effective definitive treatment as early as possible. However, due to the complexity and diverseness of RA, we still do not have comprehensive diagnostic criteria for RA readily available. To find a solution to this challenge, we aimed to develop practically useful criteria which integrate gadolinium (Gd) contrast-

enhanced magnetic resonance imaging (MRI) findings with clinical manifestations of the disease. These diagnostic criteria we propose, the "diagnostic criteria for early RA with MRI findings," are composed of two domains. The first domain consists of clinical findings suggestive of RA, which include both entry criteria—i.e., polyarthralgia of hands (joint pain of three or more joint areas confirmed by a physician), and exclusion criteria—i.e., exclusion of other rheumatic conditions including systemic lupus erythematosus (SLE), dermatomyositis and polymyositis (PM/DM), mixed connective tissue disease (MCTD), primary Sjögren's syndrome (SS), and Behçet's disease (BD). The second domain constitutes MRI criteria, which represent Gd-enhanced MRI findings indicating bilateral synovial enhancement seen in any joints of the proximal interphalangeal (PIP), metacarpophalangeal (MCP), or wrist joints. RA is defined by fulfilling all conditions of both domains. Our prospective study demonstrated that these criteria for the diagnosis of early RA, incorporating MRI findings with physical manifestations, can successfully distinguish patients with RA from those with other mimicking conditions, showing a sensitivity of 96%, specificity of 86%, and accuracy of 92%. When a case does not meet the criteria, RA can be ruled out with a high negative predictive value of 95%. We believe our "diagnostic criteria for early RA with MRI findings" can greatly help to solve unmet

**Keywords:** rheumatoid arthritis (RA), early RA, magnetic resonance imaging

Rheumatoid arthritis (RA), an autoimmune systemic inflammatory disease marked by progressive joint destruction, disability, and mortality, is the most

(MRI), gadolinium (Gd) contrast-enhanced MRI, diagnostic criteria

Proposal of MR Imaging Criteria

Division of Clinical Immunology and Rheumatology, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi, Japan

## **Chapter 1**
