Introduction to Rheumatology

SECTION 1 Introduction to Rheumatology MONOARTICULAR POLYARTICULAR AUTOIMMUNITY CONTACT INFORMATION Mary Nakamura, MD (Email) OBJECTIVES Introduce basic concepts of rheumatologic disease Introduce types of arthritis and how clinical features help determine differential diagnosis Introduce goals of Rheumatology section of I3 KEY WORDS RHEUMATOID ARTHRITIS SYSTEMIC LUPUS ERYTHEMATOSUS OSTEOARTHRITIS GOUT VASCULITIS I. WHAT IS RHEUMATOLOGY? The term rheumatology originates from the Greek word rheuma, meaning that which flows as a river or stream, and the suffix -ology, meaning the study of. Rheumatic disorders were attributed to humors that flow (rheuma) through the body to settle in joints and cause arthritis. The specialty of rheumatology cares for patients with all types of arthritis and systemic autoimmune diseases. Rheumatic diseases are a diverse group of syndromes that most frequently include pain and inflammation in the joints and connective tissues. They are often referred to as collagen-vascular diseases because the tissues most frequently affected by the immune and inflammatory processes are those rich in collagen and connective tissues as well as blood vessels. Rheumatologic diseases are not new diseases. Evidence of arthritis associated with gout has been found 123

in Egyptian mummies. Arthritis and vasculitis has been well documented for centuries. On the other hand, Lyme disease may have existed for centuries but was only recognized to be a discrete tick-born disease due to a spirochete a little more than 25 years ago. Descriptions of arthritis can be found throughout human history, dating back to Hippocrates in 400 BC. While diseases such as gout, rheumatoid arthritis and osteoarthritis became well recognized and studied by the early 1900 s, it is only more recently that we began to better elucidate the inflammatory and immune-mediated processes that are the common unifying themes of these diseases. Rheumatic diseases are considered diseases of autoimmunity and advances in basic immunology have begun to elucidate mechanism of disease and have already led to novel therapeutics to target autoimmune responses. II. WHAT ARE AUTOIMMUNE DISEASES? Rheumatic diseases are considered autoimmune because as part of the disease normal tissues have become targets for immune mediated injury. These misdirected immune responses are referred to as autoimmunity. Misdirected immune responses can involve adaptive immunity, which can be demonstrated by the presence of autoantibodies or T lymphocytes reactive with host antigens or innate immunity, with inappropriate activation of a more nonspecific response such as production of IL-1 by the inflammasome. In addition to joints, many other organ systems and tissues can be affected. Although joint involvement is predominant in many of the rheumatic diseases, joints are not a major component in all rheumatic diseases. In some autoimmune processes an initiating stimulus is sometimes known, such as an infection or drug exposure, but more commonly the onset of autoimmune disease does not have an identifiable cause. An immune response to some self-antigens is frequently identifiable, and may be characteristic of a particular disease, but generally we have not found that the response to auto-antigens always plays a clear pathogenic role. We do believe that unchecked inflammatory or immune response that either specifically or nonspecifically target effector organs causes pathology in most systemic rheumatic diseases. 124

III. IMPORTANCE AND IMPACT OF RHEUMATOLOGIC DISEASES Whereas most autoimmune and rheumatologic diseases are rare, some are quite common. The prevalence of rheumatoid arthritis (RA) and osteoarthritis (OA) is approximately 1% and 5% in the adult population, respectively. In contrast, systemic lupus erythematosus (SLE) only affects about 1 in 5-10,000 individuals. Rheumatologic disease is the most common cause of disability in adult. As a consequence, these diseases present an enormous societal burden. In 1997, it was estimated that arthritis cost the US $86 billion. These enormous costs are not diminishing. Autoimmune diseases can strike any part of the body, and thus symptoms vary widely and diagnosis and treatment are often difficult. The broad spectrum of autoimmune diseases includes multiple sclerosis (MS) and the severe type 1 diabetes mellitus. Generally diseases such as MS and autoimmune thyroiditis which are organ specific are cared for by organ-specific specialties. Autoimmune disorders that are systemic and multiorgan and/or involve the musculoskeletal system are encompassed in rheumatology. PREVALENCE PER 100,000 IV. AUTOIMMUNITY IN RHEUMATIC DISEASES What are the antigens? Male Female Rheumatoid Arthritis 440 1,100 Ankylosing Spondylitis 197 73 Gout 980 230 SLE 7 32 Scleroderma 1 5 Osteoarthritis 3,470 5,870 All Musculoskeletal conditions 15,510 20,720 There is a vast array of antigens that are the targets of the autoimmune response. Autoantibodies are produced that react with a range from extracellular proteins, such as IgG (as in rheumatoid factor and type II collagen), cell surface molecules (such as cardiolipin), or intracellular proteins and nucleic acids (such as his- 125

tones and DNA). There are really no common features that explain why these components serve as good autoantigens. However, the same autoantibody response is often seen in the same clinical setting allowing these autoimmune responses to frequently be used for diagnostic or prognostic purposes. Why do individuals make autoimmune responses, i.e., why does tolerance fail? We really don t know. In some cases an offending organism may trigger a very specific immune response and via molecular mimicry, a cross-reaction may occur, perhaps causing some local damage and inflammation that allows for the initiation of an autoimmune response. Other factors can contribute to an individual s predisposition towards developing a particular disease. But, they do not ensure that disease will develop. For instance, in the case of genetics, if one monozygotic twin has SLE the likelihood that the other will (i.e., the concordance rate) is about 25-57%. Thus, while genetic predisposition is very important, non-genetic factors clearly play a role. Genome-wide association studies (GWAS) have recently identified a number of SNPs and missense mutations that are associated with rheumatologic diseases. For instance, a polymorphism in PTPN22, identified via GWAS, alters the ability of this tyrosine phosphatase to interact with other molecules in a critical signaling pathway required to activate T cells. This polymorphism has been associated with multiple autoimmune diseases including rheumatoid arthritis, lupus, type 1 diabetes, and others. 1) Genetic factors a) Major Histocompatibility Complex (MHC) alleles b) Complement deficiency (i.e., C2 and C4) c) Fc receptors polymorphisms d) Gender e) Altered signaling proteins (i.e., PTPN22) f) Many others 2) Environmental factors a) Infections can shape an immune response or initiate a cross-reactive response to self b) Drugs (i.e., procainamide and dilantin in drug-induced lupus) c) Toxins 126

d) UV-light (unprotected sun exposure can trigger a lupus flare) 3) Status of the immune system may make it more or less sensitive towards developing pathogenic autoimmune responses 4)Status of the target organ a) Visibility of the autoantigen b) Expression level of the autoantigen c) MHC molecule expression level d) Expression of costimulatory molecules e) Ongoing inflammatory pathology V. GOALS OF COURSE To introduce basic concepts of rheumatologic diseases and diagnosis in rheumatology. To discuss clinical presentation and treatment of a few major rheumatologic diseases. Rheumatologic diseases are diverse systemic diseases that are generally share the feature of pain and inflammation in the joints and connective tissue, due to inappropriately regulated inflammatory and immunemediated processes. It is not possible to discuss all rheumatologic diseases in the time allotted. Competancies: Students will be able to recognize the major rheumatologic diseases and the characteristic group of clinical manifestations, organ system involvement and pathogenic features that distinguish them from each other. The rheumatology section will introduce you to several of the more common rheumatic diseases, each with distinct features and pathogenesis. Diseases that will be covered in lectures include: Crystalline arthritis (gout and calcium pyrophos phate deposition disease) Osteoarthritis (OA) Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE) HLA-B27 associated Spondyloarthropathies Students will be able to describe the major distinguishing signs and symptoms of the rheumatologic diseases discussed. 127

Students will be able to describe that a monoarticular inflammatory arthritis needs to be evaluated for infection. We will discuss vasculitis in a case conference and an independent learning module will be used. Students will be able to describe that vasculitis is a group of systemic diseases that share the feature of end organ damage due to inflammation in blood vessel walls leading to ischemia and recognize that vasculitic syndromes are generally categorized by the size and type of vessel involved, the type of inflammation in the blood vessel wall, and the organs involved. Students will be able to describe that rheumatologic diseases are treated with anti-inflammatory and immunosuppressive drugs, some directed at specific cytokines or molecules, but others initiating broad suppression of the immune system. Students will be able to examine a clinical case of a patient with joint or autoimmune disease symptoms, identify the key signs and symptoms that should assist them in making a rheumatologic diagnosis, propose a diagnosis and explain how the features of the case support the diagnosis of a specific rheumatologic disease. (In particular for diseases discussed in class: RA, SLE, seronegative spondyloarthropathies, OA and crystalline arthritis.) VI. DIVERSITY OF RHEUMATIC DISEASES Rheumatic diseases are a very heterogeneous in their clinical manifestations and organ system involvement. However, each disease has a characteristic set of clinical manifestations, organ system involvement and pathogenic features that allow their classification. The presentation and manifestations of some of these diseases may differ from patient to patient, some features shared among patients, but others quite unique to a patient. Classification is important for prognostic information and treatment strategies and has provided a basis for research into the immunological mechanisms of disease. 128

VII. RHEUMATOLOGIC DISEASES ARE SYSTEMIC INFLAMMATORY DISEASES It is not surprising that rheumatologic diseases are systemic diseases since they have an underlying immune or inflammatory pathogenesis. They frequently involve many organ systems and the systems involved vary from individual to individual. Here are a few noteworthy examples: DISEASE Rheumatoid Arthritis Systemic Lupus Erythematosus (SLE) Lyme Disease ORGAN SYSTEM INVOLVEMENT Joints (arthritis) Vessels (vasculitis) Eyes (scleritis and episcleritis) Hematologic (anemia, thrombocytosis) Pulmonary (pleuritis, alveolitis, etc) Joints (arthritis) Skin (photosensitive rash) Serosa (pericardial and pleural effusions) Hematologic (anemia, thrombocytopenia) Kidneys (glomerulonephritis) Lungs (interstitial disease, alveolitis, etc) CNS (cognitive dysfunction, seizures) Joints (arthritis) Skin (Erythema chronicum migrans) Heart (carditis) CNS (meningo-encephalitis) VIII. INFLAMMATORY DISEASES Some diseases, such as gout, are most often characterized by activation of the innate immune system with the predominant pathology caused by infiltration of neutrophils. When inflammation is present, the secretion of proteases and lipid mediators from the lipoxygenase and cyclooxygenase pathways play key roles in the pathogenesis that leads to arthritis. Joint involvement predominates here. Gout most commonly involves the 1st metatarsal phalangeal (MTP) joint and results from an intense inflammatory response to uric acid crystals. Osteoarthritis is often termed a non-inflammatory arthritis. This is because osteoarthritis affected joints do not display the cardinal signs of significant inflammation such as warmth and redness. In Osteoarthritis synovial fluid accumulates, but is not accompanied by a significant cellular infiltrate of neutrophils or lymphocytes. In comparison with the inflammatory arthritis of gout or rheumatoid arthritis, osteoarthritis does seem to be non-inflammatory. Osteoarthritis can be primary or secondary (i.e., associated with injury, endo- 129

crine abnormalities, etc.) and is associated with varying degrees of inflammation. However, in many cases of osteoarthritis, inflammation may not be a dominant theme. OA is usually characterized by a loss in the normal function of cartilage and some bony proliferation. It can be associated with considerable disability. Primary OA typically involves the distal interphalangeal joints, and weight bearing joints such as knee, hip and lumbar spine. In comparison to the arthritis seen with gout or RA, OA is non inflammatory because there is very little cellular infiltrate into the synovium or synovial fluid, which are hallmarks of the inflammatory arthritis of gout or RA. However, the exact role of cytokines, and activation of immune cells in OA is not entirely clear, thus a more correct term may be that it is a distinct type of inflammation. Clearly any inflammation that does occur in osteoarthritis is quite distinct from the type of inflammation seen in the inflammatory types of arthritis. OA is often called degenerative arthritis because degeneration of cartilage and a vigorous healing response of bone locally (bone spur/proliferation) are salient features of OA. IX. AUTOIMMUNE DISEASES The response of the adaptive immune system, mediated by B and T cells, plays a key role in some rheumatologic diseases. In most cases, the initiating stimuli are not known. However, for reasons that are under investigation, the activation of the innate and adaptive immune responses results in a response to selfcomponents, an autoimmune response. These responses may be directed against organ specific antigens or to more broadly expressed antigens. Disease results from the combined effects of the specific adaptive immune response (antibodies or cell-mediated) as well as the inflammatory response of the innate immune system. Rheumatoid arthritis (RA) is a symmetrical polyarthritis that tends to involve the PIPs and MCPs of the hands. Joint inflammation is thought to be mediated mainly by T cells and macrophages. Other organ systems can be involved in RA but these extra-articular manifestations generally do not dominate the clinical picture. Systemic lupus erythematosus (SLE) can also involve joints, but also many other organ systems. The hallmark of this disease is the presence of autoantibod- 130

ies directed to nuclear components. Pathology is mediated by auto-antibodies, lymphocytes and components of the innate immune system. The spondyloarthropathies are a group of diseases that tend to involve the axial skeleton (spine and associated large joints). They are very often associated with the HLA-B27 molecule. T cells and macrophages play the predominant role in these diseases. Vasculitis involves inflammation of blood vessels. This group of diseases is usually classified by the size of the vessels involved. Arthritis Arthritis, which means inflammation of the joint(s), should be distinguished from arthralgia, joint pain. GALLERY 2.1 Features of normal joints Normal diarthrodial joint The Normal Joint: The key features of the normal joint are illustrated in Gallery 2.1. Much of the pathology that can effect of a joint originates in the synovium. The normal synovium is made up of various connective tissue elements including a thin epithelial cell layer, stromal cells, vasculature, and rare lymphocytes, mast cells and macrophages. It serves to provide lubricant and maintain a non-adherent surface by making synovial fluid. This fluid is a plasma filtrate containing high levels of hyalu- 131

ronate (which has the consistency of egg-whites) and is a source of nutrients for chondrocytes. In addition to joint pain, arthritis is characterized by all of the cardinal signs of inflammation including redness, swelling, increased warmth, and fluid accumulation (synovial effusion). In addition to pain, morning stiffness is a common complaint in settings of inflammatory arthritis. Rheumatoid arthritis (RA) is a good example of what can happen in various forms of inflammatory arthritis. In RA, inflammation begins in the synovium. It is characterized by an inflammatory cell infiltrate including T and B lymphocytes, activated macrophages, and plasma cells. The cellular response is associated with the production of multiple cytokines associated with a TH1 immune response, particularly TNF-α, IL-1, OPGL (RANK-ligand), IFN-γ, IL-6 and IL-17. These cytokines induce a variety of synovial membrane changes including recruitment and differentiation of a variety of immune and inflammatory cells, especially macrophages. In addition, epithelial cell proliferation, villous hyperplasia, and neovascularization result from this inflammatory response. Ultimately the synovial tissue becomes massively enlarged, thickened and redundant in structure and is called a pannus. At times it can resemble a secondary lymphoid tissue. The synovium attaches to the bone at a site where it is not protected by cartilage or periostium. As a consequence the bone is very vulnerable here. The inflammatory response can promote early bony destruction; this is largely driven by RANK-ligand which promotes osteoclast generation. The local destruction of bone by osteoclasts leads to what appears as bone erosions on X-rays. Ultimately, such erosions and the inflammatory response destroy the joint and affect supporting structures to cause deformity and/or disability. See Gallery 2.2. Clinical Features that Help Differentiate Different Types of Arthritis: Acute versus Chronic Arthritis: In considering a patient with a rheumatologic disease, especially one with arthritis, it is often useful to distinguish whether the arthritis is acute or chronic. This is helpful in coming to a diagnosis as well as in understanding the pathogenesis of the disease. 132

Acute arthritis is of rapid onset, hours to days. This is often the result of very rapid activation of the innate immune system with the involvement of neutrophils. This cell type produces leukotrienes, prostaglandins, reactive oxygen species and has secretory granules that are very destructive because of the proteases they contain. Diseases with characteristics of this presentation of acute arthritis are gout and septic arthritis due to bacterial infection. GALLERY 2.2 Mechamisms of joint and bone destruction Osteoclasts are the primary cell type that resorbs bone. Differentiation of osteoclasts from haematopoietic myeloid precursors is driven by cytokines. The essential cytokine mediators are RANKL (receptor activator of nuclear factor- B (RANK) ligand) and M-CSF (macrophage colonystimulating factor), which are expressed by synovial fibroblasts and activated T cells. Osteoclast differentiation is promoted by the actions of tumour-necrosis factor (TNF) and interleukin-1 (IL-1), as well as of IL-17, which stimulate production of RANKL by synovial fibroblasts. In contrast, IL-4 and IL-10, produced by TH2 cells, and granulocyte/m-csf (GM-CSF) and interferon-γ (IFN-γ), produced by TH1 cells, inhibit osteoclast differentiation. Chronic arthritis will have an onset of days to weeks. Symptoms are more moderate. Those with more inflammatory arthritis will have morning stiffness as a prominent symptom. Inflammation that results from the activation of the adaptive immune response, such as in RA, ankylosing spondylitis or SLE, are more typically associated with chronic arthritis. This is a T cell mediated disease with macrophage activation as prominent pathogenetic mechanism. TH1 and TH17 T cells and macrophage derived cytokine production plays a key role in this sort of inflammatory response that can lead to joint remodeling and destruction. 133

Pattern of Joint Involvement: The number, distribution and specific types of joints involved often provides a strong clue regarding the diagnosis. Monoarticular vs Polyarticular Mono: Gout, Infection, Reactive Poly: RA, SLE Joint distribution Wrists, MCPs: DIPs: MTP: RA, SLE Osteoarthritis, Psoriatic Gout Symmetrical vs Asymmetrical Symmetrical: RA, SLE Asymmetrical: Psoriatic, Reactive X. INTRODUCTION TO THERAPY IN RHEUMATOLOGY This is a very exciting time in rheumatology because many new therapeutics are being used and becoming available. These new therapeutics, in large measure, have been developed via advances in our understanding of the basic immune system and have more specific targets. As a consequence, there are fewer off-target effects. Hence, there is less toxicity. In general, the approach to treating the patient is staged and targets the type of immune or inflammatory response that may occur. Therapy is usually ramped up in potency but with attendant toxicity risk. However, a new emerging paradigm is early, more aggressive therapy to avoid more chronic disease and disability. Specific therapies will be covered later in the course. Suppress Pain and Inflammation: Aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Non selective Cyclooxygenase (COX) -2 Selective Steroids Suppress Inflammation and Immune Response: Less specific: Steroids 134

Methotrexate Azathioprine Mycophenylate mofetil Cyclophosphamide Cyclosporin FK506 More selective biologics: Tumor Necrosis Factor (TNF)-a inhibitors Monoclonal antibodies against TNF-α Soluble receptor - Ig fusion Monoclonal antibody against IL-6R Interleukin (IL)-1 receptor antagonist anti-b cell (CD20; i.e, Rituxan) therapy Inhibitors of costimulation (CTLA4-Ig; i.e. Abatacept) FIGURE 2.1 Drugs targeting inflammatory cytokines and T cells also block osteoclast formation. TNF blockers, Tocilizumab (blocks IL-6), and Anakinra (blocks IL-1), all block production of RANKL. Denosumab (anti-rankl) blocks RANKL directly. CTLA-4 on Tregs interacts with osteoclast precursors to block osteoclast differentiation and CTLA-4-Ig (Abatacept) functions similarly to block osteoclastogenesis. Abatacept also blocks T cell activation. 135