Tufts OpenCourseware
Author: Robert A. Kalish, M.D.

1. What is Rheumatology?

Rheumatologists are often faced with explaining what it is that encompasses their field. One way to think about rheumatic disorders is to break them down into several components:

1.1. Structural disorders of the musculoskeletal system

Structural disorders that are not a direct or immediate result of trauma or injury. These disorders are diverse and innate and are related to aging (osteoarthritis), wear and tear from normal use or overuse (bursitis, tendonitis, some forms of osteoarthritis). Certain crystals may deposit in the joint and cause abnormality via the inflammatory response they incite (gout, pseudogout).

1.2. Disorders of the immune system

These may affect the joints and musculoskeletal system predominantly (rheumatoid arthritis, juvenile rheumatoid/chronic arthritis, spondyloarthropathy) or multiple organ systems (lupus, scleroderma, and vasculitis). The joint tends to serve as a sponge that takes becomes “soaked” with the participants of the immune response when the immune response has gone awry and is sytemically activated in excess. Therefore most systemic autoimmune diseases are characterized by manifestations in the musculoskeletal system.

1.3. Chronic pain disorders

Fibromyalgia is a syndrome of chronic musculoskeletal pain and fatigue in which there is as of yet no structural or immunologic basis found and instead is thought to represent an altered pain response to non-noxious or mildly noxious stimuli. Given the prevalence and disability caused by fibromyalgia it is an important entity to learn about and may serve as a model for other chronic pain states.

2. Lecture topics

The lectures in this course will cover the following topics:

2.1. Chronic arthritis

Rheumatoid arthritis – this is the prototypic and most common systemic inflammatory arthritis.

2.2. Chronic arthritis

Spondyloarthropathy and Lyme arthritis – these represent other forms of inflammatory arthritis that are important to recognize clinically but also each give important clues as to the pathophysiology of immune mediated inflammatory arthritis. Lyme arthritis presents a model in which a known infectious agent may trigger a subsequent autoimmune response in the joint.

2.3. Osteoarthritis

The arthritis of aging has a lot more to it than that and as a major cause of morbidity and disability in the population is important to understand.

2.4. Nonarticular rheumatism

Many pathologic processes that affect the musculoskeletal system occur just outside the joint in tendons, ligaments and bursas. In addition a syndrome that features chronic pain in the musculoskeletal system but has no primary musculoskeletal pathology, fibromyalgia, will be discussed.

2.5. Pediatric rheumatic diseases

Though uncommon, rheumatic diseases affect children as well and are important to learn about.

2.6. Crystal arthritis

Human physiology is not perfect and precipitation and crystallization of both uric acid and calcium can occur in joints and cause significant joint pathology.

2.7. Systemic lupus erythematosus

This is the prototypic multisystem autoimmune disease.

2.8. Scleroderma

This disease, though in the lupus family is quite different in its pathophysiologic process featuring the 3 pronged processes of autoimmunity, vascular compromise and fibrosis.

2.9. Vasculitis

This diverse and confusing group has in common inflammation of the walls of blood vessels which leads to ischemia of the affected area fed by the abnormal vessel. These will be covered in a small group setting in a case based format.

3. Learning to contrast the different diseases

During the course it will be helpful in learning to contrast the different diseases to analyze for the following characteristics:

3.1. Anatomic structures involved

The different disorders of the musculoskeletal system have different target components. A few examples include:

  • Rheumatoid arthritis occurs primarily where there is synovial tissue
  • Spondyloarthropathies target an emerging organ called the “enthesis organ”
  • Osteoarthritis is a result of pathologic processes of the cartilage
  • Lupus focuses its damage at the tissue level where the blood vessels becomes smallest and feeds the tissues and organs of the body
  • Scleroderma is multifaceted with vascular, fibrotic and autoimmune facets
  • Vasculitis targets blood vessel walls

3.2. Genetic influences

The role of the immune system is prominent in the autoimmune musculoskeletal diseases and the associations of diseases with the MHC (major histocompatibility complex) class I (e.g. – HLA-B27 in the spondyloarthropathies) and class II (e.g. – association of severity of rheumatoid arthritis with certain DR haplotypes) will be emphasized and explored.

3.3. Mechanisms of immune dysfunction

Though much remains poorly understood, research continues to elucidate which components of the immune system are central in producing the pathology of the various autoimmune diseases. Examples that will be covered include:

  • Lupus – T cells, B cells and autoantibodies
  • Rheumatoid arthritis – the role of cytokines in the disease process
  • Scleroderma – the importance of the endothelial cell’s interaction with the immune system in the vascular lesion

3.4. Interaction of the immune system with the environment

In reality this probably applies to all rheumatic disorders to some degree. This course will highlight the diseases in which this interaction has been explored in greater depth. For example only a minority of patients with Lyme arthritis continue to have joint inflammation after the causative organism Borrelia burgdorferi has been eradicated – the research looking into the possible mechanism of this provides a fascinating insight into the delicate balance the immune system has to attain in fighting off foreign invaders of our bodies and not causing harm to self while this is being accomplished.

3.5. Application to the care of patients with musculoskeletal diseases

Though the focus of this course is the pathophysiology of musculoskeletal disorders it would be a shame not to tie in to real clinical applications such as learning the clinical manifestations of the diseases that you will be seeing in the upcoming years and the treatments available, many of which are best understood in the context of appreciating the pathologic processes involved. To bring this aspect to life some of the lectures will feature interviews with patients who have the diseases. Sometimes the patients will stay for the lectures themselves.

4. Summary point

The diseases you will learn about in this course are grouped together because they indirectly or directly affect the joints (hence the term “rheumatic”), but otherwise they are very diverse in clinical presentation, morbidity and treatment. The combination of this fact, the different mechanisms that induce disease in each disorder, and the unknown etiology of many of the rheumatic diseases make them difficult to understand and conceptualize, even for experienced internists.

5. Classification of joints

Joints are comprised of a potential space between two bony surfaces, and different types of joints are characterized by anatomical differences in structure, depending on the function the particular joint serves.

5.1. Synarthroidal joints (synarthroses)

Synarthroidal joints (synarthroses) are found mainly in the skull. These joints join the cranial plates in the early phases of life, and allow for growth of the brain without significant motion. These joints cease to function after the skull grows, resulting in suture lines in the skull.

5.2. Amphiarthrodial joints (amphiarthroses)

Amphiarthrodial joints (amphiarthroses), also called fibrocartilagenous joints, feature two bones with a piece of flexible fibrocartilage between them that allow for a small amount of motion but provide a strong resistance to more than that. The costosternal joints that join the ribs to the sternum, the symphysis pubis, the acromioclavicular joint, and part of the sacroiliac joint are examples.

5.3. Diarthrodial joint

The diarthrodial joint, also called synovial joint, is the most common, most familiar, and most complex joint and provides the most motion. It features two bone ends covered by hyaline cartilage that slide against or around each other pulled by muscles, stabilized by ligaments and lined by synovial tissue.

6. Diarthrodial joint

The majority of diseases discussed in this course primarily affect the diarthrodial joint, though the spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis, reactive arthritis or Reiter’s syndrome, and inflammatory bowel disease associated arthritis) commonly affect the sacroiliac joint, and other fibrocartilaginous joints.

6.1. Structure of the diarthrodial joint

The glenohumeral joint, depicted above, is a typical diarthrodial joint. These joints are movable, and the moving bony parts are covered by hyaline (articular) cartilage. A thin layer of synovium lines the space or cavity, except where there is cartilage. Ligaments like the capsular ligament featured above and other capsular structures reinforce the joint. Articular cartilage, designated by the arrow above, measures less than 5mm in thickness and is white and glistening at young age, but turns yellow in elderly individuals.

Articular cartilage is composed of chondrocytes and the extracellular matrix. The latter consists of a type II collagen meshwork filled by hydrated proteoglycans under pressure. Small quantities of type IX and type XI collagens are also present. Since hyaline cartilage is avascular, nutrients that originate in the synovial membrane must traverse the joint cavity and diffuse through the extracellular matrix before reaching the chondrocytes. Cartilage is also aneural.

As the above diagram shows, the synovial membrane lines the inner surface of diarthrodial joints (but not the articular cartilage). Synovial tissue also lines bursae and some tendon sheaths. The synovium is made up of a thin matrix layer consisting of abundant microfibrils and proteoglycans. Embedded in this ground substance are abundant capillaries, lymphatics, nerve endings and synovial cells. Unlike many linings of the body such as the pleura and the gastrointestinal lining, no basement membrane separates the synovial cells from the underlying connective tissue. Electron microscopy of the synovial cells reveals fibroblast like cells (type B cells), macrophage like (type A cells) and a variable number of intermediate cells.

The joint capsule, which is strengthened by cord-like ligaments of high tensile strength, is composed almost exclusively of densely packed type I collagen bundles separated by thin sheets of fibrillar type III collagen. Free nerve terminals and mechanoreceptors are abundant in these structures. All of these structures work together to provide a highly functional unit that helps to provide range of motion with structural integrity and stability.

6.2. Physiology of the diarthrodial joint

6.2.1. Synovial transport

Because articular cartilage is avascular, its health depends upon a number of factors within the synovial joint. The synovium, with a rich capillary network, supplies the cartilage with its necessary nutrients. The path these nutrients take is capillary diffusion through fenestrations in the capillary wall synovial interstitium synovial fluid hyaline cartilage.

The fenestrations in the capillaries allow for the rapid exchange of water and small sized solutes. Immune and inflammatory mediators also access the interstitium through these fenestrations. All molecules, large and small, must then traverse the synovial interstitium. The interstitial barrier is most important in the overall transynovial exchange of small molecules. For most small compounds synovial permeability is inversely related to molecular size suggesting a simple diffusion process. However this is not true for glucose. In diffusion experiments, glucose enters the joint space more rapidly than expected, implying the presence of a still unidentified transport system. The system is unidirectional since it does not affect the return of glucose to the plasma. The time lag is proportional to the molecular weight of the substance. Proteins entering the joint space also do so at rates inversely proportional to their molecular size and in general larger proteins are blocked from entering the joint by the capillary basement membrane first and then by the hyaluronans and joint proteoglycans. In contrast, proteins of various dimensions leave the joint at essentially the same rate by the bulk flow of the lymphatic system.

6.2.2. Synovial fluid

Synovial fluid is a transudate of plasma. It also contains hyaluronans, and other high molecular weight molecules. The hylauronan is made by type B synovial cells (fibroblasts) in the synovium. Normal synovial fluid is pale yellow, and has a pH of about 7.44. It is clear, and is very viscous due to the presence of polymerized hyaluronic acid. Its protein content is low, but small physiologic solutes such as glucose are in full equilibration with plasma. The cellular content of normal synovial fluid is low, usually less than 200 cells/mm3, and over 80% are mononuclear cells.

6.2.3. Joint lubrication

Joint lubrication is vital for normal function of the joint. Boundary layer lubrication (when a lubricant binds to the surface of the articular cartilage) accounts for some of the low friction characteristics of normal joints. Lubricin, a small glycoprotein, binds to articular cartilage and provides this boundry. In addition lubricant helps to retain a protective layer of water molecules which provides a second form of lubrication known as hydrodynamic lubrication. Contrary to popular belief hylauronic acid does not lubricate the movement of cartilage on cartilage but does promote the movement of synovium on cartilage and is what makes synovial fluid viscous.

6.2.4. Intrasynovial pressure

In the normal state, joints are collapsed as a result of subatmospheric pressure within the joints. This subatmospheric pressure is probably due to Starling forces and pumping by the lymphatic system. Normal joints are compliant but in diseased joints like rheumatoid arthritis, the intrarticular pressure rises much more quickly for a specific volume of synovial fluid due to the tremendous increase in the volume and stiffness of the inflamed synovium:

Intrasynovial Pressure
Intrasynovial Pressure

This simple diagram shows how in a diseased joint (top curve), the intrarticular pressure is higher than in a normal joint (bottom curve). Thickening and fibrosis of the synovium and capsule lead to low compliance.

7. The diseased joint

Joints may become diseased in a variety of ways. One way to characterize joint problems is to divide the causes into those with a mechanical vs. inflammatory etiology. For example, a torn meniscus can cause knee swelling and joint instability—an example of a mechanical cause of knee pain. Rheumatoid arthritis and Lyme arthritis, characterized by a traumatic knee swelling and activation of elements of the immune response in the joint, are examples of inflammatory joint diseases. However, this division does not always follow intuition since for example the acutely swollen knee seen in ligamentous tears can be warm due to the presence of blood and fluid in the synovium and joint space, and has a physical examination suggestive of an inflammatory process. These conflicting categorizations may help to explain why grouping of the rheumatic diseases is sometimes confusing.

Joint diseases are also divided into inflammatory vs. noninflammatory based upon the synovial fluid white count. The distinction however is not hard and fast, since a disease like lupus, which is considered a systemic inflammatory disease, is characterized by low synovial fluid white counts. In lupus, though the physical examination of the joints suggests inflammation (warmth, swelling, and tenderness), the synovial fluid white counts are in the noninflammatory ranges.

The history of the complaint, combined with recognizing the pattern of joint involvement, and diagnostic tests like synovial fluid analysis, serological studies (blood tests), and radiographs all help to establish the diagnosis.

7.1. Clinical findings in an acutely inflamed joint

The classic triad of pain, warmth, redness, and swelling describes the acutely inflamed joint. Acute arthritis can be difficult to distinguish from other causes of inflammation in the area of the affected joint: cellulitis (inflammation in the skin and subcutaneous tissue), thrombophlebitis (inflammation within the deep veins), tenosynovitis (inflammation of the tenosynovium, an example of which is found around the posterior tibialis tendon), or bursitis (inflammation of the bursa, like the subacromial bursa) can be confused with acute arthritis. Acutely inflamed joints are kept in a fixed position (i.e. in the knee, 40 degrees flexion, in the wrist, neutral position) which is often called the "position of comfort". Attempts to further flex or extend the joint are met by severe pain.

7.1.1. Position of minimal intrasynovial pressure (Eyring and Murray, 1964)

Degrees of Flexion
Wrist 0
Elbow 40
Shoulder 0 (40 abduction; 0 rotation)
Hip 40 (15 abduction, 15 external rotation)
Knee 40
Ankle 15

When the normal joint is brought through range of motion, the intrasynovial pressure usually does not rise but when synovitis exists, the relationship between motion and position changes and the intrarticular pressure rises. For each joint, the position of comfort defines the degree of flexion in which the intrasynovial pressure is least. For example, in the swollen knee, the intrarticular pressure is least when the knee is partially flexed at 40 degrees, but increases if the knee is extended or flexed further:

Degrees of Flexion
Degrees of Flexion

7.2. Physiology of the acutely inflamed joint

In acute arthritis, the synovial membrane is inflamed, and synovial fluid accumulates. The inflamed synovium shows vasodilatation, edema, and neutrophilic infiltration. Hyaluronic acid depolymerization renders the synovial fluid less viscous. Thus, instead of a normal mean synovial fluid viscosity (relative to water) of 200, in septic arthritis and rheumatoid arthritis viscosity is reduced to an average of 15. Reactive oxygen species released by synovial fluid PMNs are largely responsible for the hyaluronic acid depolymerization. Synovial fluid accumulation results in high intraarticular pressures. The pressure rise may be sufficient to produce synovial ischemia, leading to further pain. Because of the loss of the adhesive property of the fluid and the mass effect of the effusion, the stability of the joint becomes more dependent on the integrity of ligaments and capsule. Swollen joints may feel weak, and occasionally unstable.

7.3. Transfer of solutes in diseased joints

In synovitis, the permeability to proteins is increased but the permeability to smaller molecules is paradoxically decreased. Thus, the synovial fluid protein levels are elevated and glucose levels are often low, particularly in septic arthritis. The reduced glucose levels reflect decreased supply (failure of the transport mechanism) and increased consumption by the inflamed synovium. Two factors explain the increased glucose consumption; one is the reduced effective circulation leading to hypoxia and increased use of the glycolytic pathway and the other is the increased cellular mass. Bacterial consumption of glucose plays a marginal role in the reduction of synovial fluid glucose levels seen in bacterial arthritis. Intrarticular acidosis is caused by excessive lactic acid production and carbonic acid generated by the oxidative metabolism.

7.4. Implications for the patient

Acute synovitis can permanently damage the joint if it is not managed properly. Untreated bacterial arthritis can result in the rapid loss of cartilage. Delaying treatment for just a few days can be deleterious to the preexisting normal joint. Crystal-induced acute arthritis (gout, pseudogout) is self-limited and consequently the risk of joint destruction is low. Nevertheless, degenerative joint disease may result from the cumulative effects of repeated attacks of crystal arthritis, along with the erosive effects of crystal-induced granulomas. Rheumatoid arthritis and other chronic inflammatory arthropathies also lead to joint damage. In contrast, joint damage in systemic lupus erythematosus (SLE) is rare. Neutrophils predominate in the synovial fluids of inflammatory joint diseases, but not in the white cells seen in the joints of patients with lupus (systemic lupus erythematosus).

Several neutrophil-related mechanisms are involved in the joint damage. One is the release of reactive oxygen species (hydrogen peroxide, superoxide radicals) during the metabolic burst of oxidation. Reactive oxygen species depolymerize hyaluronic acid, break the cartilage matrix molecules, destroy (by oxidation) proteinase inhibitors, and activate latent neutrophil collagenase. In addition, various proteolytic enzymes are released from specific and azurophil granules in neutrophils: collagenase degrades type I, II and III collagen; gelatinase acts on type V and XI collagen; and the serine proteinases, elastase and cathepsin G degrade the proteoglycan matrix. Finally, neutrophils stimulate arachadonic acid metabolism and thereby generate prostaglandins that contribute to bone resorption. Arachadonic acid metabolism also leads to the formation of leukotrienes that attract further PMNs to the lesion. (This is one reason why nonsteroidal antinflammatory drugs or NSAIDS are useful in treating rheumatic diseases). In rheumatoid arthritis, bone erosion results from the coordinated secretion of stromelysin and collagenase by dendritic cells and fibroblasts in the rheumatoid pannus. Cytokines are also important in the pathogenesis of bone erosion seen in rheumatoid arthritis.

7.5. Diagnosis and treatment

The treatment of acute arthritis depends upon an understanding of the cause of the arthritis and underlying pathogenesis. Thus, the cause of the process must be addressed while measures are taken to decrease pain and prevent joint damage. One of the first diagnostic steps in patients with swollen joints, aside from the history and physical examination of the patient, is diagnostic synovial fluid aspiration. In synovial fluid analysis, the fluid is examined for cellular content, crystals, and bacteria. Occasionally, synovial fluid glucose level is measured; it tends to be low in bacterial arthritis and rheumatoid arthritis. In bacterial arthritis, the synovial fluid white cell count is very high, and may approach 100,000 cells/mm3. Synovial fluid white counts above 2,000 cells/mm3 are generally referred to as inflammatory joint fluids and are found in the inflammatory arthritides (e.g. - crystal arthritis, rheumatoid arthritis, and Lyme disease), while those fluids with white counts less than 2,000 cells/mm3 are noninflammatory and found in osteoarthritis and many mechanical causes of joint inflammation.

Another component of synovial fluid analysis is polarizing microscopy, used to detect crystals. Gout and pseudogout, examples of acute inflammatory arthritis (see Dr. Roubenoff’s lecture) are diagnosed by visualization of intracellular monosodium urate and calcium pyrophosphate crystals, respectively. Culture of synovial fluid is critical in the diagnosis of bacterial arthritis, as is the gram stain. (Measuring levels of cytokines in diseased synovial fluid is not clinically useful at this time.) In summary, synovial fluid analysis is a valuable diagnostic tool and should always be considered in the assessment of the patient with a newly swollen joint.

The following table summarizes the characteristic features of synovial fluids seen in specific disease states:

Arthritis Type White Cell Count/mm3 Crystal Analysis Glucose Culture/Gram Stain
Septic Arthritis >100,000 none low positive/positive
Inflammatory Arthritis
R.A. >2000 none low none
Gout >2000 negatively birifringent normal none
Pseudogout >2000 positively birifringent normal none
Lyme >2000 none normal none*
Lupus <5000 none normal none
Osteoarthritis <2000 none normal none
* routine bacteriologic techniques cannot easily detect Borrelia Burgdoferi

Acutely inflamed joints are initially immobilized (placed in a splint) to decrease pain, since flexion or extension can raise the intrarticular pressure and cause ischemic pain. Passive range of motion once or twice daily is instituted early to minimize muscle atrophy. Regional muscle atrophy develops rapidly when joints are acutely inflamed; in septic arthritis of the knee profound atrophy of the quadriceps, affecting in particular the vastus medialis, can be expected in merely one week. Therefore, isometric-strengthening exercises should be initiated as soon as the patient can tolerate movement of the joint without pain.

Effective drainage of the acutely infected joint is critical in ameliorating the destructive effects of inflamed joint fluid. Aspiration and drainage reduces the discomfort that swelling produces, the reflexive inhibition of regional muscles, synovial ischemia, the distension of the capsular apparatus surrounding the joint, and the degradation of cartilage and capsular structures by neutrophilic enzymes. In addition, serial synovial fluid samples can be analyzed to assess the response to therapy, and if the synovial fluid is becoming sterile. Some joints can be aspirated easily at the bedside but many, particularly deep joints including the hip and shoulder, cannot be adequately drained by repeated needle aspiration and often require surgical lavage with an arthroscopic or by open drainage.

In sum, the proper treatment of the acutely inflamed joint involves diagnostic aspiration, immobilization, initiation of therapy, and rehabilitation. The infected joint may require surgical drainage.