Introduction to Rheumatic Diseases

Rheumatic diseases manifest as painful conditions typically caused by inflammation, swelling, and pain in the joints or muscles. Because pain, swelling, and decline in functional status are the presenting symptoms, patients with rheumatic diseases can make up a large percentage of a physiatry practice ( Table 31-1 ). There have been a growing number of people with rheumatic diseases who also largely contribute to the population of the permanently disabled. This has commanded the evolution and refinement of the treatment of these diseases. Thus, it is important to keep this chapter current and informative. Physiatrists can be the primary physicians for diagnosing and coordinating treatment for most of these diseases. To diagnose and treat these disorders, one must have an understanding of the joints and their components, as well as the nomenclature involved.

Structure and Components of Joints

All joints can be affected by rheumatic diseases. Joints are classified based on structure and function. Structure classification is based on the material that binds the bones together and the presence or absence of a joint cavity. Functional classification is based on the amount of movement allowed. There are three major types of joints in the body: fibrous joints (synarthroses), cartilaginous joints (amphiarthroses), and synovial joints (diarthroses). Fibrous joints (synarthroses) are immovable and do not have a joint cavity. An example would be the sutures of the cranium. For the purposes of this chapter as it relates to physiatry, the focus will be on cartilaginous joints and synovial joints.

The cartilaginous joints are distinguished by the connection between bones being entirely made of cartilage (fibrocartilage or hyaline). They are characterized by the amount of movement allowed across the joint. It is significantly less mobile than a synovial joint. It does not have a joint cavity. As a rule, amphiarthroses usually occur in the midline of the body. There are two types, synchondroses and symphyses. The manubrium and sternum are examples of synchondroses, whereas intervertebral disks and pubic symphysis are classified as symphyses.

The synovial joint (diarthrosis) is characterized by its joint mobility. These joints are able to move freely in multiple planes. It consists of two bony surfaces that articulate with one another. It is encompassed by a fibrous capsule with a synovial lining that contains fluid. The extracellular matrix consists of water and proteoglycans (glycosaminoglycan and hyaluronic acid). The viscoelastic properties of the synovial fluid and its inherent function as a lubricant and shock absorber are largely attributed to hyaluronic acid. The fibrous capsule has a rich network of substance P (neurotransmitter for pain) with nociceptive nerve fibers that can potentially generate pain. The limb joints are typically synovial joints (hip, knee, shoulder).

While inflammation ensues, fluid and polymorphonuclear leukocytes infiltrate the joint space. Vasodilation and venous congestion all contribute to pain-provoking capsular distention and neuronal sensitization of substance P nerve fibers. It is important to understand this cascade when educating patients on why they have joint pain and why treatment is aimed at limiting the damage from this cascade. If left untreated, the inflammatory cascade can destroy the integrity of a joint and permanently impair its function. This can lead to chronic pain and disability.

Kinematics plays an important role in the development and degradation of articular cartilage. Although joints with articular surfaces need a certain amount of load to maintain its integrity, excessive loading can lead to degradation of the joint. Altered biomechanical values between two articular surfaces also influence disease formation in joints. Normal healthy cartilage responds positively to loading by increasing regional thickness. Diseased or injured cartilage degenerates in response to load and thus decreases regional thickness. Furthermore, disruption of normal gait mechanics whether from disease, acute injury, weight gain, or improper footwear shifts loading patterns during weight-bearing activity to cartilaginous regions not well adapted for that load. Loading nonadapted areas can lead to cartilage fibrillation (softening) and degeneration.

Although not a part of the synovial joint but frequently associated with them, bursae, tendon sheaths, and entheses are important to acknowledge during the physical examination and diagnostic stages of rheumatic diseases. They act to prevent friction on adjacent structures. Bursae are flattened fibrous sacs lined with a synovial membrane and contain a thin film of synovial fluid. They are common in sites where ligaments, muscles, skin, or tendons overlie and rub against bone. Tendon sheaths are elongated bursae that wrap around a tendon that is subject to friction. Entheses are the insertion sites of tendons to bones or ligaments to bones. They are functionally integrated with the synovial joint and can be involved in the rheumatic disease processes. The relationship of the surrounding soft tissue structures will be crucial for understanding the microanatomic basis for joint disease in seronegative spondyloarthropathies and other rheumatic diseases, such as osteoarthritis (OA).

Osteoarthritis

OA is one of the most common rheumatic diseases. OA has grown to affect 27 million people in the United States. It is the leading cause of musculoskeletal pain and disability. It is predicted that with the increasing rates of obesity and the increase in the aging population, there will be an epidemic of OA in the next two decades. It is more important now than ever to have a sound knowledge base for treating and preventing this disease.

OA is classified by its failure of the structure and function of synovial joints. It is characterized by its degradation of articular cartilage, subchondral bone alteration, meniscal degeneration, synovial inflammatory response, and overgrowth of bone and cartilage. The etiology of OA is multifaceted and can affect both weight-bearing and non–weight-bearing joints. OA can be initiated as a result of mechanical, structural, genetic, and environmental factors. When repeated exposure to physical activity is not offset with reciprocal time for tissue repair, bone resorption outweighs bone deposition. This cycle over time is the precursor for degenerative joint disease. Other factors that influence bone resorption include hormone levels such as estrogen and vitamin D. Estrogen influences the rate of cell turnover. Vitamin D deficiency impairs bone deposition. Now that there is an increasing population of people that are vitamin D deficient, there is a link to OA prevalence, incidence, and progression. Most studies involving this link have been site specific to the knee.

The risk of having OA is higher with age older than 45 years, women, obesity, bone deformities, joint injuries, and certain occupations with repetitive stress on particular joints. Advanced age is the strongest risk factor for the prevalence and incidence of OA. The estimates for influence of genetic factors in radiographic OA of the knee, hip, and hand are 39%, 60%, and 59%, with a similar range of estimates for cartilage volume change and progressive knee OA.

Obesity is the primary modifiable risk factor that has the greatest potential for having an impact on treating the disease. Obese and overweight people have three times the risk of knee OA. By reducing the body mass index from more than 30 to less than 25, up to 29% of knee OA could be prevented. The estimated risk of progression from symptomatic early OA to advanced OA for adults in the United States 60 to 64 years of age is 63% during a 10-year period in obese adults versus 37% in nonobese adults. In contrast to knee OA, the association between obesity and incident of hip OA has been inconsistent.

Obesity has a systemic and a local mechanical effect on joints in OA. The radiographic findings in symptomatic OA of the hand emphasize the systemic factors in the link between obesity and OA, because unlike the knees or hips the hands are not primary weight-bearing joints. It is speculated that with excessive fat accumulation and intramuscular fat, there is some low-grade systemic inflammation. This inflammation is now considered a hallmark of obesity with evidence in elevation in interleukins (IL-1beta, IL-6), tumor necrosis factor (TNF)-alpha, and the acute-phase reactant C-reactive protein (CRP).

With advanced age and obesity being two of the major risk factors for having OA, it has to be mentioned that among the other joints the spine can be greatly affected. OA of the spine is a disorder of the synovial joints, the zygapophysial joints (z-joints), and the sacroiliac joint (SI joint). The z-joints function to support and stabilize the spine during loading, whereas the SI joint functions to transfer weight from the upper body to the lower extremities. OA does not account for all causes of z-joint and SI joint pain, but the relative percentage increases with age and obesity. Intervertebral disc degeneration and loss of inherent structural integrity can predispose the lumbar z-joints to degenerate. The L4 to L5 and L5 to S1 levels (both weight-bearing and mobility) are the eminent explanation for the highest incidence of OA. Degenerative arthrosis of SI joints may start at an earlier age and may predominantly affect the iliac cartilage. Blood vessels penetrate the subchondral bone plate of both the iliac and sacral facets and pass in close proximity to the articular cartilage. This may explain the high incidence of SI joint involvement in systemic inflammatory diseases.

There are various definitions of OA, both symptomatic and radiographic. Symptomatic OA usually includes pain, aching, and joint stiffness in the affected joint along with the presence of radiographic findings. Clinical criteria for diagnosis of knee and hip OA include pain, plus age older than 50 years old, stiffness for less than 30 minutes, and crepitus plus the radiographic finding of osteophytes. Knee OA may also include bony enlargement and bony tenderness.

Kellgren-Lawrence is the most common radiologic grading system ( Table 31-2 ). The Kellgren-Lawrence grading scale determines severity of knee OA on the presence and degree of osteophytosis, joint space narrowing, sclerosis, and deformity of the tibiofemoral joint. It is key to note that symptoms can appear before any changes occurring on x-ray (Grade 0). Also, the presence of an abnormal x-ray is not a reliable identifier for pain.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease of unknown etiology that primarily involves the joints. It also often involves soft tissues, such as tendon sheaths and bursae. In addition it may present with extraarticular manifestations. Inflammation and destruction of the joint and soft tissue may lead to joint deformity and loss of physical function. This can happen if left untreated or when the disease becomes unresponsive to treatment. The prevalence of RA varies from 0.3% to 1.5% of the population, with a female-to-male ratio of around 3 to 1.

Typically, the disease onset is insidious, with pain, stiffness, and swelling of the joints being the predominant symptoms. Morning stiffness, or stiffness after prolonged inactivity, often lasts more than an hour in the active inflammatory stage. Up to one third of patients with RA experience acute onset of polyarthritis associated with systemic symptoms including fatigue, myalgia, depression, low-grade fever, and weight loss. The most common joints involved in the early stage of the disease are the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the fingers, the interphalangeal joints of the thumb, the wrists, and the metatarsophalangeal joints of the toes. Other joints, such as the shoulders, elbows, hips, knees, and ankles are also frequently affected. Over the whole course of the disease, the facet and atlantoaxial joints of the cervical spine, and the acromioclavicular, sternoclavicular, temporomandibular, and cricoarytenoid joints may also be involved. The distal interphalangeal (DIP) joints are rarely involved in RA, perhaps resulting from less synovium than the MCPs and PIPs. In addition to involvement of the joints, tenosynovitis is also common in patients with RA, and may cause trigger finger, De Quervain disease, carpal tunnel syndrome, tendon rupture, and even compression of the cervical cord resulting from narrowing of the space available for the upper cervical cord.

In the late stage of RA, joint deformities commonly occur. Buttonhole (or bouttonière) deformity is flexion of the PIP joints, with extension of the DIP joints ( Figure 31-1, A ). Because the central extensor tendon is destroyed by tenosynovitis, the PIP joints pop up dorsally, resulting in lateral and ventral displacement of the lateral bands of the extensor tendon. In this condition, the lateral bands of the extensor tendon act as flexors of the PIP joints and, with tendon shortening, hyperextension of the DIP joints develops. In contrast, the swan neck deformity is the opposite of the buttonhole deformity, with hyperextension of the PIP joints and flexion of the MCP and DIP joints ( Figure 31-1, B ). Shortening of the intrinsic muscle exerts tension on the dorsal tendon sheath, leading to hyperextension of the PIP joints. The lateral bands of the extensor tendon sublux dorsally as the PIP joints herniate in the ventral direction. In addition, shortening of the deep flexor tendons causes flexion of the DIP joints. Other deformities include ulnar deviation ( Figure 31-1, C ) of the MCP joints, palmar subluxation of the wrists, arthritis mutilans, hammer toe deformity, clawed toe deformity, flat feet, hallux valgus ( Figure 31-1, D ), metatarsal joint subluxation, and “Z” deformity of the thumb (hyperextension of the interphalangeal joint, flexion, and subluxation of the MCP joints).

Typical deformities of the hands and foot in patients with rheumatoid arthritis. A, Buttonhole (the third finger) deformity. B, Swan neck (the second finger) deformity. C, Ulnar deviation. D, Hallux valgus and toes overriding.

As a result of the extraarticular foci of the immune response, patients with RA may have different types of extraarticular manifestations during the course of the disease. Common extraarticular features include fatigue, mild normocytic normochromic anemia, rheumatoid nodule (subcutaneous nodule, occurs in 15% to 20% of patients with RA), scleritis, episcleritis, myositis, vasculitis, neuropathy, pericarditis, interstitial pneumonitis and fibrosis, nodular lung disease, myocarditis, cardiac conduction defect, Felty syndrome (RA with neutropenia and splenomegaly), Sjögren syndrome, and amyloidosis. Vasculitis is a serious condition; it can present itself in five different clinical ways: distal arteritis, cutaneous ulceration, palpable purpura, arteritis of viscera, and peripheral neuropathy (mononeuritis multiplex or distal sensory neuropathy). Extraarticular features may be associated with poor prognosis, particularly vasculitis and rheumatoid lung disease. The presence of rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPAs) is also common in patients with RA.

Until 2010, the classification criteria for RA had been based on the 1987 American Rheumatism Association (ARA) revised criteria, which included four clinical criteria (morning stiffness, arthritis of ≥ 3 joint areas, arthritis of hand joints, and symmetrical arthritis), positive RF, the presence of rheumatoid nodules, and radiographic changes ( Box 31-1 ). The four clinical criteria must have been present for 6 weeks. These criteria may be useful for clinical study and can rule out some varieties of transient polyarthritis (e.g., acute viral polyarthritis). However, a major drawback of these criteria is their ineffectiveness in identifying some patients with early disease who subsequently have typical RA because rheumatoid nodules and radiographic erosive changes are usually not present in the early stage of disease. In addition, ACPA testing (which has a similar sensitivity for RF, but is much more specific for RA) was not previously available. In contrast, the ARA criteria did not require any exclusion, thus a patient could initially fulfill the diagnostic criteria of RA, but evolve into other diagnoses later, particularly Sjögren syndrome, scleroderma, psoriatic arthritis, crystalline arthritis, and systemic lupus erythematosus (SLE). To facilitate earlier diagnosis of RA and thus early effective treatment, The Joint Working Group of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed new classification criteria for RA in 2010 ( Table 31-3 ). The 2010 criteria comprises four domains: (1) type and number of affected joints, (2) RF and ACPA, (3) acute phase reactants (CRP and erythrocyte sedimentation rate [ESR]), and (4) the duration of symptoms. For evaluation of a patient with suspected RA, the highest category within each domain is taken and the four respective numbers are added. The maximum possible score is 10, where any score ≥6 indicates the presence of RA. The new criteria place a greater emphasis on serology and imaging studies (ultrasound and magnetic resonance imaging [MRI]), which can also be used to evaluate synovitis.

The comprehensive management of RA requires a combination of nonpharmacologic measures, medical interventions, and surgery. Nonpharmacologic measures include patient education, relative rest with appropriate exercise, physical therapy with modalities, occupational therapy, proper orthoses, shoes, and durable medical equipment. Nutritional counseling, psychosocial interventions, vocational training, and measures to prevent complications of drug therapy are also an integral part of treatment. Most of these measures are covered in the domain of rehabilitation management, which will be discussed later in this chapter.

Medical treatment of RA aims to control synovitis and prevent joint injury. Evidence suggests that significant, irreversible joint injury may occur as early as the first 2 years. Measures aimed at identifying early active RA and reducing inflammation are essential for improving disease outcomes. Over the past 3 decades, there has been a significant increase in the number of disease-modifying antirheumatic drugs (DMARDs) available. The 2010 ACR/EULAR classification criteria for RA facilitate recognition of patients with early arthritis, who are most likely to have progressive and erosive disease. The choice of treatment depends on the level of disease activity, stage of therapy (initial versus subsequent therapy), regulatory restrictions, and patient preference. Once the diagnosis of RA is established, antiinflammatory therapy with an NSAID or a glucocorticoid is suggested, and generally nonbiologic DMARD therapy begins, including methotrexate, hydroxychloroquine, sulfasalazine, or leflunomide ( Table 31-4 ). Among the different nonbiologic DMARDs, methotrexate is most commonly used. Although NSAIDs are potent antiinflammatory drugs, they are not disease-modifying and have potential serious side effects; thus their use over time as monotherapy should be avoided. Combining NSAIDs with DMARDs is recommended. Glucocorticoids are also potent antiinflammatory drugs. They are particularly useful at the onset of disease. Glucocorticoids are used as a bridging strategy, during which they are tapered while the DMARDs take effect. They can also be used during disease flare or used as local injection agents when one or two joints or soft tissues are more inflamed.

If patients show an inadequate response after several months of aggressive doses of a nonbiologic DMARD, adding a second nonbiologic DMARD (step-up combination) or a biologic DMARD is suggested. Several biologic DMARDs are FDA (U.S. Food and Drug Administration)-approved for the treatment of RA. Biologic DMARDs include TNF inhibitors (etanercept, infliximab, adalimumab, and golimumab), IL-1 inhibitor (anakinra), IL-6 inhibitor (tocilizumab), T-cell costimulation inhibitor (abatacept), and B-cell depletion therapy (rituximab, an anti-CD20 chimeric monoclonal antibody) ( Table 31-5 ). Several clinical trials have shown that TNF inhibitors, IL-1 or IL-6 inhibitors are efficacious as monotherapies for the treatment of RA. The pitfalls of biologic DMARDs are the high cost, possible side effects, and some serious adverse events (infection, tuberculosis, demyelinating syndromes, increased risk of certain malignancy, and drug-induced lupus). With regular assessment of disease activity and tight control of treatment strategies, many patients with RA remain in remission or in a state of low-disease activity; thus joint destruction and physical disability are avoided. In patients with intractable pain, severe joint destruction, or poor response to long periods of medical treatment and rehabilitation, surgery may be considered. Common surgeries for patients with RA are artificial joint replacement, synovectomy (for the hand, wrist, elbow, knee, and tendon sheath), tendon repair, osteotomy, and arthrodesis (for the wrist, ankle, or cervical spine).

Table 31-5

Biologic Agents for Rheumatoid Arthritis

Drug (Brand Name)	Molecular Structures	Response Rate; Onset of Action	Dosage	Administration Instructions	Common Side Effects	Other Comments
Non-TNF
Abatacept (Orencia)	Recombinant receptor-IgG Fc fusion protein; T-cell costimulation inhibition	50% to 70%; 4 wk	IV infusion, 500 to 1000 mg, repeat at 2 and 4 wk, and every 4 wk thereafter; or 125 mg SC once weekly	IV: Infuse over 30 min; administer through a 0.2 to 1.2 micron low-protein–binding filter SC: Allow prefilled syringe to warm to room temperature (for 30 to 60 min) before administration	Headache, dizziness, nausea, dyspepsia, abdominal pain, diarrhea, nasopharyngitis, upper respiratory tract infection, urinary tract infection, other infections, hypertension, skin rash	Higher incidences of infection and malignancy were observed in the older adult population; use caution with chronic obstructive pulmonary disease
Rituximab (Rituxan)	Chimeric monoclonal antibody specific to CD20 (B-cell depletion)	65% to 85%; 4 to 12 wk	IV infusion: 1000 mg on days 1 and 15 in combination with methotrexate; subsequent courses may be administered every 24 wk	Dilute to a concentration of 1 to 4 mg/mL in either 0.9% sodium chloride or 5% dextrose IV infusion: Start rate of 50 mg/hr; if there is no reaction, increase the rate by 50 mg/hr increments every 30 min, to a maximum rate of 400 mg/hr	Peripheral edema, hypertension, fever, fatigue, chills, headache, insomnia, pain, rash, nausea, neuropathy, abnormal liver function, hematologic abnormality	Risk of reactivation of hepatitis B virus infection; do not administer IV push or bolus; severe infusion-related reaction may happen
Tocilizumab (Actemra)	Anti–interleukin-6 receptor monoclonal antibody		IV: Initial: 4 mg/kg every 4 wk; may be increased to 8 mg/kg (maximum dose: 800 mg) SC: <100 kg: 162 mg every other week; increase to every week based on clinical response; ≥100 kg: 162 mg every wk	IV: Allow diluted solution for infusion to reach room temperature before administration; infuse over 60 min with a dedicated IV line SC: Administer the full amount in the prefilled syringe; rotate injection sites	Anaphylaxis/hypersensitivity reactions, elevated liver enzymes, fatal infection, gastrointestinal perforation, neutropenia, thrombocytopenia	Tuberculosis and malignancy have been reported; use is not recommended in patients with active hepatic disease or hepatic impairment; use with caution in patients with central nervous system demyelinating disease
Anti-TNF
Adalimumab (Humira)	Human monoclonal antibody	46% to 73%	40 mg SC every 2 wk	Prefilled pens, syringes, and vials are available for use; inject into thigh or lower abdomen	Headache, skin rash, positive ANA titer, serious infection, local injection site reaction, increased creatinine phosphokinase, upper respiratory tract infection, sinusitis	Live vaccines should not be given concurrently; anaphylaxis, tuberculosis, malignancy, demyelinating disease, heart failure are rarely reported
Etanercept	Human recombinant receptor/Fc fusion protein	59% to 86%; 2 to 4 wk	25 mg SC on 2 different days, or 50 mg once weekly
Infliximab	Chimeric monoclonal antibody
Certolizumab pegol (Cimzia)	Humanized Fab fragment
Golimumab (Simponi)	Humanized monoclonal antibody

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