5

Musculoskeletal Disorders

Musculoskeletal disorders comprise diverse conditions affecting bones, joints, muscles, and connective tissues. These disorders may result in pain and loss of function and are among the most disabling and costly conditions in the United States (USBJI, 2014a). The Social Security Administration (SSA) defines disorders of the musculoskeletal system as conditions that might result from hereditary, congenital, or acquired pathologic processes. Impairments may result from infectious, inflammatory, or degenerative processes; traumatic or developmental events; or neoplastic, vascular, or toxic/metabolic diseases (SSA, 2008).

SSA noted three categories of musculoskeletal disorders—disorders of the back, osteoarthritis (OA), and other arthropathies—as suggestions for conditions that the committee might wish to explore. Based on the committee’s clinical expertise and knowledge of the medical and research literature on musculoskeletal disorders, the committee agreed that disorders of the back and OA were two of the most disabling musculoskeletal conditions; within the category of “other arthropathies,” the committee agreed that inflammatory arthropathies in particular ranked among the most disabling conditions that might improve with treatment. Although rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are classified by SSA as “immune disorders,” their most common—and, in many cases, most disabling—manifestation is inflammation of the joints leading to joint destruction and deformity. Thus, the committee believes that those conditions merit consideration as leading causes of musculoskeletal impairment.

The specific conditions being examined in this chapter are listed in Table 5-1. These conditions commonly result in disability; however, they

TABLE 5-1 Selected Musculoskeletal Disorders

may improve with appropriate treatment and do not necessarily result in permanent disability for most adults.

As noted, the focus of this chapter is on the musculoskeletal disorders. The chapter begins with a discussion of the epidemiology of those conditions in the general population, which is followed by overall issues that are relevant across the specific musculoskeletal conditions being discussed, such as the types of medical professionals typically involved in care and the settings in which people are diagnosed or receive treatment. The remainder of the chapter presents a detailed discussion of chronic low back pain; OA of the hip, knee, and wrist/hand; and inflammatory arthropathies (RA and PsA) and responds to the remaining issues in the Statement of Task.

EPIDEMIOLOGY OF MUSCULOSKELETAL DISORDERS IN THE UNITED STATES

Musculoskeletal disorders are prevalent and are among the most disabling and costly conditions in the United States. Chronic pain and a loss of function are the primary mechanisms through which musculoskeletal disorders lead to disability and work loss. The National Health Interview Survey (NHIS)¹ for 2013–2015 estimated that one in two U.S. adults (126.6 million) had a musculoskeletal condition (USBJI, 2014a). The Global Burden of Disease Study, which provides a comprehensive annual assessment of health loss related to specific diseases, injuries, and risk factors, consistently ranks musculoskeletal disorders among the top causes of disability. In 2016 the top causes of years lived with disability in the United States included low back pain (no. 1), other musculoskeletal disorders (no. 4), neck pain (no. 6), OA (no. 12), and RA (no. 20) (Mokdad et al., 2018).

Musculoskeletal disorders have a considerable economic impact. In 2015 there were 264 million lost work-days due to back and neck pain

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¹ The National Health Interview Survey (NHIS) has monitored the health of the nation since 1957. NHIS data on a broad range of health topics are collected through personal household interviews. For more than 50 years the U.S. Census Bureau has been the data collection agent for the NHIS.

alone, resulting in $131.8 billion annual earnings lost (USBJI, 2014b). Projections based on NHIS 2010–2012 data estimate that by 2040 one in four adults (78 million) will have doctor-diagnosed arthritis and, of those with arthritis, an estimated 44 percent will report arthritis-attributable activity limitations (CDC, 2019a). In addition, people with OA lost $71.3 billion in annual earnings, and those with RA lost $7.9 billion. In 2013, there were 62.8 million health care visits for low back pain and 6.4 million hospitalizations for arthritis and other rheumatic conditions (USBJI, 2014a).

CROSS-CUTTING ISSUES FOR MUSCULOSKELETAL DISORDERS

This section discusses issues that are common to each of the musculoskeletal disorders being discussed in this chapter. The issues include the types of medical professionals typically associated with the care of people with musculoskeletal disorders, the settings involved in that care, and, finally, the issue of pain and restricted mobility that may result from these disorders.

Medical Professionals Associated with Care

A wide range of professionals may be associated with the care of people with musculoskeletal disorders. Most musculoskeletal conditions are initially diagnosed and treated in primary care, where family medicine and general internal medicine are the specialties providing most primary care for adults. Additionally, physical medicine and rehabilition physicians also diagnose and treat musculoskeletal disorders. Occupational medicine physicians may be involved in the diagnosis and treatment when a musculoskeletal disorder is associated with work-related injury or impairment. Physical medicine and rehabilitation physicians (i.e., physiatrists), physical therapists, and occupational therapists are often involved in the management of patients with functional limitations due to musculoskeletal conditions.

Patients with potential inflammatory joint or connective tissue diseases or autoimmune disorders are often referred to rheumatologists for diagnosis and, if indicated, treatment with disease-modifying antirheumatic drug therapy. Patients with advanced joint destruction, whether from OA, inflammatory disease, or trauma are typically referred to orthopedic surgeons for surgical treatment, including joint replacement. Patients with inflammatory arthropathies complicated by extra-articular disease manifestations may benefit from additional specialist consultation (e.g., patients with RA-associated interstitial lung disease benefit from consultation with a pulmonologist).

Patients with disabling chronic pain may receive care from multidisciplinary teams that include physiatrists or pain physicians (who may have

a variety of medical specializations) collaborating with psychologists, rehabilitation therapists, and other health professionals. Team-based care may include care managers (often nurses or social workers) or health coaches (who may be health professionals or lay persons).

Treatment Settings

Care for people with musculoskeletal disorders most often occurs in outpatient office-based settings; however, care may be given in ermergency departments and/or urgent care. Exercise therapies are commonly delivered or supervised by physical therapists, but they may be accessed in the community or integrative health settings as well. Studies have shown that initial triaging to physical therapists at primary health care centers has advantages regarding efficiency in the work environment and in the use of health care (Bornhoft et al., 2019). A wide range of exercise approaches have been shown to benefit patients with chronic low back pain, including strength/resistance, coordination/stabilization, aquatics, cycling, and walking (VA/DoD, 2017). Surgical care may occur in hospitals or standalone surgical centers. Rehabilitation care may be provided in offices, in the hospital following surgery, in rehabilitation centers, or in skilled nursing facilities.

Research on Musculoskeletal Disorders

Considering the population prevalence and public health burden of musculoskeletal conditions, research on these conditions is funded at a lower rate than for other chronic conditions. Gereau et al. (2014) estimated that in 2012 the National Institutes of Health (NIH) spent $4 per U.S. person affected by chronic pain, compared with $41 for diabetes and $431 for cancer. The gap in research funding is most dramatic for chronic back pain, the most common cause of disability in the United States and word-wide (Mokdad et al., 2018). According to publicly reported NIH estimates of funding for various disease or condition categories, back pain was not tracked as a condition category until 2016, and annual expenditures for fiscal years 2016–2018 were only $23 million to $30 million, compared with $1.039 billion to $1.108 billion for diabetes and $5.389 billion to $6.335 billion for cancer (NIH, 2019). This dearth of research funding has resulted in important limitations in our understanding of the disease mechanisms, prognosis, and treatments for chronic back pain and for musculoskeletal disorders in general.

Standard Measures of Outcome for Musculoskeletal Pain

Because pain and impaired function are the predominant features of most musculoskeletal disorders, treatment studies typically assess patient-reported measures of pain or function as the primary outcomes. Although pain outcomes and functional outcomes are often correlated, it cannot be assumed that improvements in pain will automatically lead to improvements in function, and vice versa. Measures that focus on or include function are most relevant to this report. Patient-reported pain or condition-specific functional measures that are commonly used in musculoskeletal outcomes research include the Brief Pain Inventory Interference scale, the Roland Morris Disability Questionnaire, and the Oswestry Disability Index.

Treatments for Pain in Musculoskeletal Disorders

Musculoskeletal disorders are the most common causes of chronic pain, and pain accounts for much of the burden of musculoskeletal conditions. According to 2016 NHIS data, the estimated prevalence of chronic pain—defined as pain on most days in the prior 6 months—among U.S. adults was 20.4 percent (50.0 million) (Dahlhamer, 2018). High-impact pain, defined as chronic pain that limited life or work activities on most days or every day during the past 6 months, affected 8 percent (19.6 million) (CDC, 2018). Most of that pain is attributable to musculoskeletal disorders.

In the systematic classification of chronic pain developed by the International Association for the Study of Pain (IASP) and adopted by the World Health Organization for the International Classification of Diseases, 11th Revision (ICD-11), chronic musculoskeletal pain is described as persistent or recurrent pain experienced in musculoskeletal structures such as muscles, bones, joints, or tendons (Perrot et al., 2019). The IASP classification distinguishes between (1) chronic pain that cannot be attributed directly to a known disease or damage process and is diagnosed independently of identified biologic or psychologic contributors (chronic primary musculoskeletal pain), and (2) chronic pain that arises from an underlying disease (chronic secondary musculoskeletal pain). Chronic low back pain is an example of a chronic primary musculoskeletal pain condition, whereas OA pain and joint pain associated with inflammatory diseases (RA, PsA) are secondary musculoskeletal pain conditions (Nicholas et al., 2019; Perrot et al., 2019).

Numerous medications and non-pharmacologic treatments are available for relieving the pain associated with musculoskeletal disorders. A recent systematic review of evidence on the treatment of musculoskeletal pain found moderate to strong evidence that exercise and psychosocial interventions were effective in relieving pain and improving function across

multiple common musculoskeletal pain conditions (Babatunde et al., 2017). Moderate but less consistent evidence suggested that pharmacologic interventions such as oral and topical analgesics and corticosteroid injections (for knee and shoulder pain, but not back or neck pain) provide short-term pain relief. Limited evidence suggested the potential of manual therapies (e.g., manipulation, massage), acupuncture, and other treatments for the relief of pain.

Guidelines recommend non-drug therapies as first-line treatments for chronic low back pain and OA pain (Bannuru et al., 2019; Qaseem et al., 2017). Medications, especially non-steroidal anti-inflammatory drugs (NSAIDs), are typically recommended as second-line or adjunct therapy. Until recently, various bodies recommended opioid analgesics for the treatment of chronic musculoskeletal pain when other treatments were ineffective. That advice was widely disseminated and resulted in widespread long-term opioid use among a large percentage of persons with chronic musculoskeletal conditions; however, the guidance has recently changed based on evidence. Opioids are no longer recommended for chronic musculoskeletal pain conditions because they are not superior to other analgesics (Busse et al., 2018; Krebs et al., 2018) and confer substantially greater risk of serious harm, including addiction, injury, and death (Bannuru et al., 2019; Dowell et al., 2016).

Further discussion of treatments to improve function is presented in relation to each medical condition below.

CHRONIC LOW BACK PAIN

Chronic back pain is the leading cause of years lived with disability in the United States and accounts for more than 264 million lost work-days per year (USBJI, 2014a). In 2013 back pain was the most common reason for health care visits among musculoskeletal disorders, with more than 57 million physician office visits. Office visits for back pain overall have increased over time. The rate of persons visiting a physician because of back pain increased from 11.8 out of every 100 persons in 1998 to 18.1 out of every 100 persons in 2013. Low back pain accounted for most of the increase in visits (USBJI, forthcoming).

Chronic low back pain is a clinical syndrome defined by the persistence of pain in the lower back for at least 3 months. In some persons, chronic low back pain may progress over time to a complex condition “involving persistent anatomical and functional changes in the central nervous system, in addition to structural changes in the back (e.g., degenerative spinal changes, atrophy, or asymmetry of paraspinal muscles)” (Deyo et al., 2014).

Chronic low back pain is sometimes associated with pain that radiates to the lower extremity in a characteristic distribution (i.e., radicular pain,

TABLE 5-2 Pharmacologic Treatments Used for Musculoskeletal Pain Conditions

SOURCES: Chou et al., 2017a; Curatolo and Bogduk, 2001.

sometimes called “sciatica”) or radiculopathy, meaning objective neurologic abnormalities associated with spinal nerve root involvement. Lumbar spinal stenosis is a clinical syndrome most common in older adults, in which characteristic pain in the buttocks or legs occurs with walking.

The presence of radicular pain or radiculopathy is associated with worse chronic low back pain severity and functional outcomes. Other factors associated with worse functional outcomes in chronic low back pain include co-existing medical and psychiatric conditions and other chronic pain conditions. In addition, the overuse of biomedical approaches to treat chronic low back pain (e.g., opioids and spine surgery) has been identified

as a potentially important contributor to disability (Buchbinder et al., 2018).

Professional Accepted Diagnostic Criteria

Chronic low back pain is defined by its location (i.e., between the lower rib margin and the gluteal folds) and by a duration of at least 3 months. It is often described as “nonspecific” because a specific cause is rarely identified (Hartvigsen et al., 2018). The vast majority of chronic low back pain cases, estimated at more than 95 percent in most employed populations, have no definable pathophysiologic abnormality (Hegmann et al., 2019). In the chronic pain classification developed by the IASP and adopted for ICD-11, back pain that persists or recurs for more than 3 months and is associated with significant emotional distress or functional impairment is categorized as a chronic primary pain condition unless the pain is better accounted for by another diagnosis (e.g., axial spondyloarthritis, multiple myeloma) (Nicholas et al., 2019).

Chronic low back pain involves diverse pathophysiologic, cognitive, emotional, and social factors that contribute to its onset, maintenance, and related impairment. Numerous local pain generators are known to be present in the low back. Cognitive and behavioral factors such as catastrophizing and activity avoidance are known to be involved in some individuals. More recently, alterations in the central nervous system structure and function related to the processing of pain and emotion have been identified. Unfortunately, there is little scientific consensus on the relative importance of those factors or the extent to which they are causes rather than consequences of chronic back pain (Vlaeyen et al., 2018). Historical diagnoses such as psychogenic pain disorder, which were previously applied to people who had chronic pain without obvious local anatomical abnormalities, have been rendered obsolete by advances in scientific knowledge (Katz et al., 2015). Diagnoses such as sacroiliac joint pain and degenerative disc disease have limited value due to the lack of defined diagnostic criteria and inconsistent usage by clinicians and researchers (Battie et al., 2019).

Routine imaging and laboratory testing are not typically indicated in the initial evaluation of chronic low back pain. As noted above, the diagnosis of chronic low back pain is a syndrome defined by subjective pain experience in a defined anatomical region for a duration of time. Imaging and laboratory testing are utilized to exclude high-risk sources of back pain in some patients, but specific imaging or laboratory testing for the diagnosis of chronic low back pain are not available. Furthermore, the presence or absence of radiographic abnormalities should not be considered when evaluating the severity or prognosis of chronic low back pain, and repeated imaging is not useful for evaluating the effectiveness

of treatment or progress. As noted by authors of the American College of Occupational and Environmental Medicine 2019 low back disorders guidelines, “abnormal” findings on X-rays, magnetic resonance images, and other diagnostic tests are so common they are normal by age 40 (Hegmann et al., 2019). Radiographic evidence of degenerative spine changes such as intervertebral disc and vertebral endplate changes are more common in people with chronic back pain, but they are also frequently present in pain-free persons and are not highly correlated with the severity of pain or degree of functional impairment (Hartvigsen et al., 2018).

Diagnostic testing is not indicated for the vast majority of low back pain patients; however, spine X-rays or magnetic resonance imaging (MRI) may be indicated for back pain that persists despite initial treatment (Hegmann et al., 2019). Targeted imaging or laboratory testing may also be indicated for selected patients with trauma, neurologic deficits, or other “red flag” symptoms or signs as well as for patients being considered for surgery.

Low back pain as a symptom is experienced by most people at some point in their lives. The first episode may occur in the second or third decade of life; approximately 40 percent of children ages 9–18 report having had back pain (Hartvigsen et al., 2018). The prevalence of back pain may be highest among middle-aged adults, but back pain remains prevalent in old age (Henschke et al., 2015). Back pain has a slight female predominance across all age groups.

Among working adults, the NHIS estimated that the prevalence of any past-year low back pain was 26.4 percent and that the prevalence of frequent and severe low back pain was 8.1 percent. Among workers with frequent and severe low back pain, 19.0 percent reported that the back pain caused them to miss at least one full day of work in the prior 3 months, and 10.7 percent reported that they had changed jobs or made a major change in work activities in the past 3 months because of back pain (Luckhaupt, 2019).

Treatments for Chronic Low Back Pain

Numerous treatments have demonstrated effectiveness for improving function in chronic low back pain. These include exercise therapies, behavioral/psychological therapies, and manual therapies. Multidisciplinary approaches, including intensive chronic pain rehabilitation programs and less intensive primary-care-based collaborative care management interventions, also have demonstrated benefits for function.

Exercise therapies are the first-line treatments recommended in guidelines for routine use in chronic low back pain (Foster et al., 2018; Qaseem et al., 2017; VA/DoD, 2017). These guidelines are supported by a large body of evidence that is somewhat limited by the methodology, size, and

heterogeneity of published clinical trials. Studies have evaluated a wide range of exercise approaches in patients with low back pain, including strength/resistance, motor control/stabilization, and aerobic exercise. In general, the approaches seem to have similar efficacy, and no one approach is effective for the majority of patients.

A comprehensive Agency for Healthcare Research and Quality comparative effectiveness review of pharmacologic and non-invasive nonpharmacologic treatments for low back pain found moderate-strength evidence that exercise therapies improve pain and function in patients with chronic low back pain (Chou et al., 2016). A comparison of trials did not find differences in effectiveness among different exercise techniques (Chou et al., 2016). Although the benefits appear to be similar for different exercise therapy techniques, factors such as the number of sessions and supervision may be associated with greater improvements. A systematic review of exercise therapy for non-acute low back pain focused specifically on work disability as an outcome and found that exercise was associated with a lower likelihood of work disability at approximately 1-year follow-up (Chou et al., 2017b; Oesch et al., 2010).

Emerging evidence supports movement-based approaches, which are sometimes considered to be complementary or integrative therapies (e.g., yoga, tai chi), as effective treatments for chronic low back pain. A synthesis of five trials of yoga versus education for chronic low back pain found that yoga was superior, with moderate-sized improvements in back-specific function (Chou et al., 2016). Four trials of yoga versus other exercise interventions yielded inconsistent results. One trial found clinically significant functional improvement in 50 percent of patients assigned to 10 weeks of tai chi compared with 24 percent of patients assigned to a wait list control group (Chou et al., 2016).

Psychologic or behavioral therapies are also considered first-line therapies for patients with chronic back pain (Foster et al., 2018; Qaseem et al 2017; VA/DoD, 2017). Cognitive behavioral therapy (CBT) interventions are well-established although the strength of evidence for improvements in pain and function has been rated as low because of limitations in the quantity and quality of published trials (Chou et al., 2016). A systematic review of cognitive behavioral interventions for nonspecific low back pain found greater improvements in pain, function, and quality of life than with a control or other therapies (Richmond et al., 2015). A randomized comparative effectiveness trial found CBT and mindfulness-based stress reduction (MBSR) were each superior to usual care, but not different from each other; the percentage of participants with clinically meaningful functional improvement at 1 year was 60.5 percent for MBSR, 57.7 percent for CBT, and 44.1 percent for usual care (Cherkin et al., 2016). After 2 years, CBT remained significantly better than usual care, and MBSR no longer

differed from the other two groups; the rates of meaningful functional improvement were 55.4 percent for MBSR, 62.0 percent for CBT, and 42.0 percent for usual care (Cherkin et al., 2016).

Multidisciplinary rehabilitation, which refers to integrated programs that typically combine exercise, behavioral, and other therapies, often with opioid tapering when applicable, are recommended for patients who do not respond to less intensive interventions, and they may be particularly relevant to the population of patients receiving Social Security Insurance and Social Security Disability Insurance (Foster et al., 2018; VA/DoD, 2017). A systematic review found that multidisciplinary rehabilitation was associated with functional improvement in the short and long term, but not with return to work (Chou et al., 2016). A review of less intensive primary-care-based coordinated care delivery models found evidence that those interventions improve function over 9–12 months (Peterson et al., 2018).

Additional conservative therapies, such as acupuncture, manipulation, and massage, may also be associated with modest long-term improvements (Bronfort et al., 2014; Chou et al., 2016; Qaseem et al., 2017; Rubinstein et al., 2011). To maximize functional outcomes, experts suggest that those therapies should be used together with active approaches, such as exercise (Kligler et al., 2018).

Interventional therapies (e.g., injections, surgery) generally lack evidence of functional benefits in chronic low back pain. The general indications for referring a patient to be considered for low back surgery include progressive neurologic deficit or a new onset of genitourinary or bowel dysfunction that correlates with an anatomic abnormality of the lower back (Abraham et al., 2016).

In general, medications are less beneficial for function than for pain in chronic low back pain, with most of their benefits demonstrated only in the short term. A systematic review conducted for use in developing the American College of Physicians low back pain guideline found evidence that NSAIDs, duloxetine, tramadol, and opioids produced small short-term improvements in functional outcomes (Chou et al., 2017a). Common medications used to treat musculoskeletal pain are listed in Table 5-2.

Foster et al. (2018) summarized treatment recommendations from recent evidence-based guidelines for chronic low back pain; these are shown in Table 5-3.

Length of Time to Improvement for Chronic Low Back Pain

The committee did not identify evidence about the likelihood that treatment will reach a point at which low back pain is no longer disabling or

TABLE 5-3 Treatment for Chronic Low Back Pain

SOURCE: Adapted from Foster et al., 2018.

how long it would require to reach that point. There is no evidence that the efficacy of chronic back pain treatments differs by age.

OSTEOARTHRITIS

OA comprises a family of degenerative joint disorders characterized by clinical and radiographic findings. It is the most common form of arthritis, affecting more than 30 million Americans (Arthritis Foundation, 2018). OA has been thought of as being the “wear and tear” form of arthritis; however, it is a complex combination of genetic, metabolic, biomechanical, and biochemical joint changes that can involve the entire joint and surrounding tissues. OA is becoming the most common cause of disability for middle-aged Americans and has become the most common cause of disability for people older than 65 years. In fact, age is one of the strongest risk factors for OA of all joints. Women are more likely than men to have OA, and their OA tends to be more severe (Zhang and Jordan, 2010).

OA is a disease that progressively damages or destroys synovial joint structure and, in particular, the bearing surfaces of the joints, that is, articular cartilage. OA can affect any synovial joint and appears in all populations. There is no known cure or method of reversing the process. For those reasons, therapy for OA is directed at decreasing joint pain and increasing function and includes both pharmacologic and non-pharmacologic interventions. Pharmacologic therapy often begins with analgesic medications or topical analgesics and NSAIDs as needed; such medications might be prescribed by a primary care physician or a physical medicine and rehabilitation physician in a physician’s office. Intra-articular injections of corticosteroids² can relieve pain, but the effect is of limited duration and should be used infrequently; such injections might be administered in a physician’s office. Non-pharmacologic therapy includes patient education, weight loss if clinically indicated, physical therapy (PT) directed at maintaining joint mobility and strengthening muscle groups or an organized low-impact exercise program, and assistive devices as needed; usually those occur within the PT or occupational therapy setting for OA of the hand. Total joint replacement might be prescribed, which would occur in a surgical suite in a hospital (Lane and Thompson, 1997). Thus, health care settings can be located in physicians’ offices, PT centers, and hospitals and rehabilitation centers.

The primary symptom of OA is joint pain that worsens during activity and improves with rest. The main feature of OA is the articular cartilage degeneration in response to stress, injury, mechanical overload, and increasing age (Frontera et al., 2019). The incidence of the disease increases in all

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² Intra-articular corticosteroid injections can be considered as an adjunct to core treatment for short-term reduction of moderate to severe pain in people with OA (Ayhan et al., 2014).

synovial joints and all populations with increasing age. Joint injury is a risk factor for OA, but the majority of cases occur without a specific history of injury.

OA typically leads to progressive damage to articular cartilage, which in turn leads to joint pain and impaired joint function. Over time the joint may lose its normal shape. The condition can cause bone spurs to grow on the edges of the joint. Bits of bone or cartilage can break off and float inside the joint space, which causes additional pain and damage. Unlike other forms of inflammatory arthropothies, OA only affects joints and not internal organs. It is most common in older people; before age 45 more men than women have OA, while after age 45 it is more common in women (NIAMS, 2016). The prevalence of symptomatic knee OA increases with each decade of life, with the annual incidence being highest between 55 and 64 years old. OA can cause pain, stiffness, and swelling, and in some cases it causes reduced function and disability; some people are no longer able to do daily tasks or work. In some instances, the disease causes progressive joint deformity, joint contractures, and joint swelling.

Primary or idiopathic OA can be localized (affecting a single joint) or generalized (involvement of three or more joints) (Frontera et al., 2019). Although joint injury is a risk factor for OA, the majority of cases occur without a specific history of injury. Obesity is a risk factor for knee OA and, to a lesser extent, for hip and hand OA. Women have a greater risk of knee OA than men. Joint dysplasia and laxity, some neuropathies and metabolic disorders, and genetic predisposition may also increase the risk of OA, as can sustained physically demanding activities.

Specific OA symptoms include pain, stiffness, reduced movement, and swelling of the affected joints. OA is typically exacerbated with activity and relieved with rest (Zhang and Jordan, 2010). Joint tenderness and crepitus on movement may also be present; there are no systemic symptoms (Frontera et al., 2019). In the early stages of the disease pain may be absent, but with advanced disease there may be grinding or locking with joint motion and buckling or instability of joints. Pain is present in patients with advanced disease, and the overuse of muscle groups can lead to the development of pain syndromes in other parts of the musculoskeletal system (Frontera et al., 2019).

The degree of functional limitation depends on the affected joint and the person’s social and work activities. Impaired mobility, locomotion, and activities of daily living are found in patients with the disease in hips and knees. Degeneration in the hands limits vocational and recreational activities and self-care. Patients might have trouble with using a computer or lifting boxes, which can progress to difficulties with activities of daily living (Frontera et al., 2019).

Professional Accepted Diagnostic Criteria for Osteoarthritis

No single test can diagnose OA. Doctors use several methods to diagnose the disease and rule out other problems (see below). A variety of medical specialties treat OA. Treatments for OA include drugs, nondrug pain relief techniques, surgery, and alternative therapies; these are discussed in detail below.

There are a few tests that a physician can perform to enable a diagnosis of OA. Generally a family physician or an internist will take a medical history to understand the symptoms and to determine whether there are other co-occurring disorders. Following a physical exam, the diagnosing physician may then require specific tests for OA, which include

• A physical exam to check general health, reflexes, and problem joints.
• X-rays to provide information about cartilage loss, bone damage, and bone spurs, although early damage may not show on X-rays.
• MRI to show damage to joint tissues, primarily articular cartilage, menisci, and subchondral bone tissues.
• Blood tests may be performed to rule out other causes for symptoms.
• Joint fluid samples might be taken to look for other causes of joint pain, such as infection or gout.

Thus, OA can be defined pathologically, radiographically, or clinically. Radiographic OA has long been considered the reference standard (Zhang and Jordan, 2010), although patients may have radiographic OA without evidence of clinical OA.

General Treatments for Osteoarthritis

There are many pharmacologic and non-pharmacologic therapies that can provide temporary relief from the pain of OA. The initial treatment should employ both approaches, although there are no pharmacologic interventions that have been shown to cure or alter the disease progress of OA (Frontera et al., 2019). The possible treatments include

• Analgesics ranging in strength from mild to strong. Many can be purchased over the counter, while the stronger medications require a prescription. Oral acetaminophen is recommended by the American College of Rheumatology as a first-line medication for hip and knee OA.
• Topical products such as ointments, gels, sprays, and creams, which can be applied directly to the skin of the affected areas. Topical

• NSAIDs have been shown to be more effective than placebo in treating OA.

• NSAIDs in oral or topical form, which provide temporary pain relief. NSAIDs block the action of specific enzymes that are involved in the inflammatory process. There are side effects, particularly stomach pain, nausea, diarrhea, and ulcer formation. NSAIDs may interfere with other medications.
• Anti-neuropathic pain medications, which act on the nervous system to reduce the nerve pain associated with the injury (e.g., gabapentin or serotonin-norepinephrine reuptake inhibitors).
• Corticosteroids, which can rapidly reduce or control inflammation. They may be taken orally or be injected; however, they do have side effects if taken for long periods of time.

The committee chose to focus its discussion on OA affecting two weight-bearing joints (hips and knees) and two non-weight-bearing joints (hands and wrists). Those are the joints most commonly affected with radiographic and symptomatic OA (Helmick, 2014).

The goals of OA treatment are to decrease or relieve pain and to improve or restore function, as there is no pharmacologic cure. Patients vary considerably in their response to treatment, depending on the affected joints and the stage of the disease (mild, moderate, or severe). The rate of progression of OA varies among patients and joints. Although there are numerous treatments available, progressive knee OA may result in reduced mobility and resulting systemic complications of immobility and deconditioning.

Initial treatments that might provide relief from pain include acetaminophen as a first-line therapy, followed by oral and topical NSAIDs. Orthotics and footwear modifications also might be useful, but their usefulness is patient specific. Exercise programs have been developed for knee OA because maintaining activity is critical to maintaining function. Numerous procedures, such as intra-articular corticosteroid injections, may help in reducing local inflammation and improving symptoms (Frontera et al., 2019). A systematic review of intra-articular corticosteroid injections found evidence of pain reduction for up to 6 weeks following injection (da Costa et al., 2016). There is conflicting evidence about the usefulness of acupuncture, but it is recommended for chronic moderate to severe OA when surgery is not possible (Frontera et al., 2019). Platelet-rich plasma, a concentrate of autologous blood growth factors, has been shown in limited studies to provide some symptomatic relief in early knee OA, including not only pain relief but functional improvement 1 year post injection (Dai et al., 2017). However, more research is needed to confirm the efficacy and long-term results of this treatment.

A stepped-care approach can be used to optimize the use and timing of the non-surgical treatment options for patients with OA; however, a study from Smink and colleagues (2014) found that there have been no statistically significant differences in changes over a 2-year period in pain and physical function between patients who received a stepped-care approach and those who received regular care. An example of one kind of stepped-care approach can be found in Table 5-4.

Knee and Hip Osteoarthritis

The prevalence of symptomatic knee OA increases with each decade of life, with the annual incidence being highest between 55 and 64 years old. Globally, the age-standardized prevalence of radiographically confirmed symptomatic knee OA is about 3.8 percent, with higher rates in women (4.8 percent) than in men (2.8 percent) (Cross et al., 2014). As noted in Frontera

et al. (2019), the knee joint is the most common site for lower extremity OA and can involve all or any of the major knee compartments: medial, patellofemoral, or lateral. OA affects all structures within and around a joint. OA is characterized by a progressive loss or erosion of articular cartilage, subchondral bone sclerosis, and the formation of osteophytes, leading to joint pain and impaired joint function and, in some instances, joint deformity and contracture (AAOS, 2017). Women are more likely to develop knee OA than men, especially after age 50 (CDC, 2019b). Between 2010 and 2011 three in five knee replacements occurred in women, and the mean age for both knee and revision knee replacements was 68 years of age. During that same time period, there were an estimated 465,000 to 512,000 hip replacement procedures, the majority (about 63 percent) of which occurred in women (USBJI, 2014a).

OA of the hip is less common than OA of the knee or hand, but it is the most prevalent pathologic condition at the hip joint. No gender differences have been identified in the rates of hip OA, but the rates do increase with age. Occupational heavy lifting and frequent stair climbing increase the risk of hip OA (Frontera et al., 2019).

Professionally Accepted Diagnostic Criteria

The diagnosis of hip and knee OA is typically made based on the patient’s history, a physical examination, and plain radiographs. Laboratory tests are typically normal. Joint pain is the primary symptom of hip and knee OA, although many patients also have a decreased range of motion and crepitus, and some patients develop joint deformity (Sinusas, 2012). Knee pain severity is a more important determinant of functional impairment than is the radiographic severity of OA. The primary radiographic evidence of OA is decreased joint space (decreased distance between the bones forming the joint, which is caused by the erosion of articular cartilage). Additional radiographic evidence of OA includes the presences of osteophytes (bone spurs) and changes in subchondral bone, the bone immediately adjacent to the articular cartilage. Subchondral bone changes associated with OA include bone sclerosis, or thickening, and bone cysts.

Groin pain is the classic symptom for hip OA; other presenting symptoms might be buttock pain, hip pain, stiffness, and associated function limitations. Hip OA might have an insidious onset, and it becomes worse with activity (particularly weight-bearing activity). It might be relieved with rest, but advanced hip OA may be painful even at rest (Frontera et al., 2019). Radiography is the primary diagnostic study for hip OA. MRI imaging is typically not necessary, nor is ultrasound, although they might be useful for defining more complex cases.

See Table 5-5 for additional clinical diagnostic criteria for OA of the hip, knee, hand, and wrist.

Treatments Demonstrated to Improve Hip and Knee Function

Exercise has been the mainstay of non-pharmacologic treatment for knee OA. The specific focus is on lower extremity stretching, aerobic conditioning, and balance exercises. Treatments for knee and hip OA are similar, with a few differences; in some patients, for example, activity modification is helpful as it can avoid or minimize activities that exacerbate pain. Non-pharmacologic therapy often starts with exercise, and there is strong evidence supporting the use of PT as a treatment to improve function and reduce pain for patients with mild to moderate symptoms of hip OA. Exercise for knee and hip OA has been shown to reduce pain by 6 percent, improve physical function by 5.6 percent, improve self-efficacy by 1.66 percent, and also have small benefits for depression (Hurley et al., 2018). Research involving supervised home-based exercise showed statistically significant improvements in a validated arthritis symptom score at 6, 12, 18, and 24 months (Sinusas, 2012). Research findings recommend that all patients with symptomatic knee or hip OA be enrolled in an exercise program commensurate with their ability (Hurley et al., 2018). The decision concerning the type of treatment should be individualized and based

TABLE 5-5 Clinical Diagnostic Criteria for Osteroarthritis of the Hip, Knee, Hand, and Wrist

SOURCE: Adapted from Sinusas, 2012.

on patient preference and ability to perform the exercises (Hochberg et al., 2012). Patients with OA of the first metacarpal joint or the wrist joint may benefit from braces or splints. Moderate-strength evidence indicates that obese patients with symptomatic OA of the hip may achieve lower absolute outcome scores after total hip arthroplasty than non-obese patients but still report a similar level of patient satisfaction and relative improvement in pain and function (AAOS, 2017).

Knee replacement, which includes both total and partial knee replacement, is performed to restore function and relieve pain in patients with severely damaged knees. Although total knee replacement is an effective treatment, postoperative complications include blood clots, wound break down, infection, and loosening or malalignment of the prosthetic component (Scott, 2015). A study by Scott et al. (2017) prospectively assessed 289 patients (≤65 years of age) who had total knee replacement. The investigators found that of the 90 percent of patients who were working before total knee replacement, 40 percent returned to work, including 34 percent who returned to the same job. A total of 41 percent retired and the remaining patients stayed on public assistance. Another study by Scott et al. (2018) assessed 55 patients (≤65 years of age), 95 percent of whom were working before receiving a revision total hip arthroplasty. The authors found that 1 year after the surgery, 33 percent had returned to work, 48 percent had retired, and 19 percent were receiving public assistance. Age was the most significant predictor of return to work; only 16 percent of patients older than 50 years returned to work.

A review of hip OA and work (Harris and Coggon, 2015) found several descriptive studies that have documented return to work following hip arthroplasty. The range in time varied from 8 days (with accelerated rehabilitation) to 13.9 weeks; however, the authors noted that published data do not provide guidance on the time to return to work following such surgery.

Joint arthroplasty should be considered for severe cases of OA. In cases of advanced OA of the hip, knee, shoulder and wrist, joint replacements may relieve pain and improve function for most patients. However, depending on the patients’ pre-operative work experience, skills, and education and the physical demands of possible work opportunities, the postoperative work experience will differ; not all patients who have successful joint replacements or fusions can return to gainful employment.

Although there are numerous treatments available, progressive knee OA may result in reduced mobility and the resulting systemic complications of immobility and deconditioning. The risk of falls will likely be increased with decreased mobility of the knee. Complications can result from the use of anti-inflammatory medications, infection can result following joint injections or surgery, and arthroscopy can damage articular surface membranes,

which can lead to damage to uninvolved cartilage. Infection, deep vein thrombosis, and intra-operative mortality can result from surgery, thus limiting surgery to a last option (Frontera et al., 2018).

There is some evidence supporting the use of pre-operative and postoperative PT to improve early function in patients with symptomatic OA of the hip following total hip arthroplasty. Post-operative PT has been shown to improve early function to a greater extent than no PT management (AAOS, 2017). Furthermore, a review of exercise interventions for knee and hip OA demonstrated that participation in exercise programs may improve physical function and decrease depression and pain (Hurley et al., 2018).

Length of Time to Improvement

The time to improvement varies considerably among patients and depends on such variables as comorbidities (obesity, diabetes, smoking, pain-catastrophizing, and others) and the complexity of the surgery and the pre-surgical condition of the patient. Pre-operative patient preparation and post-operative therapy can improve results. There is no clear evidence that age has a strong influence on improvement following hip and knee replacement.

Hand and Wrist Osteoarthritis

OA of the hand is the most common form of arthritis and is associated with aging. Estimates of hand OA reach as high as 78 percent in men and 99 percent in women over age 65. People may experience pain, stiffness, limitation in function, and reduced grip strength, but since the disease is typically gradual, most people adapt, and complaints of disability are less common than for other types of OA (Frontera et al., 2019).

OA of the wrist refers to the painful degeneration of the articular surfaces that make up the wrist joint between the distal radius and the proximal row of carpal bones. Symptoms include pain, swelling, stiffness, and crepitation. Secondary wrist OA is the most common form and most often results from posttraumatic conditions, such as distal radius fractures, carpal fractures, and carpal instability (Frontera et al., 2019).

Professionally Accepted Diagnostic Criteria

OA of the hand most commonly develops in the first carpal metacarpal joint (the base of the thumb joint), the distal interphalangeal joints of the fingers (the finger joints closest to the tips of the fingers), and the finger interphalangeal joints (the middle joints in the fingers). It is a clinical syndrome characterized by progressive loss or erosion of articular cartilage,

subchondral bone sclerosis, and the formation of osteophytes leading to joint pain and impaired joint function and, in some instances, to joint deformity and contracture (AAOS, 2017). The diagnosis of OA is typically made based on the patient’s history, a physical examination, and conventional radiographs. Radiographic evidence is highly reliable and is the preferred method of evaluating hand OA. The pain, stiffness, and disability associated with hand OA are weakly to moderately associated with radiographic findings (Frontera et al., 2019).

In the majority of cases, pain is the presenting symptom of wrist OA. The initial physical examination of an arthritic wrist includes an inspection of the entire upper limb; the most obvious finding may be a loss of motion. Other types of imagining modalities are not necessary for the diagnosis. It should be noted that the majority of the limitation in wrist arthritis arises from a lack of motion. The loss of motion mainly affects activities of daily living (Frontera et al., 2019). Wrist OA that progresses to advanced stages results in severely painful limitations of motion, which means that affected people are unable to conduct activities of daily living (Frontera et al., 2019).

Treatments Demonstrated to Improve Function in Patients with Hand and Wrist Osteoporosis

There is some evidence that occupational therapy might be beneficial for patients with hand and wrist OA. Oral acetaminophens and NSAIDs may relieve symptoms. Similarly, ice, heat, and topical creams might provide symptomatic relief. Intra-articular injections of corticosteroids or hyaluronate inconsistently provide temporary relief. Common treatments of hand and wrist OA include splinting and joint arthroplasty for the thumb carpometacarpal joint; joint splinting, corticosteroid injections, fusion, and arthroplasty for wrist OA; and joint fusion for finger joint OA. In general, surgery provides fairly predictable pain relief but may reduce function (Frontera et al., 2019). Joint arthroplasty can decrease pain for patients with severe first carpal metacarpal joint OA,³ and joint fusions can decrease pain and improve function for patients with severe wrist and finger joint OA.

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³ Osteoarthritis in the hands usually involves the distal interphalangeal joints (Heberden nodes) and proximal interphalangeal joints (Bouchard nodes), and the pain usually resolves in 1 to 2 years. However, first carpometacarpal joint osteoarthritis (CMC1 OA) often remains a chronically painful condition with exacerbations of pain and decreased function over time. Clinical symptoms do not necessarily correlate with commonly observed radiographic changes, and physical examination findings of pain over this joint might be better than a radiograph at predicting a patient’s function (Wolf et al., 2014).

Length of Time to Improvement

The length of time to improvement varies with the patients, their preoperative condition, and their post-operative therapy. In general, most patients with a successful surgical intervention achieve near-maximum benefit with 6 months. There is not clear evidence of age as a strong determinant of the outcomes of treating hand and wrist OA. Comorbidities including muscle weakness, neurologic disorders, and diabetes may adversely influence the outcomes of the procedure. Pre-operative preparation and post-operative therapy can improve results but the types of therapy and number of sessions will depend on physician judgment and the condition of the patient.

INFLAMMATORY ARTHROPATHIES

Inflammatory arthropathies are conditions characterized by inflammation of the joints and often other tissues. These include RA, PsA, ankylosing spondylitis, juvenile idiopathic arthritis, and systemic lupus erythematosus, among others. RA and PsA are among the most common inflammatory arthropathies and are important causes of disability in adults (Merola et al., 2018; Sangha, 2000), and they are therefore the focus of this section.

Rheumatoid Arthritis

RA is a chronic autoimmune disease that causes pain, aching, stiffness, and swelling in multiple synovial joints. It typically affects the small joints of the hands and the feet and usually both sides equally and symmetrically, although any synovial joint can be affected. It is a systemic disease and so can affect other organ systems, including the heart, lungs, and eyes (NICE, 2018), and it can cause other systemic symptoms, including fatigue, fever, and weight loss (Wasserman, 2011). Because the musculoskeletal impairments associated with RA are typically the most disabling and the major source of functional limitations for individuals with this condition, this section primarily focuses on those impairments, although the committee acknowledges that RA’s impacts on other organ systems may also influence global functioning (Filipovic et al., 2011). The common pathophysiology underlying musculoskeletal impairments in RA is inflammation of the synovium (Scott et al., 2010). During disease flares, inflammation results in a short-term worsening of joint pain and swelling; in patients with longstanding and severe disease, persistent inflammation will over time result in the erosion of cartilage and bone, leading to joint destruction and deformities that in turn cause chronic pain and functional limitations (Sokka and Pincus, 2001).

Professionally Accepted Diagnostic Criteria for Rheumatoid Arthritis

The diagnosis of RA is based on a patient’s clinical history, physical examination, and laboratory findings. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA form the generally accepted diagnostic criteria for the condition, although, notably, these criteria were developed for research studies to allow for the identification of individuals with earlier-stage RA and were not primarily intended for clinical practice. The criteria are outlined in Table 5-6 and are intended to be applied to individuals for whom there is clinical suspicion of RA based on definite synovitis in at least one joint, as determined by physical exam, that is not better explained by a different condition. Patients with a score of at least 6 out of 10 are considered to have “definite RA.” The 2010 ACR/EULAR criteria were designed to identify patients with recent-onset and active RA; adults with longstanding or inactive disease may be diagnosed with RA if there is a documented prior history of findings or laboratory testing fulfilling those criteria. Adults with seronegative RA who lack rheumatoid factor and anti-citrullinated protein antibody on laboratory testing might not satisfy the 2010 ACR/EULAR

TABLE 5-6 Diagnostic Criteria for Rheumatoid Arthritis

NOTE: ACPA = anti-citrullinated protien antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RA = rheumatoid arthritis; RF = rheumatoid factor.

SOURCE: Aletaha et al., 2010.

criteria (Humphreys and Symmons, 2013), but may still be diagnosed with RA if their clinical findings are otherwise characteristic of the disease and if alternative diagnoses are excluded. In those cases radiographic findings of bone erosions, which are characteristic of RA, may help support the diagnosis, although radiography is generally not required to establish a diagnosis (Scott et al., 2010).

The lifetime risk of RA is two to three times higher among women than men (Crowson et al., 2011). The onset of RA peaks between the ages of 30 and 50 years, although it may occur at any age (Tehlirian and Bathon, 2008). The risk factors include older age, a family history of RA, and current or prior cigarette smoking (CDC, 2019a; Costenbader et al., 2006).

Standard Measures of Outcomes for Rheumatoid Arthritis

The principal measures used to assess response to treatment and remission for RA are composite, multidimensional outcome measures that incorporate clinical data (i.e., the physical examination, laboratory markers such as erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP], physician’s assessment), functional assessment, patient-reported symptoms, and patient-reported global assessment (Felson and LaValley, 2014). For RA, it has long been recognized that because of the heterogeneity of its manifestations, and its impacts on multiple organ systems, improvement cannot be accurately determined based on a single domain (e.g., laboratory markers); accordingly, the use of composite outcome measures reflecting multiple disease domains has become the norm (Aletaha et al., 2008). Notably and of key importance to the current study, the routine assessment of physical functioning is strongly recommended as part of any treatment strategy for RA and is more widespread than for many other disabling medical conditions (Singh et al., 2016). We review the major measures used to assess treatment response below, noting that while these measures are widely used in research and clinical trials, their application in routine clinical practice by U.S. rheumatologists is highly variable (Anderson et al., 2012).

ACR20 is the most widely used, and it has been recommended by the U.S. Food and Drug Administration as a preferred outcome measure in studies of new drugs for RA; accordingly it is commonly used as the primary outcome in clinical trials of RA therapies (Aletaha et al., 2008; Felson and LaValley, 2014). It is not recommended for monitoring treatment response in clinical practice—other disease activity scales, described below, are considered more feasible to implement in clinical settings (Greenberg et al., 2009).

Disease activity scores correlate closely with the degree of functional impairment related to RA, and, indeed, several of the aforementioned scores are based in part on functional assessments (Carvalho et al., 2019). However, because RA causes progressive joint damage and deformity, functional impairment is possible among individuals whose disease is quiescent if it was previously active (Ishida et al., 2018; Norton et al., 2014).

Several other instruments that aim to more specifically measure work-related functioning have been validated for the inflammatory arthropathies, including the Work Productivity and Activity Impairment Questionnaire

(Tucker et al., 2019; Zhang et al., 2010), the Work Instability Scale (Revicki et al., 2015), and the Work Productivity Survey (Osterhaus and Purcaru, 2014). At present, such instruments are not widely used in either research or clinical practice, although they may hold promise.

Treatments for Rheumatoid Arthritis

The goals of RA treatment include reducing symptoms of joint pain and swelling, preventing deformity, maintaining quality of life, and limiting extra-articular disease manifestations (Wasserman, 2011). Pharmacologic treatments, specifically disease-modifying antirheumatic drugs (DMARDs), are the mainstay of therapy (Singh et al., 2016). They limit progressive joint damage and improve function through different mechanisms (Scott et al., 2010) (see Table 5-7). DMARDs are typically prescribed under the supervision of a rheumatologist. Care by a rheumatologist is associated with an earlier initiation of DMARD therapy (Rat et al., 2004; Widdifield et al., 2011) and improved treatment response (Criswell et al., 1997), resulting in less joint destruction (van der Linden et al., 2010), lower functional impairment (Ward et al., 1993), and a lower likelihood of requiring orthopedic surgery (Feldman et al., 2013). Traditional (non-biologic) DMARDs include methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine; biologic DMARDs include anti-tumor necrosis factor (TNF) agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), and non-TNF biologics (abatacept, rituximab, tocilizumab). A final class of DMARDs includes Janus kinase (JAK)-inhibitors, of which tofacitinib is the primary agent used in RA. Traditional DMARDs and tofacitinib are orally administered medications⁴ that may be taken at home; anti-TNF biologics are generally available in prefilled syringes that can be injected subcutaneously by patients in their homes (with the exception of infliximab, which must be administered via intravenous infusion in an infusion center); non-TNF biologics are generally administered via intravenous infusion in an infusion center (with the exception of abatacept, which is also available as a prefilled syringe). Medications used for short-term symptom relief include NSAIDs and steroids; the latter may be administered orally, intramuscularly, or intra-articularly. Non-pharmacologic treatments include physical and occupational therapy, exercise, patient education, and psychosocial interventions (Rindfleisch and Muller, 2005). Pain is among the most prominent and distressing symptoms among patients with RA (ten Klooster et al., 2007). It is managed using therapies that target the underlying disease, such as DMARDs, as well as through adjunctive therapies targeting pain symptoms. The latter are discussed in more detail

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⁴ Note that methotrexate may also be administered subcutaneously.

TABLE 5-7 Medications Used to Treat Rheumatoid Arthritis

NOTE: DMARD = disease-modifying antirheumatic drug; JAK = Janus kinase; NSAID = nonsteroidal anti-inflammatory drug; TNF = tumor necrosis factor.

SOURCE: NICE, 2018.

above in the Musculoskeletal Conditions and Pain section of this chapter. Surgery is indicated for intractable pain, severe loss of motion, or functional impairment that exists despite medical management (Rindfleisch and Muller, 2005).

Evidence-based treatment guidelines for the pharmacologic management of established RA (defined as a disease duration of at least 6 months) include the 2015 ACR guidelines and the EULAR guidelines (Singh et al., 2016); the latter were originally developed in 2010 and most recently updated in 2017 (Smolen et al., 2017a). Both the ACR and EULAR guidelines primarily address the use of DMARDs for RA treatment. Patients who are not in clinical remission and who have any degree of disease activity as measured using validated scales (see section on Measurement of Outcomes for Rheumatoid Arthritis for more detail) are considered candidates for therapy; indeed, it is recommended that therapy for RA be initiated as soon as possible after the diagnosis is established, as there is evidence that earlier DMARD therapy is associated with better outcomes. The specific agents recommended are determined by the degree of disease activity, prior treatments used, treatment response and toxicities, and the patients’ comorbidities (Anderson et al., 2000; Nell et al., 2004; Smolen et al., 2017). The goal of therapy is sustained clinical remission or low disease activity (Ramiro et al., 2014).

Under the 2015 ACR guidelines, monotherapy with a traditional DMARD is recommended as the first-line initial treatment for RA regardless of the level of disease activity, with methotrexate being the preferred agent. For patients who do not improve sufficiently with traditional DMARD monotherapy (i.e., RA disease activity remains moderate to high), the recommended approach is either a combination of traditional DMARDs, a biologic DMARD (with or without methotrexate), or tofacitinib (with

or without methotrexate).⁵ For patients on anti-TNF therapy alone who continue to have moderate to high disease activity, the addition of one or two traditional DMARDs is recommended (methotrexate is again the preferred agent) owing to evidence of superior efficacy compared with monotherapy with a biologic. If treatment targets are not achieved with a given biologic DMARD, it is recommended that different biologic DMARDs be tried. Short-term, low-dose glucocorticoid treatment may be added for patients on traditional or biologic DMARDs whose disease activity remains moderate or high, or for RA flares. Once low disease activity is achieved on a specific DMARD regimen, it is recommended that the regimen be continued, given that clinical experience suggests a high risk of relapse and the need for resuming therapy in the absence of DMARD treatment. If remission is achieved, tapering DMARD therapy can be considered, though the guidelines recommend against discontinuing all therapy because of the high risk of relapse.⁶

The 2016 EULAR recommendations for RA treatment are largely similar to the 2015 ACR guidelines: notably, traditional DMARDs (and specifically methotrexate) are recommended as the initial therapy for RA, the addition of biologic DMARDs or tofacitinib is recommended if improvement is not achieved, and if patients do not respond to a biologic DMARD, the guidelines recommend switching to a different biologic DMARD or tofacitinib (Aletaha et al., 2008). There are, however, several distinctions between the ACR and EULAR guidelines worth noting. First, the EULAR guidelines recommend that short-term glucocorticoid therapy be considered when initiating or changing DMARDs, whereas the ACR guidelines reserve glucocorticoid use for patients with moderate or high disease activity despite DMARD therapy. Second, for patients who do not respond to initial monotherapy with a traditional DMARD, the EULAR guidelines recommend that the choice of the subsequent agent be based on prognostic factors. Specifically, for patients with “unfavorable” prognostic indicators (i.e., the presence of autoantibodies especially at high levels, high disease activity, early erosions, or no response to two traditional DMARDs), a biologic DMARD or JAK-inhibitor (tofacitinib or baricitinib) is recommended. For patients in whom such findings are absent, the guidelines recommend adding or changing to a different traditional

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⁵ The 2015 ACR guideline to escalate therapy in patients not responding to monotherapy with a traditional DMARD is strong but is based primarily on clinical experience and indirect evidence; the ACR notes that the published evidence underlying this recommendation is only of moderate to very low quality.

⁶ The 2015 ACR guideline’s recommendation to continue DMARD therapy in patients who achieve treatment targets is strong, but it is based primarily on clinical experience; the ACR notes that the published evidence underlying this recommendation is only of variable quality.

DMARD. In contrast, the ACR guidelines do not discuss the role of prognostic factors in treatment selection.

The ACR and EULAR guidelines are based on comprehensive and systematic reviews of the evidence on RA treatment; however, they have several limitations in the context of this study. First, the guidelines do not discuss non-pharmacologic treatments for RA or the optimal combination of pharmacologic and non-pharmacologic therapies. RCTs support the use of physical exercise as a strategy to improve muscle strength and quality of life (Baillet et al., 2009; Brodin et al., 2008), whereas complementary therapies such as acupuncture and dietary changes have not been found to provide benefit (Hagen et al., 2009; Kelley, 2009; Smedslund et al., 2010; Wang et al., 2008). Second, since the publication of the guidelines, several additional therapies have been approved for RA or are currently under investigation. Sarilumab is a non-TNF biologic DMARD that was approved for the treatment of moderate-to-severe RA in 2017; it has improved efficacy relative to adalimumab, a commonly used anti-TNF biologic, with a similar safety profile (Burmester et al., 2017). Baricitinib is a JAK-inhibitor⁷ that was approved for the treatment of RA in 2018 and is therefore not discussed in the 2015 ACR guidelines; the 2016 EULAR guidelines note that there is some evidence for its superior efficacy relative to adalimumab,⁸ but because long-term safety data are limited, as with tofacitinib, it is recommended that biologic DMARDs be tried first (FDA, 2018; Taylor et al., 2017). Third, neither guideline explicitly discussed the impact of DMARDs on work-related functional capacity (Nam et al., 2014), which is the outcome of principal interest to the committee as it is especially relevant to the SSA population. Many of the individual studies on which the guidelines are based do assess the impact of DMARDs on measures of physical functioning, but there are limitations in extrapolating from those scales to estimate impacts on actual work capacity.

Beyond the ACR and EULAR guidelines, an important limitation of the RA treatment literature more broadly is the limited evidence that is available to guide the management of patients with refractory RA (Singh et al., 2016). While there is no universally accepted definition of refractory RA, the term is often used to refer to patients who have not responded to at least two different biologic DMARDs or to two different biologic DMARDs with different mechanisms of action (Buch, 2018; de Hair et al., 2018; Kearsley-Fleet et al., 2018; Roodenrijs et al., 2018). The prevalence of refractory

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⁷ Janus kinase (JAK)-inhibitors; a class of DMARDs.

⁸ The RA-BEAM trial demonstrated superior efficacy of a 4 mg once-daily dose of baricitinib relative to adalimumab; however, the U.S. Food and Drug Administration approved a 2 mg once-daily dose and declined to approve the 4 mg once-daily dose owing to a less favorable benefit–risk profile.

RA is not well established; the only published national registry study to date is from the United Kingdom, and it estimated that at least 6 percent of patients with RA have been exposed to at least three DMARDs, which is suggestive of a difficult-to-treat disease (Kearsley-Fleet et al., 2018). It is not known what share of SSA beneficiaries with RA satisfy this definition of refractory disease, but because those patients have a lower chance of clinical remission, it is likely that they are disproportionately represented in the SSA population. At present, there is limited evidence to inform the appropriate treatment strategy for patients with refractory RA. Baracitinib was efficacious in a study population in whom the majority of patients had refractory disease (i.e., had previously tried at least two different biologic DMARDs), so it may provide an alternative for those patients (Genovese et al., 2016). Other novel therapies are currently under investigation (Aletaha and Smolen, 2018; Cheung and McInnes, 2017).

While pharmacologic treatments for RA can substantially improve symptoms, they also have associated toxicities that are important to consider (Aletaha and Smolen, 2018; Graham, 2006; Harirforoosh et al., 2013; Huscher et al., 2009; Kamata and Tada, 2018; Nash et al., 2017; Rindfleisch and Muller, 2005; Saag et al., 1994; Sostres et al., 2010). Serious infections are among the most concerning potential adverse effects of biologic DMARDs and glucocorticoids because of their immunosuppressive properties. The toxicities of medications may limit their use in specific patients depending on comorbidities (particularly patients with liver, renal, or cardiovascular disease) and may prompt patients to discontinue or switch medications (Choquette et al., 2019).

Few studies have directly and rigorously assessed the impact of RA treatments on work outcomes. The committee identified a Swedish study comparing traditional DMARDs to combination therapy with infliximab and methotrexate for RA; it found no differences between the treatment arms in the number of work-days lost (Eriksson et al., 2016).

In the absence of direct evidence on the impact of specific RA treatments on work outcomes, the committee reviewed evidence of the impact of RA treatments on measures of physical functioning, specifically the HAQ. HAQ scores are predictive of work disability, and the HAQ is commonly used as a secondary outcome measure in clinical trials testing RA therapies. Among pharmacologic agents, a range of medications including traditional DMARDs (e.g., methotrexate, leflunomide) (Scott et al., 2001) and biologic DMARDs (e.g., golimumab, tocilizumab, baricitinib, certolizumab, filgotinib, sarilumab, tofacitinib, sirukumab, adalimumab, rituximab) have all been demonstrated to improve functional status in RA as measured using the HAQ (Bingham et al., 2014; Burmester et al., 2016; Dougados et al., 2017; Emery et al., 2017; Genovese et al., 2015, 2018; Keystone et al., 2017; Rigby et al., 2011; Strand et al., 2015a,b; Takeuchi

et al., 2017; Taylor et al., 2017). Comparative effectiveness analyses and active comparator trials have generally not identified significant differences between biologic DMARDs in their impact on HAQ scores in RA (Jansen et al., 2014; Strand et al., 2016), with the exception of two recent trials that found sarilumab to be superior to adalimumab in its impact on physical functioning as measured using the HAQ (Strand et al., 2018). Among nonpharmacologic treatment strategies, resistance exercises have been found to improve physical functioning as measured using the HAQ (Baillet et al., 2012).

A key limitation of those data is that most studies do not focus specifically on patients with severe or refractory RA, who might be more likely to participate in SSA programs (Kilcher et al., 2018), so it is unclear whether the aforementioned therapies would meaningfully improve work-related functional capacity within the population of interest to SSA. Of the evidence the committee reviewed, the studies that most closely reflected the population of interest (i.e., adults with severe RA resulting in functional limitations that significantly restrict work) were those evaluating the impacts of specific treatments in patients who had not responded to at least one biologic DMARD. In RA, sarilumab (Fleischmann et al., 2017), filgotinib (Genovese et al., 2018), baricitinib (Genovese et al., 2016; Smolen et al., 2017b), and tofacitinib (Strand et al., 2015b) have all been demonstrated to improve HAQ scores in patients with an inadequate response to at least one anti-TNF DMARD. Conversely, secukinumab (Blanco et al., 2017; Dokoupilova et al., 2018) was not found to improve physical functioning as measured using the HAQ in this population.

Length of Time to Improvement for Rheumatoid Arthritis

NSAIDs and low-dose glucocorticoids can provide symptom relief within days. With DMARDs, clinical improvement is typically expected within 3 months of starting therapy, although a substantial number of patients might not respond until months 3–6 (Kavanaugh et al., 2008, 2010). Accordingly, many clinical trials of RA therapeutics now assess treatment response at both 3 and 6 months, and the EULAR treatment guidelines for RA recommend changing therapy if no improvement is seen after 3–6 months (Ramiro et al., 2014).

Psoriatic Arthritis

PsA is a chronic inflammatory disease of the joints, spine, and entheses. It may affect other tissues as well (e.g., dactylitis, nail involvement) and most commonly occurs in association with psoriasis, an autoimmune skin disease that causes scaly patches over the skin (Coates and Helliwell,

2017). Skin manifestations commonly precede the arthritis; however, in some patients the skin and joint symptoms present simultaneously, and in 10–15 percent of patients the arthritis presents first. PsA is a heterogeneous condition with five recognized subtypes, though it is increasingly recognized that patients may have any combination of these features (Moll and Wright, 1973; Ogdie and Weiss, 2015): (1) mono- or oligo-arthritis (involving ≤4 joints, typically asymmetric); (2) polyarthritis (involving ≥5 joints, typically symmetric); (3) distal-interphalangeal-joint predominant disease; (4) psoriatic spondylitis/sacroiliitis; and (5) arthritis mutilans. Peripheral oligoarticular or polyarticular disease is most common; arthritis mutilans, which is the most severe and deforming disease manifestation, is more rare (Haddad and Chandran, 2013).

Professionally Accepted Diagnostic Criteria for Psoriatic Arthritis

The diagnosis of PsA is based on the clinical history, a physical examination, laboratory findings, and radiography. The most widely used diagnostic and classification criteria for PsA are the Classification of Psoriatic Arthritis criteria (Taylor et al., 2006), which are highly sensitive and specific across varied clinical settings (Chandran et al., 2008; D’Angelo et al., 2009; Leung et al., 2010; van den Berg et al., 2012). The criteria, which are outlined in Table 5-8, are intended to be applied to individuals where there is a clinical suspicion of PsA based on inflammatory disease of the joints, spine, or entheses. Patients with a score of at least 3 points are considered

TABLE 5-8 Classification Criteria for Psoriatic Arthritis

SOURCE: Taylor et al., 2006.

to have PsA. Laboratory markers are less helpful in affirmatively establishing the diagnosis of PsA than they are in excluding other inflammatory arthropathies (Gladman et al., 1987).

PsA affects men and women equally (Brockbank and Gladman, 2002). The average age at diagnoses is typically between 40 and 50 (Kerschbaumer et al., 2016). Obesity has been identified as a risk factor for the development of PsA (Kerschbaumer et al., 2016; Ogdie and Weiss, 2015).

Standard Measures of Outcomes for Psoriatic Arthritis

As with RA, PsA has heterogeneous clinical manifestations so that improvement cannot be accurately determined by considering only unidimensional measures, such as laboratory markers. The principal measures used to assess response to treatment and remission for PsA are therefore composite, multidimensional outcome measures incorporating clinical data, functional assessment, patient-reported symptoms, and global assessment (Felson and LaValley, 2014). We review the major measures used to assess treatment response below, noting that these measures were primarily developed for research and clinical trials and hence their application in routine clinical practice by U.S. rheumatologists is unclear.

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⁹ The DAS28, for example, is a measure of disease activity in RA. DAS stands for “disease activity score,” and the number 28 refers to the 28 joints that are examined in this assessment.

included as part of the standard DAS 28-joint count. Measures of disease activity that have been developed and validated specifically for PsA include the Disease Activity Index for Psoriatic Arthritis, the Psoriatic Arthritis Joint Activity Index, the Composite Psoriatic Disease Activity Index, and the Psoriatic Arthritis Disease Activity Score (Gladman et al., 2010; Mease et al., 2005; Schoels et al., 2016; Wong et al., 2012). All are composite measures based on data drawn from multiple domains (e.g., the physical exam, laboratory markers, pain symptoms, patient or physician-reported global assessments, functional measures and health-related quality of life) (Helliwell and Waxman, 2018; Wong et al., 2012).

As with RA, PsA disease activity scores correlate closely with the degree of functional impairment, and several of these scores are based in part on functional assessments. Functional impairment is still possible, however, among individuals with previously active disease that is now quiescent because PsA can cause progressive joint damage and deformity (Kerschbaumer et al., 2017).

Treatments for Psoriatic Arthritis

As in RA, the goals of treatment for PsA include controlling symptoms, preventing structural damage and deformity, and improving physical functioning and quality of life (Gossec et al., 2016). DMARDs are the mainstay of treatment because they are effective in limiting progressive joint damage and are prescribed under the supervision of a rheumatologist. As shown in Table 5-9 there is considerable overlap between the DMARDs recommended for PsA and those recommended for RA, but there are also some notable differences in the specific drug classes used. Among the agents that are specifically used in PsA, the traditional DMARDs are orally administered; the IL-12/23 and IL-17 inhibitors are available in prefilled syringes that can be injected subcutaneously by patients in their home. As in RA, there is a role for NSAIDs and glucocorticoids in short-term symptom relief. Non-pharmacologic treatment options are similar to those for RA (Singh et al., 2019). Patients with PsA commonly experience pain; adjunctive therapies targeting pain symptoms are discussed in detail in the Musculoskeletal Conditions and Pain section of this chapter. Indications for surgical intervention are the same as in RA patients.

Evidence-based treatment guidelines for the pharmacologic management of PsA include the 2018 ACR/National Psoriasis Foundation (NPF)

TABLE 5-9 Medications Used to Treat Psoriatic Arthritis

NOTE: CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; DMARD = disease-modifying antirheumatic drug; IL = interleukin; JAK = Janus kinase; NSAID = non-steroidal anti-inflammatory drug; TNF = tumor necrosis factor.

SOURCE: Modified from Singh et al., 2019.

guideline (Singh et al., 2019), the 2015 EULAR recommendations, and the 2015 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations (Coates et al., 2016; Gossec et al., 2016). Under all sets of guidelines, the goal of therapy is clinical remission or minimal to low disease activity (Gossec et al., 2016). The preferred treatment may be influenced by the disease severity, medication toxicities, and comorbidities (e.g., congestive heart failure) and by specific PsA disease manifestations (e.g., severe skin disease, axial disease, enthesitis, uveitis [Singh et al., 2019]). Notably, the evidence base underlying the PsA treatment guidelines is more limited than that underlying the RA treatment guidelines reviewed in the previous section, and there are some notable differences between the major guidelines.

Under the 2018 ACR/NPF guideline (Singh et al., 2019), options for the initial treatment of active PsA in descending order of preference are an anti-TNF biologic DMARD, a traditional DMARD, an IL-17 inhibitor, and an IL-12/23 inhibitor. For treatment-naïve patients with less active disease, NSAIDs may be considered. For patients who have not responded to initial therapy, regardless of the initial treatment strategy used, the subsequent treatment options in descending order of preference are an anti-TNF biologic DMARD, an IL-17 inhibitor, an IL-12/23 inhibitor, and abatacept or tofacitinib. Among patients who have not responded to therapy with an anti-TNF DMARD, switching to a different anti-TNF DMARD is preferred over other biologic DMARDs. For patients who have not responded to a traditional DMARD and are either not candidates for biologic DMARDs

or do not wish to take them, the options include adding apremilast to the current traditional DMARD or switching to a new traditional DMARD (except apremilast). Among patients with active PsA and psoriatic spondylitis/axial disease who have not responded to NSAIDs, anti-TNF DMARDs are preferred, followed by IL-17 inhibitors. For patients with active PsA in whom enthesitis is the predominant manifestation, NSAIDs, anti-TNF DMARDs, and tofacitinib are preferred over traditional DMARDs.

The 2015 EULAR recommendations are largely similar to the 2018 ACR/NPF guidelines, although there are several differences worth highlighting (Gossec et al., 2016). First, in the 2015 EULAR recommendations traditional DMARDs are preferred as a first-line therapy over biologic DMARDs. In patients with mild disease, NSAIDs and intra-articular glucocorticoids are considered acceptable initial therapy, but in patients with more severe disease or unfavorable prognostic factors (i.e., many swollen joints, structural damage, high inflammatory markers, and extra-articular manifestations) traditional DMARDs are recommended, and within this class, methotrexate is the preferred agent. Second, whereas IL-17 inhibitors are preferred over IL-12/23 inhibitors in the 2018 ACR/NPF guideline, the EULAR guidelines do not favor one class over the other. Finally, the EULAR guidelines do not address abatacept or tofacitinib, which were approved for the treatment of PsA more recently. The 2015 GRAPPA recommendations are similar to the 2015 EULAR recommendations for the management of peripheral arthritis, axial disease, and enthesitis (Coates et al., 2016).

The ACR/NPF, EULAR, and GRAPPA guidelines were all based on systematic reviews of the evidence on PsA treatment together with expert opinion. Similar to the RA treatment guidelines previously reviewed, one limitation of the guidelines—in the context of this study—is that they do not explicitly discuss the impact of pharmacologic treatments on work-related functional capacity, which is the outcome of principal interest to the committee. A challenge in the PsA treatment literature more broadly is the limited evidence available to guide the management of patients with PsA and, in particular, those with arthritis mutilans or other forms of severe or treatment-resistant disease who may be disproportionately represented in the SSA population (Bakirci Ureyen et al., 2018). Ixekizumab, ustekinumab, and secukinumab were efficacious for patients who had previously been treated with anti-TNF DMARDs with an inadequate response, so they may provide an alternative for these patients (Merola et al., 2017; Nash et al., 2017; Raychaudhuri et al., 2017; Ritchlin et al., 2014). Other novel therapies are currently under investigation (Chiricozzi et al., 2019).

The pharmacologic treatments for PsA overlap substantially with those used for RA, and therefore so do their toxicities. Toxicities of therapies for RA and PsA are summarized in Table 5-10.

TABLE 5-10 Toxicities of Therapies for RA and PsA

NOTE: DMARD = disease-modifying antirheumatic drug; IL = interleukin; NSAID = nonsteroidal anti-inflammatory drug; TNF = tumor necrosis factor.

SOURCES: Gossec et al., 2016; Graham, 2006; Mease et al., 2017a,b,c; Singh et al. 2019.

As with RA, few studies have directly and rigorously assessed the impact of PsA treatments on work outcomes. Certolizumab was found to significantly decrease absenteeism and presenteeism relative to placebo in an employed sample (Kavanaugh et al., 2015); infliximab was found to improve patient-reported work productivity, but with no significant impact on employment status (Kavanaugh et al., 2006).

Given the limited direct evidence on the impact of specific PsA treatments on work outcomes, the committee reviewed evidence of the impact of PsA treatments on measures of physical functioning, specifically the HAQ, which is predictive of work disability. For PsA, a number of different biologic DMARDs have been found to achieve clinically meaningful improvements in HAQ scores (e.g., apremilast, certolizumab, tofacitinib, golimumab, certolizumab, adalimumab, ixekizumab, ustekinumab) (Edwards et al., 2016; Gladman et al., 2014, 2017; Kavanaugh et al., 2017; Mease et al., 2014, 2017a; Rahman et al., 2016). Abatacept is an exception (Mease et al., 2017b). Evidence of the effect of other DMARDs on physical functioning in PsA as measured with the HAQ is limited. Of note, a clinical trial of methotrexate for PsA found no significant improvement in HAQ scores (Kingsley et al., 2012).

As with RA, a key limitation of the PsA literature is that most studies do not focus specifically on patients with severe or refractory disease who might be more likely to participate in SSA programs, and it is therefore unclear whether the aforementioned therapies would meaningfully improve work-related functional capacity within our population of interest. Of the evidence we reviewed, the studies that most closely reflected our population of interest (i.e., adults with severe PsA resulting in functional limitations that significantly restrict work) were those evaluating the impacts of specific treatments in patients who had not responded to at least one biologic DMARD. In PsA, tofacitinib has been found to improve HAQ scores among adults who have not responded to at least one anti-TNF biologic (Gladman et al., 2017). Ustekinumab has also been evaluated in this population, but it did not achieve a clinically meaningful impact on physical functioning (Rahman et al., 2016).

Length of Time to Improvement for Psoriatic Arthritis

As with RA, NSAIDs and low-dose glucocorticoids can provide symptom relief within days for PsA. With DMARDs, clinical improvement is typically expected within 3 months of starting therapy, though some patients might not respond until months 3–6 (Schoels et al., 2018). Accordingly, as with RA, many clinical trials of PsA therapeutics assess treatment response at both 3 and 6 months, and the EULAR treatment guidelines

for PsA recommend changing therapy if no improvement is seen after 3–6 months (Gossec et al., 2016).

NEW AND DEVELOPING TREATMENTS FOR MUSCULOSKELETAL DISORDERS

The use of biologics in orthopedics has become popular as an adjuvant in healing musculoskeletal injuries. Reports of improved outcomes when biologics are combined with standard therapies have led to further clinical interest. For example, biologics have shown some benefit in improving function and pain scores and in reducing time to heal in foot and ankle traumatic injuries (Zhao et al., 2018). The use of JAK-inhibitors has gained attention because of their potential utility in numerous immune-medicated diseases (Schwartz et al., 2017); however, there are limitations in their use, such as JAK selectivity, optimal routes, and dosing regimens.

According to Zhang et al. (2019), advanced drug delivery strategies for the treatment of musculoskeletal disorders involve therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., three-dimensional printing and tissue engineering techniques), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery). Those strategies have been developed for various drugs in a variety of vehicle forms and aimed at treating musculoskeletal disorders involving bone, cartilage, tendons, ligaments, and skeletal muscles. The use of bioactive factors in the clinical management of cartilage injury, in particular, has progressed, and innovative biologic and engineering strategies have improved the efficacy and efficiency of those factors (Patel et al., 2019).

Accordingly, techniques and methods in material synthesis, polymer modification and functionalization, carrier development, and scaffold fabrications have enabled the delivery of treatments to the joint environment. Similarly, with the application of nanotechnology, new treatments using nanomaterials are creating improvements to the retention profiles of drugs within the joint space related to injected free drugs (Brown at al., 2019). That is important because the joint has poor bioavailability for systemically administered drugs and experiences rapid clearance of therapeutics after intra-articular injection. Martin et al. (2019) describes emerging tissue engineering and regenerative approaches for articular cartilage injuries, noting that cartilage regeneration technology has the potential to repair and prevent the progression of debilitating knee OA.

A review by Gu and colleagues (2018) examines three-dimensional bioprinting techniques, which are useful for fabricating scaffolds for biomedical and regenerative medicine and tissue engineering applications. Such techniques permit rapid manufacture with high precision and control over

size, porosity, and shape, and they make possible the creation of bones, vascular, skin, cartilage, and neural structures. Additional reviews discuss how the emerging field of regenerative rehabilitation integrates biologic and bioengineering advances—in particular, the use of stem cell therapy to promote tissue repair and regeneration (Loebel and Burdick, 2018)—and clinical advances where stem cells and stromal cells have been used to stimulate musculoskeletal tissue, including delivery strategies to improve cell viability and retentions (Rando and Ambrosio, 2018).

SUMMARY AND CONCLUSIONS

Musculoskeletal disorders are a set of diverse conditions affecting bones, joints, muscles, and connective tissues. These disorders may result in pain and loss of function and are among the most disabling and costly conditions in the United States. Chronic pain and loss of function are the primary mechanism through which musculoskeletal disorders lead to disability and work loss.

SSA noted three categories of musculoskeletal disorders in its Statement of Task to the National Academies: disorders of the back, OA, and other arthropathies. Based on the committee’s clinical expertise and knowledge of the medical and research literature on musculoskeletal disorders, the committee determined that those disorders encompass the most disabling musculoskeletal conditions and that although RA and PsA are classified by SSA as “immune disorders,” their most common, and in many cases, most disabling manifestation is inflammation of the joints leading to joint destruction and deformity. Thus, the committee decided that those conditions merited consideration as leading causes of musculoskeletal impairment.

Chronic low back pain is a primary musculoskeletal pain condition defined by pain for more than 3 months. It is highly prevalent in all adult age groups and is the top cause of years lived with disability. Chronic low back pain is sometimes associated with pain that radiates to the lower extremity in a characteristic distribution (i.e., radicular pain, sometimes called “sciatica” or radiculopathy). The presence of radicular pain or radiculopathy is associated with worse chronic low back pain severity and functional outcomes. Other factors associated with worse functional outcomes include co-existing medical and psychiatric conditions and other chronic pain conditions. In addition, the overuse of biomedical approaches to treat chronic low back pain (e.g., opioids and spine surgery) has been identified as a potentially important contributor to disability. On the other hand, numerous treatments have demonstrated effectiveness for improving function in chronic low back pain, including exercise therapies, behavioral/psychologic therapies, and manual therapies. Multidisciplinary approaches, including intensive chronic pain rehabilitation programs

and less intensive primary-care-based collaborative care management interventions, also have demonstrated benefits for function. In general, medications are less beneficial for function than for pain in chronic low back pain, with most benefits demonstrated only in the short term. The committee did not identify evidence about the likelihood of treatment leading to a point at which low back pain is no longer disabling or the time it would take to reach that point. There is no evidence that the efficacy of chronic back pain treatments differs by age.

OA is a disease that destroys synovial joints over time. There is no known cure or method of reversing the process. Chronic pain and joint stiffness are hallmarks of this condition. OA can become disabling if it is severe enough to make work and daily tasks difficult. It is most common in older people, and gender differences vary by age. Before age 45 more men than women have OA; however, after age 45 it is more common in women. The prevalence of symptomatic knee OA increases with each decade of life, with the annual incidence being highest in people between 55 and 64 years old. Although there are numerous treatments available, progressive OA may result in reduced mobility and the resultant systemic complications of immobility and deconditioning. There is moderate to strong evidence suggesting that exercise therapy and psychosocial interventions are effective for relieving pain and improving function for many patients with OA pain. Complications can result from the use of anti-inflammatory medications. Although joint arthroplasties and fusions can relieve pain and improve function, they can also cause infection and deep vein thrombosis, and sometimes lead to intra-operative mortality. For those reasons, joint replacements and fusions should generally be considered only when nonsurgical approaches have not been effective in controlling pain and providing acceptable function.

Inflammatory arthropathies are conditions characterized by inflammation of the joints and often other tissues. These include RA, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and systemic lupus erythematosus, among others. RA and PsA are among the most common inflammatory arthropathies and are important causes of disability in adults.

RA and PsA are systemic inflammatory diseases whose most common and prominent clinical manifestations include inflammation and destruction of the joints. These conditions are an important cause of work-related functional impairment. Effective treatments exist for RA and PsA, and the number of treatment options has expanded significantly in recent years as newer biologic agents have been approved. Because physical functioning is commonly assessed as a secondary outcome in trials of RA and PsA therapies, there is more evidence available about the impacts of specific arthritis treatments on functional capacity than for treatments for many other disabling medical conditions.

Many existing pharmacologic treatments for RA and PsA have been found to improve physical functioning as measured using the HAQ, including a number of biologic DMARDs, which are indicated for more severe disease. However, the extent to which those therapies can improve work-related functional capacity among individuals with impairments severe enough to qualify for SSA programs remains uncertain for several reasons. First, few clinical trials have tested therapies in individuals with such severe impairments, so treatment outcomes in this population are not well understood. Second, because the likelihood of functional improvement falls as the duration of disease and the number of prior DMARDs trials increases, treatment response is likely to be more modest among those with refractory disease. Third, both RA and PsA can result in irreversible joint damage, which may limit how much functional improvement can be achieved through medical management alone in the absence of surgery. Early diagnosis and treatment to prevent joint destruction and deformity is therefore of critical importance for patients with RA and PsA. It is unclear how much improvement might be expected in patients who do not receive early DMARD therapy. Finally, evidence linking specific RA and PsA therapies directly to work outcomes is extremely limited, though HAQ scores are highly correlated with work disability.

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