6

Inflammatory Arthritis

Inflammatory arthritis is a broad term for a group of chronic autoimmune diseases characterized by joint pain, swelling, warmth, and tenderness in joints along with stiffness that lasts for an hour or more. Most inflammatory forms of arthritis include systemic effects such as skin rashes, eye inflammation, hair loss, and dry mouth. The types of inflammatory arthritis include immune-related arthritis and crystal-induced arthritis. Immune-related arthritis is a category that includes rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondylitis as well as some of the diseases covered in other chapters—systemic lupus erythematosus, myositis, Sjögren’s syndrome, and systemic sclerosis. Crystal-induced arthritis includes gout and pseudogout (Zamora and Naik, 2022). Unlike the more common osteoarthritis, or arthritis that is caused by the physical wear and tear of a joint over time, inflammatory forms of arthritis present in children as well as in adults. In 2019 inflammatory arthritis accounted for 60 percent of all Social Security disability beneficiaries receiving benefits for immune system disorders, not including HIV (Communication with Social Security Administration, April 14, 2021). This chapter will cover the clinical features, classification, disease course, and treatments of RA, PsA, and juvenile idiopathic arthritis (JIA). The chapter does not include spondyloarthritis, nor does it include a discussion of microcrystalline diseases, as they were not specified in the committee’s statement of task.

RHEUMATOID ARTHRITIS

Clinical Features, Diagnosis, and Disease Course

Clinical Features

RA is a chronic autoimmune inflammatory disease that predominantly affects the joints. However, given its systemic nature, it may also cause fever, weight loss, marked fatigue, and muscle atrophy (Wasserman, 2011) as well as other organ-specific features, including scleritis, accelerated cardiovascular disease, and interstitial lung disease (NICE, 2018). The lifetime risk of RA is two to three times higher among women than among 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). Risk factors include older age, a family history of RA, and current or prior cigarette smoking (Costenbader et al., 2006). Mortality in RA is 1.5–2-fold higher than in age- and gender-matched non-RA controls (Liao, 2017) predominantly due to accelerated cardiovascular disease and interstitial lung disease.

The arthritis of RA, as with any inflammatory arthritis, typically presents with joint pain and swelling as well as prolonged stiffness in the early morning. Early RA may present in a single joint (monoarthritis) or in a few joints (oligoarthritis) but characteristically tends to evolve into a symmetrical polyarthritis of small and large joints which, if left untreated or inadequately treated, will cause damage to articular structures and disability. RA-associated interstitial lung disease may cause severe respiratory impairment leading to the need for transplant or death, although the musculoskeletal impairments associated with RA are more commonly the most disabling and the major source of functional limitations for individuals with this condition. This section focuses on those impairments, although the committee acknowledges that RA may also influence global functioning through other mechanisms such as fatigue (Filipovic et al., 2011). The common pathophysiology underlying musculoskeletal impairments in RA is inflammation of the synovium (Scott et al., 2010).

Clinical Diagnosis and Professionally Accepted Classification Criteria for Rheumatoid Arthritis

The diagnosis of RA is based on a patient’s clinical history, physical examination, and laboratory findings. Although there are no validated or universally accepted diagnostic criteria for RA, the 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria for RA inform generally accepted

diagnostic criteria for the condition. It is important to remember that these classification criteria were developed for research studies to allow for the identification of individuals with early-stage RA and were not intended for clinical practice. The criteria are outlined in Table 6-1 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; however, adults with longstanding or inactive disease also may be diagnosed with RA if there is documentation indicating that they have previously fulfilled those criteria. Adults

TABLE 6-1 Classification Criteria for Rheumatoid Arthritis

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

SOURCE: Aletaha et al., 2010, with permission.

with inflammatory arthritis but who lack both rheumatoid factor and anti-citrullinated protein antibody on laboratory testing might not satisfy the 2010 ACR/EULAR criteria (Humphreys and Symmons, 2013), but may still be diagnosed with (seronegative) 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).

Disease Course, Outcomes, and Variability

While patients with RA exhibit considerable heterogeneity in terms of their disease course, the severity of the disease, and their response to various therapies, it is clear that untreated RA inexorably leads to progressive joint damage and disability, sarcopenia, weight loss, and premature mortality. This trajectory is largely preventable with early and aggressive treatment with the goal of achieving and sustaining a state of disease remission or at least of low disease activity throughout the course of the disease.

ACR and EULAR guidelines for the treatment of RA advise measurement of disease activity every 2 to 4 months and adjustment of the therapy if there is neither remission nor low disease activity (Fraenkel et al., 2021; Smolen et al., 2020). These outcomes (remission and low disease activity) are defined for each specific disease activity measure, and the clinician can determine whether the patient is at goal at the time of the visit.

The principal outcome measures used to assess response to treatment for RA are composite, multidimensional outcome measures that use the same elements that make up the disease activity scores. These include clinical data (i.e., the physical examination, laboratory markers such as erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP], and a physician’s assessment), functional assessment, patient-reported symptoms, and patient-reported global assessment (Felson and LaValley, 2014). Because of the heterogeneity of RA and its impact 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, the routine assessment of physical functioning is strongly recommended as part of any treatment strategy for RA, and reduced physical functioning is more widespread in RA than in many less painful but equally 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., 2011).

For patients with RA, the ACR has developed several definitions of a response to therapy, including the ACR20, the ACR50, and the ACR70, which indicate an improvement of at least 20 percent, 50 percent, or 70 percent, respectively, on a set of core outcome measures (Felson and LaValley, 2014). These core measures include the swollen joint count, the tender joint count, and three out of the following five measures: pain visual analog scale (patient-reported pain symptom scale), patient global assessment, physician global assessment, inflammatory marker levels (either ESR or CRP), and a measure of physical functioning (commonly the Health Assessment Questionnaire [HAQ] Disability Index or one of the newer modifications of the HAQ, described above). Of these, the ACR20 is the most widely used, and it has been recommended by the U.S. Food and Drug Administration (FDA) as a preferred outcome measure in studies of new drugs for RA; accordingly it has been commonly used as the primary outcome in clinical trials of RA therapies (Aletaha et al., 2008; Felson and LaValley, 2014) although more stringent outcomes (ACR50 or ACR70) have been increasingly used in the last decade.

However, the ACR 20/50/70 responses are not recommended for monitoring treatment response in clinical practice. Rather, an assessment and calculation of the level of disease activity at each visit is strongly recommended, using one or more of the above scales, as these are more feasible to implement in clinical settings (Greenberg et al., 2009). There are defined ranges for high, moderate, and low disease activity levels as well as for remission for the commonly used measures of disease activity (DAS28,¹ the Clinical Disease Activity Index, the Simple Disease Activity Index). The goal in clinical practice is the achievement of remission. However, remission is not feasible or attainable in some patients with RA; in this case the goal should be attainment of low disease activity. Examples of patients in whom remission may not be attainable include but are not limited to: (1) those who have failed multiple other RA therapies and have few options left, (2) those whose disease activity is driven largely by pain while all other measures of disease activity suggest remission, (3) comorbid illnesses and associated therapies that limit safe options for tight control of the RA.

There are no professionally accepted definitions of “severe” RA, and the severity of the disease is generally determined at a particular point in time by the validated measures of disease activity, including those described above, while cumulative severity is generally reflected by a measure of function or by assessment of articular damage demonstrated on radiographs, or both. Specifically, ACR-endorsed instruments to measure RA disease activity and to define remission include: DAS and its variants such as DAS28-CRP and

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¹ The DAS28 is a measure of disease activity in rheumatoid arthritis. DAS stands for “disease activity score,” and the number 28 refers to the 28 joints that are examined in this assessment.

DAS28-ESR, the Clinical Disease Activity Index (CDAI) and the Simplified Disease Activity Index (SDAI), the Patient Activity Scale (PAS), the PASII, and the Routine Assessment of Patient Index Data 3 (RAPID-3), (Johnson et al., 2020). All scales are multidimensional, composite measures and most draw on data from several different domains (e.g., physical exam, laboratory markers, functional measures, pain symptoms, physician- and patient-reported global assessments), although some are completely based on patient self-report (e.g., PAS). All are sensitive in discriminating between different levels of disease activity (Johnson et al., 2020). These measures are commonly reported as secondary outcomes in clinical trials of drugs for RA, and they are recommended for routine assessments in clinical practice (Anderson et al., 2011; Greenberg et al., 2009).

Disease activity scores correlate closely with the concurrent 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 cumulative joint damage and deformity, functional impairment is possible among individuals whose disease is quiescent if there has been significant previous damage (Ishida et al., 2018; Norton et al., 2014).

RA-associated damage to the joints is reflected on plain radiographs by new or worsening erosions in articular bone or by new or worsening joint space narrowing, which is an indirect reflection of cartilage erosion. Generally, hand and foot radiographs are used for this purpose, as they provide a multitude of joints for examination. Erosions and joint space narrowing reflect damage rather than disease activity, and thus they do not correlate tightly with symptoms. Radiographic damage may or may not correlate with functional scores/measures, depending on the extent and severity of damage. For example, severe damage in a single knee or ankle may be far more disabling than extensive joint damage in the hands because of the weight-bearing nature of the lower extremity joints.

Although RA is a chronic disease with daily discomfort, patients also frequently experience disease flares. During disease flares, worsening inflammation results in an exacerbation of joint pain and swelling and the potential for new joint damage. In patients with longstanding and severe disease, persistent synovial inflammation will result in the erosion of cartilage and bone, leading to joint destruction and deformities, which in turn cause chronic pain and functional limitations (Sokka and Pincus, 2001).

Treatment and Management of Rheumatoid Arthritis

The goal of RA treatment is to attain and maintain control of disease activity in an effort to reduce the symptoms of joint pain and swelling, prevent deformity, maintain quality of life and function, and limit

extra-articular disease manifestations (Wasserman, 2011). Pharmacologic treatments, specifically disease-modifying anti-rheumatic drugs (DMARDs), are the mainstay of therapy (Singh et al., 2016) as they limit progressive joint damage and improve function (Scott et al., 2010). DMARDs are typically prescribed under the supervision of a rheumatologist. Care by a rheumatologist is associated with an earlier initiation of DMARD therapy (Rat and Boissier, 2004; Widdifield et al., 2011) and improved treatment response (Criswell et al., 1997), resulting in less joint destruction (van der Linden et al., 2010), less functional impairment (Ward, 1997), and a lower likelihood of requiring orthopedic surgery (Feldman et al., 2013). Table 6-2 summarizes the types of medications used to treat RA as well as some examples of drugs in each category. All of the targeted biologic medications can be administered subcutaneously by the patient at home, except infliximab and rituximab, which require intravenous infusion.

Evidence-based treatment guidelines for the pharmacologic management of RA include the 2021 ACR guidelines and the 2019 EULAR guidelines (Smolen et al., 2020). Both the ACR and EULAR guidelines primarily focus on the pharmacologic management of RA. Patients who are not in clinical remission and who have any degree of disease activity as measured using validated scales 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, the prior treatments used, the

TABLE 6-2 Medications Used to Treat Rheumatoid Arthritis

NOTE: DMARD = disease-modifying anti-rheumatic drug; JAK = janus kinase; NSAID = nonsteroidal anti-inflammatory drug.

SOURCE: NICE, 2018.

treatment response and toxicities, and the patients’ comorbidities (Anderson et al., 2000; Nell et al., 2004; Smolen et al., 2016). The goal of therapy is sustained clinical remission or low disease activity (Ramiro et al., 2014).

Under the 2021 ACR guidelines, monotherapy with methotrexate is recommended as the first-line initial treatment for RA patients with moderate to high disease activity, and hydroxychloroquine is recommended for those with low disease activity. For patients who do not improve sufficiently with methotrexate monotherapy (i.e., the RA disease activity remains moderate to high), the addition of a biologic DMARD or a targeted synthetic DMARD is recommended in preference to a combination of conventional DMARDs. If treatment targets are not achieved with combination therapy, it is recommended that the biologic or targeted synthetic DMARD be switched to an agent with a different class (mechanism) rather than to a second agent within the same class. Glucocorticoid treatment is discouraged for the treatment of RA at any point in the course of RA due to toxicity concerns; however, if its use is believed to be necessary, it should be given at the lowest effective dose for the shortest duration possible. Once remission or low disease activity is achieved on a specific DMARD regimen, continuation of that regimen is recommended because discontinuation of DMARDs is associated with a high risk of relapse and the need to resume DMARD therapy. For patients in remission or who have experienced low disease activity for at least 6 months, the gradual tapering of one of the DMARD therapies can be considered, but maintenance of at least one DMARD is recommended. Again, the guidelines recommend against discontinuing all therapy due to the risk of relapse.

The 2019 EULAR recommendations for RA treatment are largely similar to the 2021 ACR guidelines: notably, conventional DMARDs (and specifically methotrexate) are recommended as the initial therapy for RA; the addition of, or switch to, an alternate DMARD 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. 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 caution against any use of glucocorticoids if possible. Second, for patients who do not respond to an initial monotherapy with a conventional 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 janus kinase (JAK)-inhibitor is recommended. For patients in whom such findings are absent, the guidelines recommend adding or changing to a different conventional 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 document. First, the guidelines do not discuss non-pharmacologic treatments for RA or the optimal combination of pharmacologic and non-pharmacologic therapies. Randomized controlled trials 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 et al., 2009; Smedslund et al., 2010; Wang et al., 2008). Second, neither guideline explicitly discusses the impact of DMARDs on work-related functional capacity (Nam et al., 2017), which is the outcome of principal interest to the committee because it is especially relevant to the Social Security Administration (SSA) disability 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 in order 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 targeted DMARDs or to two different targeted 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 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 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 which the majority of patients had refractory disease (i.e., had previously tried at least two different biologic DMARDs without success), 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).

Likelihood of Improvement Given Treatment

Nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose glucocorticoids can provide symptom relief within days. With DMARDs, clinical

improvement is typically expected within 1–3 months of starting therapy, although a substantial number of patients might not achieve full response until months 3–6 (Kavanaugh, 2010; Kavanaugh et al., 2008). 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).

The likelihood of improvement depends on the severity of the disease. A EULAR task force (Smolen et al., 2020) suggests the following factors as predictive of poor prognosis:

• Persistently moderate or high disease activity despite conventional synthetic DMARD therapy according to composite measures including joint counts
• Failure of two or more conventional DMARDs
• High acute-phase reactant levels
• High swollen joint count
• Presence of a rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA), especially at high levels
• Presence of early erosions

The task force notes that there is no evidence for differential response that can be attributed solely to disease duration. However, disease duration can be associated with more radiographic damage, especially if the initiation of disease modifying therapy is delayed (Smolen et al., 2020).

Secondary Impairments from Treatment

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, 2020; Nash et al., 2013; Rindfleisch and Muller, 2005; Saag and Cowdery, 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).

Table 6-3 provides a summary of the toxicities of RA therapies, which also apply to PsA.

TABLE 6-3 Toxicities of Therapies for Rheumatoid Arthritis and Psoriatic Arthritis

NOTE: DMARD = disease-modifying anti-rheumatic drug; JAK = janus kinase; 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.

Select Treatments Currently in Clinical Trials

Clinical trials are currently in progress for novel therapeutic interventions for inflammatory arthritis. A search on the ClinicalTrials.gov website for actively recruiting clinical studies in RA and PsA was performed, yielding 376 and 33 listings, respectively. Given the large number of ongoing clinical trials for drugs that treat inflammatory arthritis, the list was further restricted to multicenter, multinational, double-blind randomized trials of novel agents not currently FDA-approved. The final list is shown below in Table 6-4.

Disease-Specific Functional Limitations

People with RA often have functional impairments that lead to difficulties in physical functioning. In a study looking at a wide range of valued life activities (VLAs), ranging from self-care to household chores, social activities, and recreation, half of a large cohort of people with RA were unable to perform one or more VLA (Katz et al., 2006). Disease activity accounted for a large portion of activity impairment.

TABLE 6-4 Novel Agents in Clinical Trials for Rheumatoid Arthritis and Psoriatic Arthritis

Accommodations to address limitations are widely used, including limiting the frequency or time in activities and taking more time for activities (Katz et al., 2007).

Pain, limited joint mobility, impaired muscle strength, decreased aerobic capacity, fatigue, and low levels of physical activity have been identified as contributing factors to lower physical function in patients with RA (Baker et al., 2017; Hanaoka et al., 2019; Piva et al., 2010; Roubenoff et al., 1992). Hand and foot involvement are present in the vast majority of people with RA, and each can lead to significantly reduced function (Alkabeya et al., 2019; Gijon-Nogueron et al., 2018; Glinatsi et al., 2020; Stolt et al., 2017). Escalante and colleagues demonstrated two distinct impairments in RA—joint inflammation and joint deformity—that contribute to functional limitations (Escalante et al., 2005). While treatments for RA have improved and led to reduced levels of disease activity and improved quality of life, a systematic review concluded that similar improvements in pain, fatigue, and functional disability have not been realized (Carpenter et al., 2020).

Work limitations are common even among people who remain employed, and the rates of work disability are higher in RA than in the general population (Uhlig et al., 2014). In studies from the late 1980s and 1990s, 30–50 percent of people with RA who were employed developed permanent work disability after 10 years of RA (Burton et al., 2006; Verstappen et al., 2004). The risks of permanent work loss were higher among older people with RA and among those with less formal education and more physically demanding jobs. In spite of improvements in medications and treat to target approaches, the rate of work loss did not decrease between 1999 and 2015 (Ward et al., 2022; Wolfe et al., 2007). Disease-related factors, demographics, and education influence work status. Older workers appear to be the most susceptible to loss of work, which may reflect the accrual of disease damage prior to the availability of newer treatments (Ward et al., 2022). A Swedish study comparing traditional DMARDs to combination therapy with infliximab and methotrexate for RA found no differences between the treatment arms in the number of workdays lost (Eriksson et al., 2016).

In the absence of direct evidence concerning the impact of specific RA treatments on work outcomes, the committee reviewed evidence on 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 conventional synthetic DMARDs (e.g., methotrexate, leflunomide) (Scott et al., 2010) and targeted DMARDs (e.g., tumor necrosis factor [TNF] inhibitors, anti-IL-6R antibodies, inhibitors of T-cell activation,

B-cell depleting agents, and JAK inhibitors) have all been demonstrated to improve functional status in RA as measured using the HAQ (Bingham et al., 2014; Burmester et al., 2014; Dougados et al., 2013; 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., 2018; Taylor et al., 2016). Comparative effectiveness analyses and active comparator trials have generally not identified significant differences between targeted 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).

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., 2016), 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.

Although HAQ is the most widely used measure of functional capacity in RA, newer measures of functional status have been introduced to address some of the weaknesses of the HAQ, most notably the significant floor effects. Newer measures include the HAQ-II, the Multidimensional HAQ (MDHAQ), and physical function measures from the NIH Patient Reported Outcome Measures Information System (PROMIS), all of which were recently recommended for use by ACR (Barber et al., 2019).

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.

PSORIATIC ARTHRITIS

Clinical Features, Diagnosis, and Disease Course

Clinical Features

PsA is a chronic inflammatory disease of the joints, spine, and entheses. It may affect other tissues as well (e.g., dactylitis, nail involvement, sacroiliitis, enthesitis) and most commonly occurs in association with psoriasis, an autoimmune skin disease manifested by erythematous plaques covered by silvery scales (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 acknowledged that patients may have any combination of these features (Moll and Wright, 1973; Ogdie and Weiss, 2015): (1) mono- or oligo-arthritis (involving up to four joints, typically asymmetric); (2) polyarthritis (involving five or more 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 rare (Haddad and Chandran, 2013).

Clinical Diagnosis and Professionally Accepted Classification 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 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 6-5, are intended to be applied to individuals for whom 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 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 diagnosis 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).

TABLE 6-5 Classification Criteria for Psoriatic Arthritis

SOURCE: Taylor et al., 2006, with permission.

Disease Course, Outcomes, and Variability

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 currently the same as those used for RA, and they represent 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. More specific outcome and disease activity measures for PsA are currently under development by the Group for Research and Assessment in Psoriasis and Psoriatic Arthritis (GRAPPA) and the Outcome Measures in Rheumatology groups.

The ACR20, developed for RA and described above, is also frequently used in clinical trials of medications for PsA. Other treatment response criteria developed specifically for PsA include the Psoriatic Arthritis Response Criteria (PsARC) and the Minimal Disease Activity (MDA) criteria. The PsARC defines treatment response as achieving two of the following: tender and swollen joint count improvement by at least 30 percent (Mease et al., 2005), patient global improvement by one point on a five-point Likert scale, or physician global improvement by the same amount. The MDA criteria

are achieved when low scores are obtained in five of the following seven domains: tender joint count, swollen joint count, body surface area affected by psoriasis, pain symptoms, patient-reported global disease activity, Health Assessment Questionnaire Disability Index, and tender entheseal points count (Wong et al., 2012).

RA disease activity measures such as the DAS have also been used in PsA clinical trials, though it has been noted that because of differences in the clinical presentation of RA and PsA, some of the RA-specific measures may be less accurate when applied to PsA. The DAS, for example, may not be appropriate for patients who have predominantly lower extremity or distal interphalangeal joint disease since these joints are not 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, 2010; Mease et al., 2005; Ogdie et al., 2020; Schoels et al., 2016; Wong et al., 2012). All are composite measures based on data drawn from multiple domains (e.g., the physical examination, 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 if accumulated joint damage and deformity have occurred (Kerschbaumer et al., 2016).

The HAQ, developed for RA and described above, is also commonly included as an outcome measure in PsA clinical trials (Mease et al., 2005; Ogdie and Weiss, 2015).

Treatment and Management of Psoriatic Arthritis

As with 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 they are prescribed under the supervision of a rheumatologist. As shown in Table 6-6, 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. Agents that are specifically used in PsA but not RA are apremilast and inhibitors of IL-12/23, IL-23 and IL-17. Conventional DMARDs are orally

TABLE 6-6 Medications Used to Treat Psoriatic Arthritis

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

SOURCE: Modified from Singh et al., 2019.

administered, while the IL–12/23, IL-23, and IL–17 inhibitors are available in prefilled syringes that can be injected subcutaneously by patients at home. There may be 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 Chapter 2. The indications for surgical intervention are the same as in RA patients.

Clinical Practice Guidelines for Receiving Treatments

Evidence-based treatment guidelines for the pharmacologic management of PsA include the 2018 ACR/National Psoriasis Foundation (NPF) guideline (Singh et al., 2019), the 2015 EULAR recommendations, and the 2015 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., 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), the options for the initial treatment of active PsA in descending order of preference are: a TNF inhibitor, a conventional synthetic 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: a TNF inhibitor, an IL-17 inhibitor, an IL-12/23 inhibitor, and abatacept or tofacitinib. Among patients who have not responded to therapy with a TNF inhibitor, switching to a different TNF inhibitor is preferred over using other biologic DMARDs. For patients who have not responded to a conventional DMARD and are either not candidates for biologic DMARDs or do not wish to take them, the options include adding apremilast to the current conventional DMARD or switching to a new conventional DMARD (except apremilast). Among patients with active PsA and psoriatic spondylitis/axial disease who have not responded to NSAIDs, TNF inhibitors are preferred, followed by IL-17 inhibitors. For patients with active PsA in whom enthesitis is the predominant manifestation, NSAIDs, TNF inhibitors, and tofacitinib are preferred over conventional DMARDs.

The 2019 EULAR recommendations differ somewhat from the 2018 ACR/NPF guidelines (Gossec et al., 2020). First, in the EULAR recommendations, conventional DMARDs are preferred as the first-line therapy over biologic DMARDs for PsA patients with polyarthritis or with monoarthritis/oligoarthritis and poor prognostic factors; when skin involvement is also present, methotrexate is preferred. Second, when there is an inadequate response to conventional synthetic DMARDs, a biologic DMARD is recommended; however, there is no order of preference except when there is concomitant skin involvement, in which case an IL-17 or IL-12/23 inhibitor may be preferred over other biologics. Third, in patients with inadequate responses to both a conventional and a synthetic DMARD, a JAK inhibitor may be considered. Fourth, for enthesitis or axial disease that is not responsive to conventional DMARDs, a biologic DMARD is recommended; usually this will be a TNF inhibitor, but an IL-17 may be used if there is also skin involvement. Finally, phosphodiesterase-4 inhibitors are reserved for patients with mild disease who have had an inadequate response to one or more conventional DMARDs and for whom a biologic DMARD or a JAK inhibitor is not appropriate.

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 (Ureyen et al., 2018). Ixekizumab, ustekinumab, and secukinumab were efficacious for patients who had inadequate responses to TNF inhibitors, 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). Several other novel therapies are currently under investigation (Chiricozzi et al., 2019).

As with RA, NSAIDs and low-dose glucocorticoids can provide symptom relief within days for PsA. With DMARDs, clinical improvement is typically expected within 1–3 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).

Secondary Impairments from Treatment

The pharmacologic treatments for PsA overlap substantially with those used for RA, and therefore so do their toxicities (see Table 6-3).

Select Treatments Currently in Clinical Trials

Several novel agents are currently under investigation for PsA in randomized clinical trials, most notably Tyk-2 and IL-23 inhibitors (see Table 6-4).

Disease-Specific Functional Limitations

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 evidence that used 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, 2014; Mease et al., 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 from the perspective of this report 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).

JUVENILE IDIOPATHIC ARTHRITIS

JIA, formerly known as juvenile rheumatoid arthritis (JRA), is an umbrella term for several types of inflammatory arthritis in childhood. JIA excludes arthritis that is part of a larger systemic illness, such as systemic lupus erythematosus (SLE) or inflammatory bowel disease (IBD). The subtypes of JIA share the common features of joint pain and inflammation with the adult inflammatory arthropathies discussed above. By convention, JIA pertains to children less than 16 years of age, and joint inflammation needs to be present for 6 continuous weeks. JIA is the most common chronic rheumatic disease of childhood, and it affects approximately

300,000 children in the United States (Helmick et al., 2008). Typically, once an individual has been diagnosed with JIA, the diagnosis remains for the full extent of disease throughout the individual’s lifespan. Hence there are individuals of all ages that may carry the diagnosis of JIA. JIA is a heterogenous group of diseases with different features, treatments, and outcomes.

Clinical Features, Diagnosis, and Disease Course

The diagnosis of JIA is made clinically with supporting laboratory and imaging studies. The International League of Associations for Rheumatology (ILAR, formerly the International League Against Rheumatism) criteria are used for diagnostic and classification purposes (Petty, 2001). The ILAR criteria separate JIA into 7 subgroups: persistent or extended oligoarticular, rheumatoid factor + (RF+) polyarticular JIA, RF-polyarticular JIA, enthesitis-related arthritis, psoriatic JIA, systemic JIA, and undifferentiated. An international effort is under way to revamp the current guidelines as there are some areas that lack precision (Onel et al., 2021). As these different groups are often treated differently—for example, systemic JIA does not respond to usual treatments for polyarticular JIA—proper grouping is important. As several of the groups resemble a type of adult inflammatory arthritis, many think that the age cutoff should be removed and childhood arthritis described as per adult designations. Age cutoffs imply a biologic relevance that is not existent—i.e., many children do not “outgrow” JIA (Glerup et al., 2020).

Descriptions of the current subtypes are offered in the following subsections.

Oligoarticular JIA (Persistent or Extended)

Oligoarticular JIA involves less than 5 joints at onset, per ILAR criteria (Petty, 2001) and is most common in young girls (with rates five times higher in females than males) with typical involvement of large lower extremity joints such as knees (Ringold et al., 2019). The peak age of onset is 2–3 years. Oligoarticular JIA is further separated into persistent or extended disease (involvement of more than five joints, 6 or more months after onset). Of all categories, persistent oligoarticular JIA is the most likely to remit over time (Glerup et al., 2020). Oligoarticular JIA is often painless. Children may present with a loss of motor milestones or flexion contractures. Due to open epiphyses, leg length discrepancies can occur, with the involved side becoming longer, which can then lead to a compensatory scoliosis. Hips are almost never involved. Inflammatory markers are frequently normal. Previously some considered older teenagers with isolated

joint swelling as a subgroup of oligoarticular JIA; however, this has fallen out of favor since the prognosis is very different.

Oligoarticular JIA can be complicated by uveitis of the anterior chamber. Uveitis is generally painless, and for that reason frequent screening is recommended. If uveitis is not treated promptly, scarring and vision problems can develop, including glaucoma, cataracts, and eventually loss of vision. Uveitis can occur during or after JIA and even after the disease has resolved into adulthood. Uveitis is most common in very young children who are positive for antinuclear antibodies, and they should be screened every 3 months after diagnosis.

Polyarticular JIA (RF- and RF+)

Polyarticular JIA involves more than five joints at the onset and is separated into two subclassifications by the presence or absence of RF (Rosenberg, 2020). For the diagnosis of RF-positive polyarticular JIA, RF should be positive on two occasions at least 3 months apart. Polyarticular JIA is three times more common in girls than boys and has bimodal peaks of presentation (at 1–3 and 9–14 years). RF-positive polyarticular JIA has a course most similar to RA and is highly unlikely to permanently remit over time. Typically, RF-positive disease is a symmetric polyarthritis involving the small bones of the hands and feet with erosions early in the course of disease. RF-negative polyarticular JIA has a much more variable course. Large and small joints may both be affected. Uveitis may occur but is less common than in oligoarticular JIA. Frequent involvement of the temporomandibular joint can lead to mandibular hypoplasia and micrognathia, a major source of morbidity. Systemic inflammation may or may not be present. Extra-synovial manifestations of RF-positive JIA are similar to those seen in adult-type RA, including interstitial lung disease and nodulosis.

Enthesitis-Related Arthritis and Juvenile Psoriatic Arthritis

Enthesitis-related arthritis (ERA) is a form of juvenile spondyloarthritis (Weiss and Colbert, 2018). To fulfill the criteria for the diagnosis of ERA, children must have arthritis plus enthesitis or arthritis plus at least two of the following: presence of or a history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain; presence of HLA-B27 antigen; onset of arthritis in a male over 6 years of age; acute (symptomatic) anterior uveitis; or history of ERA, sacroiliitis with IBD, reactive arthritis, or acute anterior uveitis in a first-degree relative. ERA is often associated with axial disease and enthesitis or inflammation at the insertion sites of tendons, ligaments, fascia, or capsule into bone. However, younger children more often present

initially with asymmetric lower limb large joint involvement. ERA is more common in boys than in girls and typically presents from 10 to 13 years of age. Hips may be involved early in the disease course. There is considerable overlap with the arthritis seen to accompany IBD.

Juvenile psoriatic arthritis (PsJIA) generally presents in a bimodal distribution, with younger patients resembling oligoarticular JIA and older patients presenting with disease reminiscent of adult psoriatic arthritis (Stoll et al., 2006). Dactylitis is commonly seen. A diagnosis of PsJIA may be made in the absence of psoriasis if typical features are present and there is a first-degree family member with psoriasis. PsJIA that presents in middle to older childhood exhibits a sex ratio of 1:1.

ERA and PsJIA presenting late in childhood are also unlikely to permanently remit. Studies have suggested that children with ERA and PsJIA experience worse quality of life, function, and pain than children with other JIA categories, resulting in significant morbidity over time (Weiss et al., 2014).

Systemic JIA

Systemic JIA (sJIA) is distinct from other types of JIA, and many would characterize it as an autoinflammatory disorder. Although the ILAR criteria require the presence of synovitis for a diagnosis, synovitis may present years after systemic symptoms (Petty, 2001). ILAR criteria include presence of quotidian fever (daily return to normal) for 2 weeks (documented for at least 3 days) with 6 weeks of arthritis and one of the following: evanescent rash, serositis, organomegaly, or lymphadenopathy. sJIA remains a clinical diagnosis of exclusion. Other causes of fever, including infections, malignancy, and other autoinflammatory syndromes must be excluded prior to treatment. Disease occurs equally in boys and girls. sJIA may occur at any age and is distinguished from adult-onset Stills’ disease (AOSD) by an arbitrary age cutoff of 16 years, although the two diseases are essentially equivalent (Colafrancesco et al., 2019). Notably, the Yamaguchi criteria used to diagnose AOSD do not require arthritis if other clinical features are present. Up to 40 percent of cases of sJIA are associated with macrophage activation syndrome (MAS), a secondary hemophagocytic syndrome. MAS can be life-threatening, requiring urgent recognition and treatment (Minoia et al, 2014). MAS can present at any time during sJIA, including when patients are on treatment and the disease is otherwise quiescent and is frequently triggered by infection.

Extra-articular manifestations are common and include: high quotidian fevers, evanescent macular rash, lymphadenopathy, hepatosplenomegaly, pericardial effusion, peritonitis, arthritis, sore throat, and pharyngitis. The initial treatment is tailored to the severity of systemic, arthritic, or

MAS features. Early aggressive and targeted therapy is favored, given a postulated “window of opportunity” (Nigrovic, 2014). A biphasic model of sJIA has been proposed with a preponderance of innate and systemic features in the initial phase, which, if not controlled, then transitions to an adaptive phase dominated by chronic arthritis. Prior to the establishment of current treatment practices, many sJIA patients had to be treated with chronic glucocorticoids, sometimes for years, which caused many side effects, most notably growth failure. Hip replacements were not uncommon.

Disease Activity Measures and Treat to Target

Validated disease activity measures are being used more often to guide treatment. Several validated disease activity measures for childhood arthritis exist (Trincianti and Consolaro, 2020). There is a lack of evidence that any specific measures are superior to others, and undoubtably future changes in these measures will occur. Measures that can be considered include ACR provisional criteria for inactive disease (Wallace Criteria), the Juvenile Arthritis Disease Activity Score (JADAS), and clinical cJADAS, among others (Ravelli et al., 2018).

In recent years the paradigm of explicitly defining a treatment target and applying tight control with necessary therapeutic adjustments to reach the target has been incorporated into “treat to target” (T2T) recommendations for adult RA. Much work has been done to define these targets for children with JIA.

The HAQ assesses four outcome dimensions: disability, discomfort and pain, drug side effects, and dollar costs. The questionnaire has been adapted for children (CHAQ), and this version focuses on disability, discomfort, and pain (Greer and Iverson, 2020). Disability is measured in the categories of dressing, arising, eating, walking, hygiene, grip, and activities. Discomfort is determined by the presence of pain and its severity. The CHAQ is either parent- or self-administered. Studies have shown that parents are reliable proxy-reporters for their children’s functional status. The major drawback to the CHAQ is a ceiling effect that enables minor disabilities to be missed (Greer and Iverson, 2020).

The JADAS-71, a composite activity measure, uses (1) the Physician Global Assessment (PhGA) (range 0–10), (2) the Patient Global Assessment (range 0–10), (3) active joint count assessed in 71 joints, and (4) ESR (normalized to 0–10) (Consolaro et al., 2008). The cutoff value for inactive disease is 1. The JADAS has been adapted for sJIA by adding a fifth metric—the Systemic Manifestation Score (SMS). The SMS uses seven clinical and laboratory features to quantify the systemic manifestations of JIA: fever, rash, generalized lymphadenopathy, hepatomegaly and/or

splenomegaly, serositis, anemia, and platelet and ferritin levels (Tibaldi et al., 2020). The clinical JADAS requires no laboratory studies.

The ACR provisional criteria for clinical inactive disease include the following: (1) no active joints; (2) no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA; (3) no active uveitis; (4) normal ESR and/or CRP level; (5) a PhGA that indicates no disease activity; and (6) duration of morning stiffness of no more than 15 minutes (Wallace et al., 2004). For complete remission of medication, the criteria for inactive disease on medication has to be fulfilled for a minimum of 6 continuous months. To be in complete remission, patients must have had inactive disease for a continuous period of at least 12 months during which they do not receive any antiarthritis or antiuveitis medication.

Articular damage and extra-articular damage may be scored according to the two parts of the Juvenile Arthritis Damage Index (JADI): the JADI articular (JADI-A) and JADI extra-articular (JADI-E) scores (Viola et al., 2005). For the JADI-A, the score for articular damage ranges from 0 to 72. The JADI-E encompasses ocular complications, non-articular musculoskeletal damage, cutaneous features, endocrine abnormalities, malignancies, and secondary amyloidosis (ranges 0 to 17).

A JIA task force has defined remission as the treatment target on which to base future research studies of polyarticular JIA (Ravelli et al., 2018). In a pilot study, Klein et al. (2020) evaluated 63 children with active JIA who had been treated using T2T methods and found that T2T greatly improved the likelihood of achieving remission or low disease activity. Buckley et al. (2020) reported similar excellent results by standardizing point-of-care disease activity monitoring and implementing clinical decision support to reduce treatment variation. More work is needed to understand the feasibility of T2T methods within usual clinical management.

T2T approaches have also shown to be effective in sJIA. In 2019 ter Haar et al. used a dose escalation strategy for anakinra for new-onset sJIA with a dose taper and discontinuation at 3 months if the target of inactive disease was achieved. Seventy-six percent and 96 percent achieved inactive disease at 1 and 5 years, respectively, with 52 percent and 75 percent being off medication. Damage (articular/extra-articular) was noted in less than 5 percent, and the majority (67 percent) of patients did not need steroids. Defining targets in certain other of the subtypes, such as ERA, has proven to be challenging and is actively under investigation.

Prognosis

In the short term, remission on medication has proven to be an attainable goal. Remission off medications has been more challenging. Quartier (2020) evaluated tapering strategies for canakinumab withdrawal for

children with sJIA. Patients in remission on canakinumab monotherapy were randomized to either taper by dose reduction or prolongation of interval. Seventy-one percent of those with dose reduction taper versus 84 percent of those on prolongation of interval taper for canakinumab maintained clinical remission for 24 weeks, and 33 percent overall discontinued canakinumab. Studies of TNF inhibitor (TNFi) withdrawal for children with polyarticular JIA have been relatively unsuccessful (Lovell et al., 2018; Simonini et al., 2018). Children with polyarticular JIA in longstanding remission on TNFi have been shown to have high rates of flare within the first 1–2 years after medication withdrawal. This is especially true for children with RF-positive polyarticular JIA. Of particular interest is one study that demonstrated an almost 20 percent flare rate within the 6 months prior to medication withdrawal in patients who were thought to be in remission on medication and who were seen more frequently than usual because they were enrolled in a trial (Lovell et al., 2018). A Canadian study found that over a 5-year time period, almost 50 percent of the total population was able to come off medication; however, many children came in and out of remission several times over the period of follow-up (Guzman et al., 2016). In fact, many children with JIA have active disease long into adulthood. Glerup et al. (2020) recently published 18 years of follow-up for the Population-Based Nordic Juvenile Idiopathic Arthritis Cohort. From an original group of over 500 children treated for JIA in the post-biologic era, 44 percent still had signs of active disease 18 years later. Children with persistent oligoarthritis and sJIA were the most likely to be in remission, whereas children with ERA were the least likely. Functional outcomes were generally good, although many patients had permanent articular and extra-articular damage.

Not all children will be able to attain complete remission with medication, and many will require multiple different medications to get there, accruing damage during periods of active disease. More than half of JIA children with polyarthritis in the United States require a switch in biologic treatment over the first 10 years of treatment, and many require more than two biologics (Mannion et al., 2021). Almost 50 percent have active disease despite treatment with two or more biologics, and 20 percent are treated with unapproved therapies for JIA (Brunner et al., 2020). New medications are clearly needed for children with JIA.

Fatigue is common in children and young adults with JIA (Arnstad et al., 2021). High levels of fatigue are strongly associated with disease activity and severity, and they contribute to regular school absences. Approximately 20 percent of JIA patients have persistent school absences as long as 8 years after diagnosis. Children with JIA experience barriers at school, especially physical challenges, with a need for accommodations (Chomistek et al., 2019). Decreased participation and increased social anxiety are key

barriers. Similar to children with other chronic illnesses, higher levels of anxiety and depression are found in children with JIA than in healthy controls (Fair et al., 2019). A German registry study showed that persons with JIA have significantly lower educational achievements than the general population (Schlichtiger et al., 2017). Missing school leads to decreased independence and job attainment.

Work is similarly affected. Approximately 20 percent of individuals with JIA in Germany lost a significant number of workdays; adults with JIA who lost work had an average of 34 days of lost work per year (Schlichtiger et al., 2017). A higher level of unemployment was also seen, especially in those with long disease duration who were still under treatment. In the Nordic Cohort, the same percentage of work disability was present; 18 years later, 20 percent had either limited or no work experience (Glerup et al., 2020). Direct costs (health care and non-health care costs) and indirect costs (productivity loss due to sick leave and work disability) remain high into adulthood. The mean total cost of late JIA (active and inactive) was estimated to be 3,500 (range 1,500–17,000) euros per patient per year, of which the direct cost contributed more than half (Minden et al., 2004). This number is likely to be at least two-fold higher in the United States, given relative health care costs.

Transition remains a major problem in most health care systems. In the Nordic study, notably, only 42 percent of the participants were followed up by a physician or rheumatologist even though approximately 46 percent had active disease at the last follow-up visit, indicating that some of the participants might have been lost to follow-up after transfer to adult care even in government-funded health care systems with minimal out-of-pocket copayments (Glerup et al., 2020). Thirty-seven percent of the participants with active disease did not receive any systemic treatment.

In general, damage from JIA is similar to that seen from arthritis affecting adults. Although in younger children erosions may not be seen on plain x-rays until late in disease, MRI studies demonstrate significant joint perturbations. In addition, growing children may develop specific secondary impairments, including leg length discrepancies and micrognathia. Intraarticular corticosteroid injections are thought to decrease the likelihood of excessive growth in the involved limb, although the literature is mixed (Jennings et al., 2014). Secondary scoliosis is a potential consequence. Micrognathia secondary to mandibular hypoplasia from temporomandibular joint (TMJ) involvement remains a problem and is associated with obstructive sleep apnea and difficulty eating (de Carvalho et al., 2012). A fusion of the cervical spine may be seen, leading to decrease mobility (Espada et al., 1988). Early-onset subclinical cardiovascular damage is more likely in children with JIA than in healthy controls (Bohr et al., 2016). Exercise tolerance is impaired as well. Individuals with JIA are at an increased global

risk of serious infection and cancers, irrespective of treatment (Beukelman et al., 2012; Hurd and Beukelman, 2013).

The treatment of JIA-related eye disease has improved since the introduction of conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs). Methotrexate is the first choice DMARD recommended (Cuchacovich, et al. 2012). Recent JIA cohorts confirm an annual incidence of uveitis of 2–4 percent in the first years after the onset of arthritis and an estimated cumulative incidence of 10–20 percent (Heiligenhaus et al, 2019). Among JIA patients with uveitis, approximately 20 percent will not achieve quiescent disease with current treatments for uveitis. In addition, of those attaining an inactive disease state, almost 33 percent will flare within the next 2 years, irrespective of articular activity. Damage including cataracts, glaucoma, band keratopathy and synechiae are seen commonly (Foeldvari et al., 2019). Because outcomes can be difficult to predict, frequent screening exams are required, and these are a major source of missed school and work for children with JIA. As with articular disease, uveitis may persist into adulthood.

The treatments for JIA carry their own risk factors. Although corticosteroids are used much less often in children than in adults, effects on growth and lipid balance remain a problem. Especially for children with refractory sJIA, the combination of aggressive hip synovitis and avascular necrosis can result in damage that necessitates total joint replacements. Although total arthroplasty done for JIA has decreased in the United States, the rate remains approximately 0.13 total arthroplasties per 100,000 people per year, with most occurring after attainment of adult age (Mertelsmann-Voss et al., 2014).

Long-term registries are critical. A highly fatal lung disease has recently been observed in some children with sJIA, most of whom were treated with bDMARDs (Saper et al., 2019). The observed risk factors include younger children with MAS, children with a history of reactions to tocilizumab, and those with trisomy 21. The exact etiology for sJIA-associated lung disease is not known at this time, although an association with common HLA-DRB1*15 haplotypes has been suggested (Saper et al., 2022).

Immunomodulatory medications present a particular challenge for children who often spend time in such congregate settings as day care, summer camp, and school (K–12, college). Young children may need to be treated with immunosuppressive medications prior to receiving their primary immunizations, making them particularly vulnerable to common infections such as varicella (CDC, 2021). The ability to respond to inactivated or mRNA vaccines such as COVID-19 depends on one’s level of immunosuppression and the specific treatments undergone and is hard to predict (Boyarsky et al., 2021; Ruddy et al., 2021). This may also play a role in school absences and social isolation.

Treatment and Management

ACR has published several guidelines for the treatment of JIA. Originally published in 2011/2013, these guidelines have been under revision since 2017. The first part, including recommendations for the treatment of polyarthritis, enthesitis, sacroiliitis, and uveitis, has been published (Angeles-Han et al., 2019; Ringold et al., 2019). A second part, including recommendations for oligoarthritis, TMJ arthritis, and systemic JIA with and without MAS, was recently accepted for publication (Onel et al., 2021). The guidelines are notable for the decreased reliance on NSAIDs and glucocorticoids and the early use of DMARDs. Treatment choice varies not only by subgroup but by severity as well. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) has developed consensus treatment plans for several subtypes of newly diagnosed JIA in order to evaluate the comparative efficacy of different treatment modalities as they become available (DeWitt et al., 2012; Ringold et al., 2014). However, high-quality evidence to aid in decision making is rare because of the lower numbers of involved individuals, variability between subtypes, poor diagnostic criteria, and limited research funding. Hopefully, the rise of research networks such as CARRA and PRINTO (Pediatric Rheumatology International Trials Organization) will aid in the development of needed research. Treatment options for children with JIA are frequently limited by FDA restrictions because of the children’s age despite the fact that the children have clinical phenotypes that are similar to the way in which the disease presents in adulthood.

Although treatment algorithms are similar between subtypes, there are a few key differences. Some agents used in adults have demonstrated efficacy and safety and are commonly used by pediatric rheumatologists but have only recently been approved by FDA for use in children. NSAIDs and joint injections may be used as needed. Corticosteroids should be minimized unless MAS is present. Drug approvals for children with JIA have continued to increase. The approval of tofacitinib for polyarticular JIA in 2020 represented access to a new class of medications. At the recent scientific meeting of ACR, Brunner and colleagues (2020) presented the results of the JUNIPERA trial (NCT03031782), a phase 3 trial of secukinumab, which demonstrated efficacy for the treatment of ERA and psoriatic type JIA. FDA granted approval for this drug in late December 2021.

The optimal sequence and timing of csDMARD and bDMARD administration in JIA remains unclear. Start Time Optimization of Biologics in Polyarticular JIA (STOP-JIA) was a prospective, observational CARRA registry study comparing the effectiveness of: (1) Step Up, or initial csDMARD monotherapy, adding biologic if needed; (2) Early Combination, or csDMARD and bDMARD started together; and (3) Biologic First,

or bDMARD monotherapy (Kimura et al., 2021; Ong et al., 2021). The achievement of a clinically inactive disease off steroids did not significantly differ between groups at 12 months. There was a statistically significant higher likelihood of achieving a clinical Juvenile Arthritis Disease Activity Score–10 joints (cJADAS10), low disease activity, and pediatric ACR70 in the early combination group, and these results require further exploration (Ong et al., 2021).

SUMMARY

Inflammatory arthritis is a broad term for a group of chronic autoimmune diseases characterized by joint pain, swelling, warmth, and tenderness in joints along with stiffness that lasts for an hour or more. Most inflammatory forms of arthritis include systemic effects such as skin rashes, eye inflammation, hair loss, and dry mouth. Unlike the more common osteoarthritis, or arthritis that is caused by physical wear and tear of a joint over time, inflammatory forms of arthritis present in children as well as adults. In 2019, inflammatory arthritis accounted for 60 percent of all Social Security disability beneficiaries who were receiving benefits for immune system disorders, not including HIV.

RA is a chronic autoimmune inflammatory disease that predominantly affects the joints. However, given its systemic nature, it may also cause fever, weight loss, marked fatigue, and muscle atrophy as well as other organ-specific features including scleritis, accelerated cardiovascular disease, and interstitial lung disease. The lifetime risk of RA is two to three times higher among women than men. The onset of RA peaks between the ages of 30 and 50 years, although it may occur at any age. Risk factors include older age, a family history of RA, and current or prior cigarette smoking. Mortality in people with RA is 1.5 to 2 times higher than in age- and gender-matched non-RA controls, a difference that is due predominantly to accelerated cardiovascular disease and interstitial lung disease.

The arthritis of RA, as with any inflammatory arthritis, typically presents with joint pain and swelling along with prolonged stiffness in the early morning. Early RA may present in a single joint (monoarthritis) or a few joints (oligoarthritis) but characteristically tends to evolve into a symmetrical polyarthritis of small and large joints which, if left untreated or inadequately treated, will cause damage to articular structures and, ultimately, disability. RA-associated interstitial lung disease may cause severe respiratory impairment leading to the need for a transplant or, sometimes, death; however, the musculoskeletal impairments associated with RA are more commonly the most disabling and the major source of functional limitations for individuals with this condition. This chapter focuses on those impairments, although the committee acknowledges that RA may also

influence global functioning through other mechanisms such as fatigue. The common pathophysiology underlying musculoskeletal impairments in RA is inflammation of the synovium.

Although RA is a chronic disease with daily discomfort, patients also frequently have disease flares. During disease flares, patients experience worsening inflammation, which results in an exacerbation of joint pain and swelling and the potential for new joint damage. In patients with longstanding and severe disease, persistent synovial inflammation will result in the erosion of cartilage and bone, leading to joint destruction and deformities, which in turn cause chronic pain and functional limitations. The goal of RA treatment is to attain and maintain control of disease activity in an effort to reduce symptoms of joint pain and swelling, prevent deformity, maintain quality of life and function, and limit extra-articular disease manifestations. Pharmacologic treatments, specifically DMARDs, are the mainstay of therapy as they limit progressive joint damage and improve function.

PsA is a chronic inflammatory disease of the joints, spine, and entheses. It may affect other tissues as well (e.g., dactylitis, nail involvement, sacroiliitis, enthesitis) and most commonly occurs in association with psoriasis, an autoimmune skin disease manifested by erythematous plaques covered by silvery scales. 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.

The diagnosis of PsA is based on the patient’s clinical history, a physical examination, laboratory findings, and radiography. 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 currently the same as those used for RA and represent composite, multidimensional outcome measures incorporating clinical data, functional assessment, patient-reported symptoms, and global assessment. PsA affects men and women equally, with an average age at diagnosis between 40 and 50. Obesity has been identified as a risk factor for the development of PsA.

JIA, formerly known as JRA, is an umbrella term for several types of inflammatory arthritis in childhood. The subtypes of JIA share the common features of joint pain and inflammation with the adult inflammatory arthropathies. By convention, JIA pertains to children less than 16 years of age with joint inflammation present for 6 continuous weeks. JIA is the most common chronic rheumatic disease of childhood, and it affects approximately 300,000 children in the United States. Once an individual has been diagnosed with JIA, the diagnosis remains for the full extent of disease throughout the individual’s lifespan.

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