Postgraduate Medicine: Volume 121: No.2

An Overview for Primary Care Physicians

Lawrence H. Brent, MD

Abstract: Continuing advances in the treatment of inflammatory arthritides such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) have made remission a realistic goal for patients. Despite these advances, early diagnosis of inflammatory arthritis by primary care physicians (PCPs) and subsequent referral to a rheumatologist remain a challenge. Delayed diagnosis and referral, which may extend to several years in some cases, may lead to irreversible joint destruction and compromised function. The aim of this review is to aid PCPs in preventing the potential delay in disease recognition and patient referral by highlighting the currently accepted criteria for disease activity, clinical response, and remission of RA, AS, and PsA. In addition, a discussion of the benefits and risks of the currently approved traditional disease-modifying antirheumatic drugs and biologic treatments, and the importance of comanagement of these conditions across specialties, will be addressed. Because PCPs are often the first point of contact for disease recognition, they can play a critical role in the management of these patients.

Inflammatory arthritides are a group of chronic inflammatory rheumatic diseases that include but are not limited to rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). The progressive inflammation typically associated with these conditions can lead to considerable pain, joint destruction, and diminished patient function and well-being.¹ Although inflammatory arthritides are associated with significant health care costs, the greatest burden of these conditions is their impact on individuals in terms of physical limitations and disability.²

Fortunately for patients, there has been progress in the management of inflammatory arthritis. Clinicians are moving away from the traditional method of therapy, involving symptom relief with sequential monotherapy, in favor of earlier and more aggressive approaches to gain control of the disease and reduce structural damage and functional decline. Disease remission has now become a realistic treatment goal for many patients. Early recognition of inflammatory arthritis by primary care physicians (PCPs) and subsequent referral to a rheumatologist are vital for patients to obtain the optimal benefit of treatment. This review will provide an overview of disease burden and treatment options for inflammatory arthritis, as well as the importance of comanagement across specialties. Approximately 1% of adults in the United States have RA (Table 1).³ Rheumatoid arthritis is associated with significant pain and disability⁴ that limits ability to work and to engage in everyday activities.^{5, 6} Women with RA experience a greater degree of disease activity, pain, functional decline, and psychological distress than men.^{7, 10} Patients with RA in lower socioeconomic groups experience delayed consultation with a rheumatologist,¹¹ greater disease activity,^12-14 diminished quality of life,¹⁵ and excess mortality¹⁶ compared with those in higher socioeconomic groups. In addition, the disability associated with RA may diminish the ability to work^{5, 17} and participate in social activities.⁶ Rheumatoid arthritis is associated with excess morbidity¹⁸ and mortality, mainly as a result of increased cardiovascular mortality,^{19, 20} increased risk of lymphoma,^{21, 22} and infection.²³ Rheumatoid arthritis is associated with a number of other comorbidities, including osteoporosis and peptic ulcer disease. 18 Patients with RA also experience considerable psychological distress that manifests as depression, anxiety, and fatigue.²⁴ Thus, not surprisingly, patients with RA experience diminished quality of life relative to those without RA.^25-27 Ankylosing spondylitis is the prototypical spondyloarthropathy, and its prevalence ranges from 0.1% to 0.2% in the general US population to 2.5% in the adult Native Alaskan population (Table 1).^{28, 29} Ankylosing spondylitis is associated with significant pain, functional limitation, and mortality.^{30, 31} More than half of AS patients report problems with daily activities, including sleeping, driving, shopping, and having energy for social activities.³² About 1 in 5 AS patients report high disease activity,³³ and about 1 in 4 report severe pain.³³

As well as the characteristic inflammatory back pain and diminished spinal mobility, AS is associated with a number of extraspinal manifestations that contribute to disease burden, including peripheral arthritis, enthesitis (inflammation at sites of tendinous or ligamentous attachments to bone), dactylitis (sausage-shaped swelling of the fingers or toes), uveitis (inflammation of the uvea or middle layer of the eye), and inflammatory bowel disease.³⁴ Like patients with RA, patients with AS report significant fatigue relative to the general population.³⁵ Moreover, patients with AS have a significantly higher prevalence of cardiovascular diseases and associated risk factors.³⁶

The diminished functioning associated with AS leads to a reduced ability to work and a lower quality of life in many affected patients, particularly in women.³⁷ Compared with the general population, patients with AS have a lower rate of employment,38 with nearly one-third of younger patients (aged < 37 years) quitting their jobs because of the disease.³⁹ It is estimated that the prevalence of psoriasis is about 2% in the general US population⁴⁰ and that inflammatory arthritis occurs in 6% to 42% of psoriasis patients (Table 1).⁴¹ Spondylitis is present in up to 40% of patients with PsA; therefore, it is classified as a spondyloarthropathy.⁴¹ Patients with psoriasis have an increased risk for developing the metabolic syndrome.^{42, 43} Accordingly, patients with PsA have a significantly higher prevalence of heart disease, including ischemic heart disease and congestive heart failure (CHF), hypertension, peripheral vascular disease, type 2 diabetes mellitus, and hyperlipidemia.³⁶

Similar to the other inflammatory arthritides described above, PsA can be erosive and destructive, resulting in diminished functional capacity and poor quality of life similar to that of RA.⁴⁴ One in 4 patients with PsA report severe pain as a result of their condition, 1 in 4 consider themselves to be in poor health, and 1 in 8 report severe disability.³³ The skin manifestations of PsA also contribute to disease burden in terms of negative effects on psychological and psychosocial functioning, dissatisfaction with the management of their disease, depression, suicidal ideation, and negative impact on daily living activities.^{45, 46} The extent of RA disease activity can be assessed using the Disease Activity Score (DAS, using a 44-joint count) and the modified DAS that includes a 28-joint count (DAS28). The DAS is calculated using the Ritchie score, the number of tender joints and swollen joints, the erythrocyte sedimentation rate (ESR), and the patient’s general health assessment.⁴⁷ More recently, the Simplified Disease Activity Disease Index (SDAI) and Clinical Disease Activity Index (CDAI) have been used in the evaluation of RA disease activity. The SDAI takes into account swollen and tender joints, patient and physician global assessment, and C-reactive protein (CRP) levels,⁴⁸ whereas CDAI does not take into account acute-phase reactants, such as CRP.⁴⁹

Clinical responses to treatment of RA are measured by the American College of Rheumatology (ACR) criteria and the European League Against Rheumatism (EULAR) criteria (Table 3). The ACR20 criteria define clinical response as a 20% improvement in tender and swollen joint counts and 20% improvement in 3 of 5 core set measures, which include patient global assessment, physician global assessment, pain, disability, and acute-phase reactants.⁵⁰ Similarly, the ACR50 and ACR70 responses are measures of 50% and 70% improvement in both swollen and tender joint counts and 3 of the 5 core set measures.⁵¹ The EULAR response criteria rank patients as good responders, moderate responders, or nonresponders using individual changes in DAS and the DAS score.^{47, 52} The DAS and EULAR criteria offer an advantage over ACR20 because they take into account current disease activity. However, EULAR and ACR20 response criteria performed similarly in their ability to distinguish placebo from treatment.⁵³ Most studies determine remission using either ACR, DAS, or DAS28 criteria.⁵⁴ According to ACR criteria, remission is defined as 5 or more of the following 6 items: morning stiffness lasting ≤ 15 minutes, ESR < 30 mm/h for females or < 20 mm/h for males, and the absence of fatigue, joint pain, tenderness/pain on motion, and joint swelling.⁵⁵ Remission is also defined as DAS < 1.6 and DAS28 < 2.6.^{56, 57}

In addition to assessment of clinical signs and symptoms, patients receiving therapy for RA are typically monitored for radiographic progression. Although conventional radiography is the gold standard for assessment of joint damage, ultrasound and magnetic resonance imaging (MRI) are also increasingly being used. High-resolution ultrasound allows imaging of joint synovitis, tenosynovitis, and erosion and has several potential advantages, including lower cost, relative ease to perform, lack of ionizing radiation, and capability of examining joint regions in different areas of the body with little effort.⁵⁸ Limitations of ultrasound include an inability to penetrate bone and lack of reliability in acquiring and interpreting images (eg, weightbearing surfaces of the joints and surfaces covered or shadowed by overlapping bones).⁵⁸ Magnetic resonance imaging is more sensitive than conventional radiography for identifying erosions and inflammatory changes (eg, synovitis, tendinopathy, bone edema) in affected joints.⁵⁸ Limitations include the cost of the machine and the studies, and decreased specificity in some situations. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) are validated, self-administered assessments of AS disease activity and patient function, respectively (Table 3). The BASDAI is a composite index of a visual analog scale of fatigue, axial pain, peripheral pain, enthesopathy, and morning stiffness.⁵⁹ The BASfiassesses the limitations of daily activities imposed by AS.⁶⁰ Responses in these disease activity measures are used to assess treatment effects. The Assessments in Ankylosing Spondylitis 20% response (ASAS20) is also commonly used to measure improvement with therapy in AS (Table 3).⁶¹ The ASAS 5-out-of-6 response measure, which includes both subjective and objective criteria, was designed for trials of tumor necrosis factor (TNF) antagonists (Table 3).⁶¹

As a result of improving therapies in AS, low disease activity and remission are realistic therapeutic goals. In clinical trials of TNF antagonists, low disease activity has been defined as BASDAI ≤ 3.^{62, 63} Assessments in Ankylosing Spondylitis partial remission is defined as a score of < 20 mm in each of 4 outcomes (visual analog scale of 0–100 mm), which include a patient global assessment in the previous week, spinal pain, function measured by the BASFI, and inflammation measured by the BASDAI.⁶¹ As reviewed by Zochling and Braun, ASAS20 response rates after TNF-a antagonist treatment ranged from 58% to 79%, and rates of partial remission ranged from 0% to 31%.⁶¹ It is worth noting that in a study that reported 0% partial remission at 6 weeks,⁶⁴ a partial remission rate of 33% was observed at 12 weeks,64 and a rate of 31% was observed in a 54-week, open-label follow-up study.⁶⁵

The sacroiliac joints and spine are primarily affected in AS, although peripheral joints and entheses can be affected. Sacroiliac lesions are characterized by irregular erosion and sclerosis, and continued disease progression can result in fusion of vertebrae.²⁸ Radiographic evidence of sacroiliitis can predict development of AS; however, sacroiliac joints may appear normal in early disease.⁶⁶ It should be noted that to date, none of the biologic agents have been definitively shown to alter the radiographic progression of disease in AS. The use of MRI has proven feasible and beneficial in the early detection of sacroiliitis and spondylitis in patients lacking radiographic evidence.⁶⁷ Many of the disease activity and clinical response measures in PsA (Table 3) are adopted from RA and AS because of the considerable similarity of their joint symptoms.^68-71 The Psoriatic Arthritis Response Criteria (PsARC) were developed for assessing PsA patient clinical response and comprise 4 measures: patient global assessment, physician global assessment, tender joint count, and swollen joint count.⁶⁸ The Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire is a self-assessment tool that takes into account both joint symptoms and function.⁷² Psoriasis activity in PsA is often measured in clinical trials using the Psoriasis Area and Severity Index (PASI) and incorporates measures of lesion erythema, induration, scale, and area affected.⁶⁸

Because of the heterogeneity of PsA manifestations and the wide degree of variation required in therapeutic approaches, as well as the lack of consensus in diagnosing PsA, defining remission in PsA has been challenging. Despite these difficulties, new advances in the use of biologic agents in PsA are increasing the plausibility of establishing attainable goals of near remission or low disease activity. Kavanaugh and Fransen⁷³ have recently proposed a series of positions to serve as the basis for future development of PsA remission criteria. Rheumatoid arthritis was once considered to be a relentlessly progressive disease in which treatments provided little hope of significantly improving long-term outcomes.⁷⁴ Over the last 5 to 10 years, improvements in therapy, recognition of the importance of early treatment, and advances in clinical trial design and in measures of disease activity are cause for optimism among clinicians treating patients with inflammatory arthritis. Several strategies have been used for more effective control of RA progression in patients with active disease, including the early use of conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate or the use of biologic agents as monotherapy or in combination with conventional DMARDs, tighter disease control with prespecified clinical endpoints, and the induction of remission with biologic agents followed by maintenance therapies with DMARDs.⁷⁵

Disease-modifying antirheumatic drug therapy, particularly methotrexate at higher doses (up to 20–25 mg per week), can be an effective treatment approach for RA.⁷⁶ The acceptance of this approach has been reflected in changing treatment patterns over time. Pincus et al⁷⁷ reported that the range of methotrexate doses in the treatment of RA increased from 7.5 to 15 mg per week to 5 to 30 mg per week from 1985 to 2000.

An overview of approved biologic agents and their indications as they relate to inflammatory arthritis is presented in Table 2. Clinical trials of drugs targeting TNF-a in combination with methotrexate have shown significant improvements in ACR response criteria and in measures of radiographic progression.^78-80 More importantly, treatment is now more frequently aimed at achieving low disease activity or remission. Indeed, for many patients, remission is an appropriate goal of treatment for RA,⁷⁴ AS,⁶¹ and PsA.⁷³ As well as the TNF-a antagonists, 2 recently approved agents for treating inflammatory arthritis include abatacept, a costimulation modulator that prevents T-cell activation, and rituximab, a monoclonal antibody that depletes CD20+ B cells. These agents have demonstrated improvements in clinical symptoms and patient-reported outcomes as well as slowing of joint damage.^81-86 Other avenues of investigation for the treatment of inflammatory arthritides include agents targeting interleukin-6 (IL-6),^{87, 88} IL-1, IL-15, IL-17, IL-22, janus kinase, spleen tyrosine kinase, and p38 mitogenactivated protein kinase pathways.^89-91 Early aggressive treatment of RA has a sound rationale: radiographic evidence of joint damage is found in up to 70% of RA patients within 2 years of symptom onset,⁹² disease progression may be greater early in the disease course (ie, in the first year),⁹³ and long-term joint damage can result from delays in initiation of treatment of as little as 4 months.⁹⁴ Recent data also suggest that early and intensive intervention improves employment outcomes in patients with RA.⁹⁵ These observations support the concept that the earlier treatment is initiated, the better the chances of halting or slowing the rate of disease progression with aggressive treatment.⁹⁶

Ample data support the aggressive treatment of early RA, demonstrating that combination therapy, usually consisting of methotrexate and a TNF-a antagonist, often results in higher rates of clinical remission and less radiographic progression than monotherapy, conventional sequential therapy, or step-up therapy (Table 4). Early intervention with traditional DMARD therapy can control disease activity and delay disease progression.^{94, 97, 98} Intensive treatment with DMARDs to achieve tight control of disease has been shown to improve disease activity and reduce radiographic progression in early RA.⁹⁹ Combination DMARD therapy (methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone) was shown in the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) study to be more effective at achieving remission than monotherapy.¹⁰⁰ Adding infliximab to the FIN-RACo combination DMARD therapy regimen resulted in a higher percentage of early RA patients achieving remission (70% vs 53%; P = 0.08) at 24 months compared with combination DMARD therapy alone.¹⁰¹ In the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset, combination therapy with infliximab (6 mg/kg per dose) plus methotrexate was associated with significantly higher rates of remission and less radiographic progression at 54 weeks than methotrexate monotherapy.⁸⁰ A subsequent analysis reported that patients with high CRP levels, ESR, or persistent disease activity experienced greater radiographic progression while taking methotrexate alone, whereas patients receiving combination therapy experienced little radiographic progression, even in the presence of high levels of these predictors of disease activity.¹⁰² Similarly, about one-third of all patients in the Behandel Strategieën (BeSt) study experienced clinical remission, and the combination therapy groups showed less radiographic progression than the monotherapy or step-up combination therapy groups (Table 4).¹⁰³ Interestingly, once patients in the BeSt study achieved a DAS ≤ 2.4 with intense therapy, they were likely to experience continued low disease activity without therapy adjustments, regardless of treatment group.¹⁰⁴ These results confirm that patients clearly benefit from early interventions based on tight monitoring of disease activity. Although no studies have specifically evaluated the effects of early aggressive treatment of AS and PsA, the available clinical literature suggests that the TNF-a antagonists currently in use produce substantial clinical structural benefits in these conditions.^{61, 105} Thus it is reasonable to expect that, as observed with RA, the management of AS and PsA would benefit from earlier and more aggressive interventions to improve physical function and quality of life. Patients with RA see multiple health care providers and experience frequent discontinuity of care,¹⁰⁶ therefore it is important that PCPs facilitate care and management across multiple providers. Because the inflammatory arthritides discussed in this review are primarily clinical diagnoses and because complications begin to develop within months of presentation, early referral to a rheumatologist may be important to confirm the initial diagnosis. Early recognition and/or referral are also important because early treatment improves the chance of achieving good outcomes and possibly remission, and reducing structural damage. Moreover, RA care is improved (through increased use of DMARDs and combination therapy) when rheumatologists are involved continuously rather than intermittently.¹⁰⁷ Early referral recommendations for patients with suspected RA include the presence of any of the following: ≥ 3 swollen joints, metacarpophalangeal and metatarsophalangeal joint involvement (positive squeeze test), or morning stiffness of ≥ 30 minutes (Figure 1).¹⁰⁸ Delay in diagnosis (which can be as long as 8–10 years) is a long-standing challenge in AS.^{34, 109} This may be explained in part by low awareness of the condition, slow progression to radiologic sacroiliitis needed to confirm diagnosis, and the lack of well-defined clinical indicators to help with early detection.¹¹⁰ A set of screening parameters has been suggested to assist PCPs in identifying patients for rheumatologist referral (Figure 2).¹¹¹ Similarly, a set of classification criteria for PsA has been proposed (Table 5) that can assist PCPs in identifying patients for referral.¹¹² Primary care physicians should be aware of comorbidities associated with inflammatory arthritides, including the increased risk of cardiovascular disease, metabolic syndrome, malignancy, and infection. Primary care physicians also need to be aware of potential complications associated with DMARDs and biologic agents commonly used in inflammatory arthritis therapy. For example, methotrexate has been associated with pneumonitis.¹¹³ In addition, patients should be monitored for liver and hematologic toxicities during methotrexate therapy.¹¹⁴ As summarized in Table 6, complications from biologic agents may include infusion/injection site reactions, infections, the potential for reduced effectiveness of immunizations, mucocutaneous reactions, cytopenias (mostly leukopenia), and more rare events such as demyelinating disorders associated with TNF-a antagonists and progressive multifocal leukoencephalopathy with rituximab. Serious infections are a major concern in patients with inflammatory arthritides. The risk of infections attributable to biologic agents and DMARDs is difficult to ascertain because inflammatory rheumatic disease is itself associated with an increased risk of serious infections (particularly opportunistic infections).¹¹⁵ Moreover, not surprisingly, inhibition of TNF-a, B cells, and T cells by biologic agents or a reduction of white blood cells by methotrexate can increase the risk of infection, given that these mediators play vital roles in host defense. Infections reported with TNF-a antagonists include tuberculosis, including reactivation of latent tuberculosis, therefore patients should be tested for latent tuberculosis before initiating TNF-a antagonist therapy. Patients on TNF-a antagonists are also at increased risk for histoplasmosis, coccidioidomycosis, and other fungal infections.

An increased risk of lymphoma has been reported in RA patients receiving TNF-a antagonists; 21 however, there is also a well-established increased risk for lymphoma in RA patients, particularly in those with higher disease severity.¹¹⁶ Therefore, it is difficult to determine whether lymphoma risk is really increased in patients with RA treated with TNF-a antagonists.¹¹⁷ Nonetheless, because an enhanced risk cannot be excluded, it is prudent to monitor patients for the development of lymphoma. Signs and symptoms include swollen, painless lymph nodes in the neck, armpit, or groin areas, fever, night sweats, fatigue, weight loss, abdominal pain or swelling, chest pain, coughing or shortness of breath, and extremely itchy skin.¹¹⁸

The incidence of cardiovascular disease and CHF risk is elevated in patients with inflammatory arthritides,^{36, 119, 120} and there have been reports of worsening CHF in patients receiving TNF-a antagonists. Therefore, patients should be monitored carefully while receiving these drugs.^121-123 Patients receiving TNF-a inhibitors can develop autoantibodies and, rarely, a lupus-like syndrome.^121-123 Live vaccines should not be administered to patients receiving biologic agents.^121-125 The ultimate goal of treating inflammatory arthritis is to prevent or minimize long-term sequelae, such as joint damage, loss of function, and loss of ability to work and/or perform everyday activities. Early recognition of the signs and symptoms of inflammatory arthritis by PCPs, followed by referral to a rheumatologist for confirmation and treatment, is critical to optimize patient outcomes. Primary care physicians are often the first point of contact for disease recognition, and given the discontinuity of care across specialties, can play a critical role in the management of this patient population. Moreover, because the availability of rheumatologists can make it difficult for patients to be referred early, PCPs may consider beginning therapy in obvious high-risk patients. The author would like to thank Rick Davis, MS, RPh, and Benjamin Scott, PhD, whose work was funded by Amgen Inc., for providing assistance in the drafting of this manuscript. Editorial support was provided by Complete Healthcare Communications. Lawrence Brent, MD discloses conflicts of interest with Abbott Laboratories, Amgen, Inc., Genentech, Trubion, and Wyeth.



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