Management of Rheumatoid Arthritis: The Newly Diagnosed Patient

CASE STUDY

A 32-year-old woman presents with a 4-month duration of pain rated at 8 on a scale of 1 to 10 and swelling in her hands, wrists, left elbow, right knee, ankles, and forefeet. This started initially with 2 months of bilateral wrist and forefoot pain and progressed over time to involve more joints. She is currently 10 months postpartum, after having given birth to her third child. She has a history of 3 cesarian births and an appendectomy. She is an ex-smoker, having stopped 7 years ago, and uses no alcohol. She had no associated history of photosensitivity, alopecia, nasal mucosal ulcers, rashes, fevers or weight loss. She is experiencing many difficulties in performing homemaking tasks, particularly in lifting and bathing her young son. The general physical examination revealed no rashes, nodules, adenopathy, or other findings. The musculoskeletal exam revealed eight swollen and tender, and two tender-only joints out of 28, as revealed in Figure 2-1 . Her metatarsal phalangeal joints were also noted to be very tender and swollen. She rated her disease activity as an 8 on a scale of 1 to 10. Initial investigations revealed that she had an antinuclear antibody test score (ANA) of 1:80, a positive rheumatoid factor (RF) of 53 IU, and a normal chest radiograph. The anti–cyclic citrillinated peptide (anti-CCP) test was 100 IU. Radiographs of the hands and feet showed soft tissue swelling at the proximal interphalangeal joint and wrist joints, and periarticular osteopenia of the hands. No erosions or joint space narrowing were noted. Her baseline liver function tests were normal; Hepatitis B and C status were negative. The C-reactive protein (CRP) was elevated at 23.5 mg/L. We rated her disease activity as a 7 on a scale of 1 to 10.

New-Onset Rheumatoid Arthritis

When a patient presents with new onset inflammatory polyarthritis consistent with rheumatoid arthritis (RA), initial principles of management are to (1) confirm a diagnosis, (2) provide the patient with an understanding of his or her disease process and potential prognosis, (3) provide opportunities for physical/occupational therapies and information about exercise. You also need to discuss factors that the patient may be able to control (e.g., dietary and lifestyle changes) and advise how to learn about self-management. These are important aspects of therapy, as is a complete investigation and initiation of pharmacotherapy.

INITIAL EVALUATION AND INVESTIGATION

Patients presenting with a history of at least 12 weeks of synovitis, fulfill the American College of Rheumatology (ACR) criteria for the classification of RA, and would be considered to have newly diagnosed or early RA. It is important to note that the ACR criteria are worthwhile for classification purposes but not for diagnostic purposes in clinical practice. If a patient is seen very early in the course of disease (within 12 weeks of onset of symptoms), disease-modifying antirheumatic drug (DMARD) therapy will be recommended once other causes of inflammatory arthritis are excluded. When faced with patients with early disease such as in our case, it is important to characterize the extent of disease severity and look at predictors of prognosis to determine if they are at risk for rapid radiographic deterioration. To this end, initial investigations to consider include radiographs of the hands and feet, as well as acute-phase reactants (erythrocyte sedimentation rate, CRP), a tender and swollen joint count, and a RF and anti-CCP antibody. In the future, there may also be a potential role of magnetic resonance imaging (MRI) or musculoskeletal ultrasound (US) with power Doppler (PD) studies to characterize the extent and severity of synovitis and identify early bony erosions unrecognized on baseline radiographs.

Recent guidelines from the ACR and the European League Against Rheumatism (EULAR) recommend the use of standardized composite outcome measures to aid in therapeutic decisions with regard to the treatment of RA. In the absence of having a full questionnaire completed inquiring more detailed information based on patient-reported outcomes, the simplest outcome measures include the Disease Activity Score 28 (DAS28) (erythrocyte sedimentation rate [ESR] or CRP) the Simplified Disease Activity Index (SDAI) or the clinical disease activity index when a CRP level is not available. The calculation of these and value ranges indicating remission, low, moderate, and high disease activity are shown in Tables 2-1 and 2-2 .

Table 2-1

Calculation of Clinical Outcome Measures

	DAS 28	SDAI	CDAI
Swollen joint count	0.28 × √(0–28)	0–28	0–28
Tender joint count	0.56 × √(0–28)	0–28	0–28
Patient global score	0.014 × (0–100)	0–10	0–10
Physician global score		0–10	0–10
ESR	0.70 × Ln(ESR)
CRP (mg/dL)		0.1–10
Range of score values		0.1–86	0–76

DAS, Disease Activity Score; CDAI, Clinical Disease Activity Index; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; SDAI, Simplified Disease Activity Index.

Table 2-2

Current and Proposed Definitions of Disease Activity

Index	Disease Activity State	Original Definition	Newly Proposed Definition
SDAI	Remission	≤5	≤3.3
	Low disease activity	≤20	≤11
	Moderate disease activity	≤40	≤26
	High disease activity	>40	>26
CDAI	Remission		≤2.8
	Low disease activity		≤10
	Moderate disease activity		≤22
	High disease activity		>22
DAS28	Remission	≤2.6	≤2.4
	Low disease activity	≤3.2	≤3.6
	Moderate disease activity	≤5.1	≤5.5
	High disease activity	>5.1	>5.5

CDAI, Clinical Disease Activity Index; DAS, Disease Activity Score; SDAI, Simplified Disease Activity Index.

From Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23(Suppl 39):S100–8.

Based on these scoring instruments, our patient’s pretreatment DAS28 was 5.8, her SDAI was 36, and her CDAI was 33, confirming that her disease activity was moderate to high after 4 months of symptoms of inflammatory arthritis consistent with RA.

DISCUSSION OF PROGNOSTIC FACTORS

Patients with new-onset RA can have a variable disease course. Anywhere from 10% to 30% of patients are at risk for developing rapid and potentially severe deterioration. Selected markers of poor prognosis have been identified ( Table 2-3 ). When more than one of these poor prognostic factors is present, it is possible that even with effective nonbiologic DMARDs, patients will have suboptimal responses. Patients who do not reach a low disease activity state by month 4 will continue to have more radiographic damage. Thus, it is important to estimate the patient’s prognosis based on available clinical tools to identify which patients merit close follow-up in the initial stages, to identify earlier than later those who may need an adjustment in their treatment paradigm.

Table 2-3

Markers of Poor Prognosis in Patients Presenting with Early Rheumatoid Arthritis

Young age

Female gender

High titers of rheumatoid factor (RF), and/or anticyclic citrullinated peptide antibodies (anti-CCP)

Evidence of early erosive disease

Elevated acute phase reactants: ESR or CRP

High disease activity measure by the DAS28, SDAI, or CDAI

Extra-articular disease (Sjögren’s, pulmonary disease)

CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; SDAI, Simplified Disease Activity Index.

An anti-CCP test was performed on this patient to provide more information on the prognosis of her inflammatory arthritis. Lee et al. summarized the emerging data that a positive anti-CCP can provide prognostic information on the severity of the disease, and the likelihood that the arthritis will rapidly worsen. They note that in numerous studies, patients with anti-CCP antibodies have more radiographic damage and progression than those without anti-CCP. This patient had high titers of anti-CCP levels (100 IU), indicating that her disease may not respond well to initial treatment with DMARDs and that she merits a treatment approach that will rapidly result in full control of her synovitis so as to reduce the risk of rapid radiographic progression.

ROLE OF HIGH-SENSITIVITY IMAGING IN THE INITIAL EVALUATION OF PATIENTS WITH NEWLY DIAGNOSED RHEUMATOID ARTHRITIS

Despite the normal radiographic findings in our case, there may be a potential benefit to know if she has subclinical erosions. This would be of particular importance had there not been other features of poor prognosis such as a high CRP or positive anti-CCP antibodies. Researchers are now evaluating the role of high-sensitivity imaging including MRI or US with PD studies of the dominant wrist or metacarpophalangeal joints (MCPs) to provide more information as to the patient’s risk of further disease progression based on presence or absence of early subclinical erosions.

To further investigate whether there is a rationale for MRI using either high-resolution MRI machines (≥ 1.5 Tesla) with or without gadolinium or lower Tesla (0.2–1.0) office-based units on the dominant wrist or MCPs, a limited number of studies have been performed. To date, these studies have involved only small numbers of patients and have not yet fully evaluated the role of this technology in clinical practice. A recent review by the American College of Rheumatology Extremity Magnetic Resonance Imaging Task Force concluded that there is currently insufficient evidence for employing MRI in patients with early-stage inflammatory arthritis. This was based on the paucity of longitudinal trials to show prognostic capabilities of this technique, poor positive and negative predictive capacity of this modality, and the lack of trials to show that information obtained with peripheral MRI may alter the clinical decision-making process or impact clinical outcomes. Nonetheless, as further studies are undertaken, this viewpoint may change.

GOALS OF THERAPY IN THE NEWLY TREATED PATIENT WITH RHEUMATOID ARTHRITIS

The goal of medical treatment in RA patients is to achieve a state of low disease activity and, if possible, a state of remission, in order to minimize structural damage and improve functional status. Our patient has a number of clinical features to suggest that she could have a poor clinical outcome including young age, female gender, high disease activity as noted by a high number of tender and swollen joints, a high CRP, and a positive RF and anti-CCP antibody. A number of treatment strategies are discussed, including how they can be implemented to achieve this goal.

Joint damage can be viewed from two perspectives: (1) soft tissue damage seen as deformities that occur rapidly as a result of nature’s forces acting on joints whose capsules have undergone prolonged distention causing ligamentous laxity, and (2) radiographic damage defined as joint space narrowing and marginal bony erosions. The latter is more easily measured, with validated scores measuring radiographic damage becoming a key outcome along with clinical and functional measures to evaluate the success of either DMARD or biologic therapy. While progression of radiographic abnormalities has limited effects on function initially, over time, accumulation of destruction is associated with a decline of functional capacity and quality of life, making the elimination of radiographic progression a key goal in therapy.

Debates remain as to whether the goal of reaching, at minimum, a state of low disease activity and, at best, a state of EULAR clinical remission is sufficient. Recent studies suggest that more stringent outcomes should be targeted in terms of goals of treatment, indicating that true remission will be achieved only when synovitis is fully eliminated and only then will radiographic progression be halted. In a recent study evaluating the frequency of inflamed joints in patients thought to be in clinical remission, 42 of 102 patients defined as being in sustained clinical remission using the DAS28 score of less than 2.6 followed for 1 year, 87% still had synovial hypertrophy and 56% had increased PD signals on musculoskeletal ultrasound. Despite being in clinical remission, 19% of the patients displayed deterioration in joint damage using high sensitivity imaging instruments over the study period. Whether or not these high-sensitivity imaging techniques should be routinely incorporated into daily practice to determine whether achieving a state of true remission yields better functional outcomes remains to be proven. The current trend among rheumatologists is to use an optimal treatment strategy to eliminate synovitis. To that end, our patient was immediately started on methotrexate (MTX) therapy (by subcutaneous injections) at 15 mg weekly and increasing over 2 to 4 weeks to 25 mg subcutaneously, and her knee, elbow and wrists were injected with glucocorticoids. The rationale for this particular treatment regimen is explained in the next section.

INITIAL TREATMENT STRATEGY IN THE PATIENT WITH NEWLY DIAGNOSED RHEUMATOID ARTHRITIS

Treatment goals of RA have changed significantly over the past decade. Previously, a conservative strategy was used in which DMARDs were initiated only when the diagnosis was established and a trial of nonsteroidal anti-inflammatory drugs had failed. Now, a preventive strategy is used in which DMARDs are initiated from the first recognition of synovitis in conjunction with typical features of RA such that the current standard of care is to immediately initiate DMARD therapy in the newly diagnosed RA patient to ideally induce a remission and halt joint damage. It is still not known why some patients even with early institution of DMARD therapy continue to have active disease. Studies are in progress to determine if serum biomarkers, genetic profiling, and proteomic studies will help identify those patients who continue to experience progression of damage despite drug therapy. What also remains inconsistent among clinicians is determining what should be the ideal initial treatment approach. Recent treatment guidelines and recommendations are not consistent as to which DMARD should be the first chosen for patients such as ours. Conventional nonbiologic DMARDs, meaning small molecules that reduce inflammation and have structure-modifying properties, are used as monotherapy or in combination during the long-term therapy of RA. The most frequently used DMARD is MTX, which is now considered the anchor drug of RA treatment.

In light of the many published clinical trials studying recently diagnosed patients with RA, it has become clear that the most effective initial therapy is MTX. The ACR has recently published recommendations for the use of nonbiologic and biologic DMARDs. Following a systematic review of the scientific evidence, a series of treatment algorithms were developed based on disease duration and features of poor prognosis, which were validated using a series of clinical scenarios ( Fig. 2-2 ).