Pharmacotherapy and Management Guidelines

A New Treatment Paradigm

Early diagnosis leads to earlier treatment. With earlier treatment of rheumatoid arthritis (RA), there is a better chance for less radiographic damage, less disability and thus lower overall costs of care. Since morbidity and mortality in RA are consequences of uncontrolled inflammation, early and aggressive interventions may also improve morbidity and mortality rates in RA. With the introduction of newer therapies and more aggressive treatment approaches in the last 4 decades, there is evidence that fewer surgical interventions have been needed for RA patients. Data have also shown that RA patients on methotrexate (MTX), combination therapy, or tumor necrosis factor (TNF) inhibitors experience less morbidity and mortality, presumably the result of abrogating the effects of systemic inflammation on cardiovascular risk.

In years past, treatment of the newly diagnosed RA patient was guided by the so-called ‘therapeutic pyramid’ paradigm. This approach was based upon the prevailing view at the time that RA was in general a benign disease that might remit or respond to modest therapies and that the potential adverse effects of the therapies generally outweighed the possible benefits in treating the disease. Under this paradigm, each patient’s care began with education, rest, exercise and physical therapy. Drugs then were added sequentially, based on their presumed safety and their ability to minimize pain, inflammation and disability. Analgesic agents, salicylates and other nonsteroidal anti-inflammatory drug (NSAIDs), utilized first and often, were the mainstays of therapy.

The use of the so-called disease-modifying drugs (DMARDs), such as hydroxychloroquine (HCQ), injectable gold salts, or D-penicillamine was added when NSAID treatment failed. DMARDs were considered to require 6 to 12 months of use for their benefit, lack of benefit, or side effects to be realized. The convention was to switch to another DMARD when lack of efficacy or toxicity was noted. Steroids, immunosuppressive and cytotoxic agents, investigational drugs and surgery were reserved for the patients with the most refractory disease, often late in the disease. This approach has been largely abandoned for several reasons.

It is now appreciated that RA is a chronic progressive disease in nearly all patients and that damage to the joints begins early in the disease. In fact, nearly 70% of patients ultimately developing articular erosions will manifest some damage within 2 years of disease onset. Studies of the traditional DMARDs have shown them (and NSAIDs) to be symptom modifying rather than disease modifying, meaning they do not generally alter the natural progression of the disease for the majority of patients. Moreover, the durability of DMARDs was disappointing as only 20% to 40% of patients remained on these drugs after 2 years.

Early Referral to a Rheumatologist

Patients with early RA are rarely seen by a rheumatologist during the first few months of symptoms. Reasons for this are several and may include patient reluctance to seek medical attention (especially for new, nonlimiting symptoms), variable self-referral (to primary care physician (PCPs), orthopedists, etc.), lack of health care access and limited access to rheumatologists. These patients are often seen by a PCP who provides the initial evaluation, testing and empiric therapy. Fortunately, many patients with symptoms of only a few days or weeks will have a self-limited process and may not require prolonged or specialized care.

On the other hand, patients with persistent joint complaints (>6 to 12 weeks) may benefit from an early and accurate diagnosis that can be confirmed by a rheumatology consultation. Early consultation will help to establish or confirm the diagnosis, avoid unwarranted testing or imaging, initiate appropriately aggressive therapy and establish a cooperative plan of care with the patient and the PCP. The PCP should be encouraged to initiate testing and NSAIDs or corticosteroids at first evaluation and obtain an expedient consultation with a rheumatologist if symptom duration or signs warrant.

Emery and colleagues have suggested guidelines for early referral of RA patients (Table 6-2) that include the presence of synovial swelling in three or more joints, 6 weeks of symptoms, a positive metacarpophalangeal (MCP) squeeze test, an elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or serum rheumatoid factor (RF), or anti-cyclic citrullinated (CCP) antibodies. Less predictive of an RA diagnosis are family history of RA, marked fatigue, prolonged morning stiffness, positive ANA test, or a favorable response to steroids or NSAIDs.

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Initial Choice of Therapy

Patients with early arthritis will seek help from a variety of sources and providers and for a variety of reasons. Foremost among these will be pain, stiffness, or functional impairment. Patients need not manifest red, warm, or swollen joints at the outset to have an inflammatory arthritis or early RA. Moreover, several reports have suggested that a variable percentage (6% to 55%) of early arthritis patients will evolve into RA patients. Regardless, the clinician is faced with the challenge of making a timely and accurate diagnosis while responding to the patient’s complaints. NSAIDs and/or low-dose corticosteroids are often used as initial therapy while the clinician’s evaluation continues over time. For patients with early undifferentiated arthritis, Quinn and colleagues evaluated a pragmatic step-up approach in 100 patients with early undifferentiated arthritis of the hands, by employing either:

NSAIDs

A single intramuscular or intraarticular corticosteroid injection

DMARD therapy.

The best outcomes were observed in those who achieved an early remission with NSAIDs or steroid injection. Persistence of synovitis beyond 12 weeks was predictive of the development of RA (14% of patients) and the need for DMARD therapy (30% of patients). Those with synovitis 12 months later were more likely to be seropositive for RF and have polyarthritis at the outset. This study underscores the value of both an initial graded approach to therapy, a crucial 12-week reassessment for the persistence of symptoms, and the need for early DMARD initiation.

Disease/Risk Stratification

PCPs and rheumatologists alike need to assess the persistence and severity of the patient’s disease at the first encounter and, if symptoms persist, plan for frequent reassessment. Several clinical, laboratory and imaging features have been associated with aggressive disease and poor outcomes in RA. A poor outcome in RA would include articular erosions, deformity, disability, the need for surgical intervention and even premature death. The predictive factors for poorer outcomes include polyarticular arthritis (e.g., ≥10 joints involved), functional disability, the presence of extra-articular manifestations (i.e., rheumatoid nodules), high serum titers of RF or anti-CCP antibodies (also known as ACPA), persistently elevated serum levels of acute-phase reactants (e.g., ESR, CRP), radiographic evidence of bony erosions, or the presence of the shared epitope (specific HLA-DR alleles, such as HLA-DR4 associated with RA risk and severity).

Patients with low socioeconomic status and fewer years of formal education are more likely to exhibit a poor clinical outcome, possibly related to factors such as limited access to medical care, financial hardship and suboptimal patient compliance with a resultant augmented risk for comorbidities. These prognostic factors appear to predict the poorest outcomes in RA. Based on such prognostic features, some have suggested that patients can be stratified as having either slowly progressive or aggressive RA (Table 8-1). This schema underscores that in either instance, RA is a progressive disorder and requires chronic, if not aggressive, treatment.

Patients with slowly progressive RA may be seronegative, with few tender or swollen joints, low or absent levels of rheumatoid factor (RF), CRP, or ESR and appear to develop disability or radiographic damage at a much slower rate. Several studies have shown better outcomes in RA patients who are seronegative for both RF and CCP antibodies. Patients with slowly progressive disease are often treated more conservatively with the early use of NSAIDs, intraarticular steroid injections, low-dose oral corticosteroid and DMARD therapies (MTX, hydroxychloroquine (HCQ), or sulfasalazine (SSZ)).

Patients with aggressive RA are at significant risk for poorer outcomes, and as such, this phenotype mandates a prompt and aggressive approach to therapy. Aggressive RA may be identified early or late in the disease. Such patients will often be seropositive, have many involved joints and experience functional impairment. Nodules, radiographic erosions and laboratory abnormalities (e.g., RF, ESR, CRP) are commonly found in such patients. While NSAIDs and corticosteroids are often used, they are insufficient to control rheumatoid inflammation. In such cases, early aggressive DMARD, combination or biologic therapies are needed. MTX is the most commonly used DMARD in aggressive-RA patients. Other agents commonly employed for aggressive RA include SSZ, leflunomide, combination DMARDs, biologics (i.e., etanercept, infliximab, adalimumab, golimumab, certolizumab; abatacept, rituximab, tocilizumab and sarilumab) and targeted synthetic DMARDs (e.g., JAK inhibitors: tofacitinib, baricitinib, upadacitinib). The most commonly used combination at present is MTX in combination with biologic therapies (especially TNF inhibitors). The efficacy and safety of these aggressive regimens in patients with early RA has been demonstrated in several trials.

Classification of RA as either slowly progressive or aggressive is an ongoing dynamic process that may be modified by appropriate therapy. Hence cases initially labeled as slowly progressive may become more aggressive with time. Close follow-up and repeated evaluations are imperative to assess changes in severity, treatment response and the need for more aggressive therapy. These follow-up evaluations must assess disease activity, changes in functional status, response to the therapy (e.g., control of pain and inflammation) and development of adverse effects related to therapy.

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“Treat-to-Target” Strategy

In many other areas of medicine, treatment targets have been defined to improve outcomes in chronic, progressive conditions, leading to a reduction in the risk of organ damage. For example, ongoing treatment decisions for patients with diabetes, hyperlipidemia and hypertension are guided by specific treatment targets such as blood lipid values, blood glucose and HbA1c levels and blood pressure. If established target values are not achieved, the therapy is adapted accordingly.

Over the past 15 years, particularly since the introduction of biologic DMARDs (bDMARDs), there have been many paradigmatic changes in the treatment of RA. Today, remission, or at least low disease activity, may be an achievable goal in many patients. Furthermore, rapid attainment of remission or low disease activity has been shown to halt joint damage and improve long-term outcomes irrespective of the type of DMARD, synthetic or biological. The key to such success is tight control of disease activity—inflammation in RA. A post-hoc analysis of data from the PREMIER and OPTIMA trials found that baseline disease activity was one of the strongest predictors of MTX failure and addition of adalimumab after MTX failure was associated with better clinical, functional and radiographic outcomes.

Recommendations for implementing a “treat-to-target” paradigm were developed by an international expert committee. The specific recommendations were based on several overarching principles, namely: the primary goal of treating the patient with RA is to maximize long-term health-related quality of life through control of symptoms, prevention of structural damage and normalization of function and social participation. Abrogation of inflammation is the most important way to achieve these goals and treatment to target by measuring disease activity and adjusting therapy accordingly optimizes outcomes in RA. The specific recommendations are listed in Table 8-2. These basic recommendations for a treat-to-target strategy are generally reflected in the most recent ACR and EULAR treatment recommendations.

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American College of Rheumatology (ACR) Guidelines

In 2021, the ACR updated their 2015 guidelines for the use of pharmacotherapy in RA. Unlike earlier ACR guidelines which divided recommendations based on disease duration (early or late), the new recommendations instead highlight the importance of the level of disease activity, prior therapies used and the presence of comorbidities on treatment choices. As in the 2015 guidelines, prognostic factors are were not directly considered by the panel while devising the population, intervention, comparator and outcomes (PICO) questions that guided the literature search for the 2021 guidelines. The panel devised new PICO questions and developed a total of 44 recommendations (7 strong and 37 conditional) on DMARD initiation, MTX administration (new in 2022), treatment modification, DMARD tapering and specific patient populations (expanded to include patients with subcutaneous nodules, pulmonary disease, non-alcoholic fatty liver disease, persistent hypogammaglobulinemia without infection and nontuberculous mycobacterial lung disease).

MTX remains the cornerstone initial therapeutic agent for DMARD-naïve patients with moderate-to-severe RA (strong recommendation). Addition of a bDMARD or a targeted synthetic DMARD (tsDMARD) is conditionally recommended over addition of sulfasalazine and HCQ (triple therapy) for patients who do not meet their treatment target on maximally tolerated MTX monotherapy. The centrality of the treat-to-target approach is maintained, with a strong recommendation for bDMARD- or tsDMARD-naïve patients and a conditional recommendation for patients with inadequate response to bDMARDs or tsDMARDs. In contrast to the earlier guidelines which recommended DMARD tapering for patients in remission, the 2021 guidelines conditionally recommend continuation at the current dose over dose reduction, dose reduction over gradual discontinuation and gradual discontinuation over abrupt discontinuation. Recognizing the long-term toxicity of glucocorticoids, the guidelines strongly recommend against their long-term use, limiting it to the lowest effective dose for the shortest possible duration. For additional recommendations, refer to the guidelines publication.

ACR Guidelines for Vaccination in Patients with Rheumatic and Musculoskeletal Diseases (RMD)

In addition to the pharmacologic guidelines described above, in 2022 the ACR issued a guideline focused on vaccinations in patients with RMD, including RA. The guideline contains recommendations on the use of specific vaccines in patients with RMD and whether to hold medication or delay vaccination in patients on immunosuppressive medication for RMD.

Recommendations for specific vaccines include:

• Influenza vaccination: For adult patients (>18 years of age) with RMD who are on immunosuppressive medication, a high-dose or adjuvanted influenza vaccine is conditionally recommended over a regular-dose influenza vaccine.
• Pneumococcal vaccination: Strongly recommended for patients with RMD <65 years of age who are on immunosuppressive medication.
• Recombinant zoster vaccine: Strongly recommended for patients with RMD >18 years of age who are on immunosuppressive medication.
• HPV vaccine: Conditionally recommended for patients with RMD >18 and <45 years of age who are on immunosuppressive medication and not previously vaccinated against HPV.

The guideline conditionally recommends giving multiple vaccines on the same day over individual vaccines on separate days for RMD patients.

Recommendations for medication management at the time of non-live attenuated vaccine administration include:

• Immunosuppressive medications: see Table 8-3 for conditional recommendations.
• Glucocorticoids: All non-live attenuated vaccines are strongly recommended for patients taking prednisone ≤10 mg daily or the equivalent dose of another glucocorticoid and conditionally recommended for patients taking prednisone >10 mg and <20 mg daily or the equivalent dose of another glucocorticoid. Influenza vaccination is conditionally recommended for patients taking prednisone ≥20 mg daily or equivalent, while it is conditionally recommended to defer non-influenza non-live attenuated vaccination until glucocorticoids are tapered to the equivalent of prednisone <20 mg/day.

Recommendations for medication management at the time of live attenuated vaccine administration include:

• For patients with RMD who are receiving immunosuppressive drugs, it is conditionally recommended to defer live-attenuated vaccines.
• Holding immunosuppressive medication for an appropriate period before and after vaccination (see Table 8-4) is conditionally recommended for patients with RMD.

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EULAR Guidelines for Management of RA

The European League Against Rheumatism (EULAR) developed their first set of recommendations for the management of RA with DMARDs in 2010. These guidelines have most recently been updated in 2022 and are based on disease activity and other patient factors, such as structural damage, comorbidities and safety issues. The guidelines recommend that DMARD therapy be initiated as soon as the diagnosis of RA is made. MTX should be part of this initial strategy, unless patients have a contradiction to MTX, in which case leflunomide or sulfasalazine should be considered. If the treatment target is not achieved with the first conventional DMARD (csDMARD) strategy, then other csDMARDs should be considered in the absence of poor prognostic factors. If poor prognostic factors are present, the addition of a bDMARD or a tsDMARD should be considered. Refer to the treatment algorithm (Figure 8-1) for additional information.

Recommendations specifically for the management of early arthritis have also been published by EULAR, with the most recent update in 2016. These guidelines cover the entire spectrum of management of early arthritis, including recognition, diagnosis, classification, non-pharmacological interventions, pharmacological treatments and other issues.

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ACR Guidelines for Non-Pharmacologic Management of RA

To supplement the pharmacologic guidelines for the management of RA, in 2022 the American College of Rheumatology (ACR) issued a guideline focused on integrative interventions for RA management. The guideline contains 23 recommendations, grouped in four categories of “exercise”, “rehabilitation”, “diet” and “additional”. The only strong recommendation is for consistent engagement in exercise over no exercise; specific forms of exercise and rehabilitation strategies are all conditionally recommended. In the domain of diet, the Mediterranean diet is conditionally recommended, while non-Mediterranean forms of formally defined diets and dietary supplements are conditionally recommended against. Cognitive behavioral therapy, mind-body approaches, acupuncture, massage therapy and thermal (e.g., cryotherapy, heat, therapeutic ultrasound) are conditionally recommended. Electrotherapy and chiropractic therapy are conditionally recommended against because currently available evidence suggests no benefit and potential harm (cervical spine complications), respectively.