Incorporating current evidence into common cases of patients presenting with rheumatoid arthritis (RA), these authors offer pertinent insights into clinical decision-making with these informative case studies.

We know rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disorder that primarily involves synovial membranes and articular surfaces of multiple joints. We know the disease affects approximately one percent of the adult population worldwide.

However, the treatment of RA has changed dramatically in the past decade. A better understanding of the pathogenesis of RA has led to the development of more targeted treatment.

With this in mind, let us take a closer look at the following case studies involving common clinical presentations and key considerations in facilitating optimal management of these patients.

Case One: When Early Combination Therapy May Be Effective
Amy is a 40-year-old woman with a three-month history of pain and swelling in her hands, wrists and feet. She has associated fatigue and stiffness that lasts for two hours in the morning. She has tried over-the-counter, non-steroidal antiinflammatory drugs (NSAIDs) but has experienced minimal relief.

Upon the physical examination, the clinician notes swelling and tenderness in multiple metacarpophalangeal joints (MCPs) and proximal interphalangeal joints (PIPs), and her right wrist. Her knees are warm and tender with moderate effusions. Compression of the metatarsophalangeal joints (MPJs) in her feet elicits pain. Using a 28 joint count scale, the treating clinician notes a total tender joint count (TJC) of 14. She has a swollen joint count (SJC) of 10.

Switching Agents After Anti-TNF Failures: What One Study Reveals

Amy’s complete blood count (CBC) is normal except for mildly low hemoglobin (11 gm/dl). Her liver and renal functions are normal, the C-reactive protein (CRP) is 2.0 mg/dL and the erythrocyte sedimentation rate (ESR) is 46 mm/hr.

Her rheumatoid factor (RF) is 320 IU/ml and the antinuclear antibody (ANA) is negative. Amy’s anti-cyclic citrullinated peptide (CCP) antibody test is positive at 80 units. Her Hepatitis B and C serologies are negative.

Hand radiographs reveal soft tissue swelling of her MCPs and PIPs bilaterally and mild periarticular osteopenia but no erosions. Given the patient history, physical exam and supporting laboratory data, the clinician diagnoses Amy with RA.

Amy initially receives a regimen of prednisone 5 mg daily and methotrexate at 15 mg weekly in conjunction with daily-dosed folate. The clinician titrates her methotrexate dose to 20 mg weekly over the next month and the patient requests discontinuation of the steroid. At the two-month follow-up, her clinical response is limited. The patient’s disease activity score (DAS 28) has changed only slightly from 6.3 to 5.9, reflecting persistently active disease.

At this point, which of the following therapeutic agents should you prescribe for this patient?
a) add sulfasalazine
b) add hydroxychloroquine
c) add sulfasalazine and hydroxychloroquine
d) add an anti-tumor necrosis factor (TNF) agent (after evaluating for latent tuberculosis)
e) c or d

Understanding Shifts In Initial Management of RA And Regular Disease Activity Assessment
Historically, the standard practice was to initially treat RA with NSAIDs. Clinicians would only introduce more potent therapy when persistent disease continued over time. However, this approach often resulted in the progression of disease and development of clinical disability.

What Two Studies Show About Using Newer Biologics After Anti-TNF Failure

More recently, researchers have emphasized using disease modifying antirheumatic drug (DMARD) therapy earlier in the course of RA and have shown this practice results in better outcomes.^1-5 Our current goal is to start the most effective therapy as early as possible and to monitor disease activity closely while tailoring therapy to control disease activity.

Yet there is still no consensus as to what degree of disease activity represents an insufficient response to drive these changes in therapy. In clinical studies, disease remission, utilizing American College of Rheumatology (ACR) or disease activity score (DAS 28) criteria, is often the goal.^6-8 When it comes to therapeutic decisions in clinical practice, they are driven by patient and clinician satisfaction with current treatment while weighing the risks of increased therapy with the benefits of minimal disease activity. It is clear that utilizing objective measures of patient outcomes does improve control of RA.^4,9 While it is beyond the scope of this review to discuss all available measures, many tools have been validated and one can apply these in clinical practice.^10-12

Switching Anti-TNF Agents: A Closer Look At The ReACT Trial

The Tight Control of RA (TICORA) trial demonstrates the effectiveness of treatment decisions based on routine clinical disease activity measures.⁴ In the TICORA study, researchers showed that adjusting therapy by monitoring disease activity scores (DAS) at each visit and making protocol defined changes result in better outcomes compared to routine care. The study also illustrates that tight control substantially improves disease activity, radiographic progression and quality of life at no additional cost.⁴

Studies also demonstrate that triple therapy (methotrexate, sulfasalazine and hydroxychloroquine) or DMARDs in combination with biologic therapy have greater efficacy in comparison to monotherapy or dual therapy with these agents.^9,13-16 (See “What Selected Clinical Trials Reveal About Combination Therapy” above.)

The BeST study demonstrates that early combination therapy outperforms sequential monotherapy or step-up therapy in which one serially adds DMARDs in sequence over time. The results of the BeST study show greater functional improvement and lesser radiographic damage with initial combination therapy through two years of follow up.⁹

An important feature of both studies is that support of scheduled disease activity assessment drives changes in therapy. In clinical practice, this sets a minimal standard of three months for following new patients with aggressive RA. To accomplish the goals of frequent laboratory monitoring, patient counseling and safety assessments, one often needs to see patients even more frequently when disease activity is high.

Aggressive treatment with combination therapy, either triple DMARD therapy or DMARD with biologic therapy, is superior to mono, dual or step-up therapy in early RA. Based on this data, one might argue that the clinician should have placed the patient on aggressive combination therapy at the first visit.

Increasing evidence suggests the early introduction of aggressive therapy (within the first few months after diagnosis) dramatically improves outcomes. However, the time to discuss the new diagnosis and the introduction of multiple new medications and restrictions imposed by local third party payers can often limit the practicality of this approach in clinical practice.
Answer: e

Case Two: When A Patient Has A Suboptimal Response To Initial DMARDs
Jane is a 50-year-old woman who was diagnosed with RA seven months before her follow-up visit. She is currently on methotrexate 20 mg weekly, prednisone 5 mg daily, hydroxychloroquine 400 mg daily and sulfasalazine 2 mg daily.

Jane has continued to have pain and swelling of the MCPs and wrists. This has been accompanied by morning stiffness lasting 30 to 45 minutes. Her past medical history is significant only for emphysema and she continues to smoke half a pack of cigarettes per day. A physical examination reveals a TJC of 10 and SJC of eight.

Switching Anti-TNF Therapy: What The Studies Show

Her labs at this visit show a CRP of 1.5 mg/dL and an ESR of 34 mm/hr. Liver, renal and cell counts are normal. Her DAS 28 is very active (5.6). Jane’s hepatitis serologies are normal and she has a negative tuberculin skin test. Jane’s normal adult immunizations, including pneumonia and flu vaccinations, are up to date.

What would be the next appropriate therapeutic step?
a) Add an anti-TNF agent
b) Add abatacept
c) Add rituximab
d) Any of the above

Recognizing The Value Of Anti-TNF Therapy
Tumor necrosis factor alpha plays an important role in the pathogenesis of RA. Anti-TNF therapy continues to contribute to major advances in clinical and radiographic outcomes.17 These agents have become the standard of care in RA patients with moderate to severe, active disease who do not respond adequately to DMARD therapy.

Quality evidence from many randomized, double-blind, placebo-controlled trials demonstrates the efficacy of these agents for improving clinical symptoms and signs in patients with early RA as well as those with active RA.^2,3,5,18-21 This evidence also supports that biologic agents work best when one uses them in combination with traditional DMARDs.

Note that a significant portion of patients with mild to moderate RA responds well to DMARD therapy alone and biologic therapy is not necessary in all patients. However, data also suggests that radiographic progression can occur despite clinical improvement.^3,19,22 This implies routine radiographic assessment may also be necessary to guide optimal management.

Currently, there are no published clinical trials that compare TNF-agents to each other.²³ No single agent has demonstrated clear efficacy or safety superiority to the other.²³ Accordingly, the choice of agent depends on other factors such as patient convenience, access to treatment, clinical preference, reimbursement and patient costs.

Prior to initiating any therapy, it is important to address with patients the risks associated with suboptimally controlled chronic autoimmune diseases such as RA. It is also necessary to discuss the risks of treatments, including non-specific and specific immunosuppression.

Discussing the increased risks of infection, malignancies and cardiovascular disease is paramount to facilitating a patient’s informed decision on treatment. Additionally, patients require appropriate screening prior to treatment. This includes evaluation for viral hepatitis, active infections and latent tuberculosis. Clinicians should also ensure that patients are up to date on recommended adult immunizations.

When Newer Biologics Would Not Be Appropriate
Abatacept (Orencia, Bristol-Myers Squibb) is approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe active RA in adults with an inadequate response to one or more traditional DMARDs or TNF inhibitors.^24-27

Abatacept is a T-cell co-stimulation modulator. It binds to the CD80/86 on antigen presenting cells (such as dendritic cells, macrophages or B-cells) and prevents costimulatory binding of CD28, thus preventing full T-cell activation.

However, patients with chronic obstructive pulmonary disease (COPD) show a higher rate of infectious complications than those on placebo.²⁸ Therefore, in this particular case study, abatacept may not be the best choice for this patient. Indeed, this case illustrates the need to individualize treatment decisions for patients with moderate to severe RA and other comorbidities.

Rituximab (Rituxan, Genentech) is also not indicated in this case. Some studies have demonstrated rituximab’s efficacy in combination with methotrexate in DMARD treatment failures. However, it is currently not approved for this indication.^29,30 Instead, the FDA indication for rituximab is for moderate to severe RA patients on methotrexate who have experienced an inadequate response to at least one anti-TNF agent.^31,32

For now, anti-TNF agents are the first choice biologic agents in most clinical scenarios. There is over 10 years of clinical experience with these agents in addition to quality efficacy and safety data. There are cases in which comorbidities such as heart failure, latent granulomatous infections (tuberculosis, histoplasmosis and coccidiomycosis), pulmonary disease and others may justify the use of certain biologic agents over other agents.

Indeed, this case illustrates the need to individualize treatment decisions for patients with moderate to severe RA and other comorbidities.
Answer: a

Case Three: When There Is A Secondary Anti-TNF Inadequate Response
Erica is a 47-year-old female with RA. Her RA has been well controlled for two years with methotrexate 15 mg weekly and adalimumab 40 mg bi-weekly. Erica presents with complaints of pain in her feet and wrists with morning stiffness lasting for 40 minutes over the past six to eight weeks.

Upon examination, Erica has synovitis in her wrists and swelling in her ankles. A MPJ test is positive for tenderness. The 28 swollen joint count is four and the tender joint count is six. The X-rays of her wrists show new erosions in carpel bones in comparison to the baseline X-rays.

Lab tests reveal a CRP of 1.8 mg/dl in comparison to 0.6 mg/dL three months earlier, and an ESR of 30 mm/hr. Both the CBC and CMP tests are normal. Erica has moderate disease activity with a DAS 28 score of 4.7.

What is the next best therapeutic approach for this patient?
a) Continue current therapy
b) switch to another anti-TNF agent
c) discontinue adalimumab and add rituximab
d) discontinue adalimumab and add abatacept
e) continue current therapy and add abatacept
f) b, c or d

This case represents a patient who is a secondary anti-TNF non-responder. In effect, the patient experiences a good anti-TNF response for a period of time followed by a loss of efficacy. Erica is presenting with increasing signs and symptoms of inflammation, an increased number of swollen and tender joints and an increased CRP. The etiology of lost efficacy with anti-TNFs is not well characterized. However, the development of anti-drug antibodies, pharmacokinetic factors or perhaps alterations in the biology of her disease may be responsible for her loss of response.

Switching Between Anti-TNF Agents: Should You Do It?
Switching between anti-TNF agents is known to result in improved disease control for some patients.^33-36 (See “Switching Anti-TNF Therapy: What The Studies Show” above.) However, the outcomes from a second or third anti-TNF medication are seemingly less robust with certain patient populations. This is especially true for primary non-responders in comparison to secondary non-responders.³⁷ (See “Switching Anti-TNF Agents: A Closer Look At The ReACT Trial" above)

What Selected Clinical Trials Reveal About Combination Therapy

Keep in mind that most data supporting switching between anti-TNF agents comes from RA registries or other open-label designed trials. The inherent design flaws in these studies make the data less reliable than data from randomized, double-blind, placebo-controlled trials. Nonetheless, these studies have produced the only currently available data regarding the use of consecutive anti-TNF agents for RA. In some patients, this is clearly an effective management strategy. While researchers have demonstrated efficacy in switching with all three anti-TNF agents, there are currently no published guidelines available to direct the progression of switching from one agent to another.

Newer biologic agents that work through unique mechanisms are also available for patients with moderate to severe RA. The Abatacept Trial of Anti-TNF Inadequate Responses (ATTAIN) shows that abatacept is an effective treatment option for moderate to severe active RA in patients with inadequate response to traditional DMARDs and anti-TNF therapy.27 (See “What Two Studies Show About Using Newer Biologics After Anti-TNF Failure” above.)

Another group of newer biologic agents target B cells. Currently, the only available B cell agent is rituximab. Rituximab binds to the cell surface marker CD20 on peripheral B-cells, leading to the rapid elimination of B-cells from the circulation. Rituximab is currently approved for patients who have inadequate responses to TNF antagonists and are receiving concomitant methotrexate.31,32 (See “Switching Agents After Anti-TNF Failures: What One Study Reveals” above.)

In addition to rituximab, it is also worth noting that the myriad of other B-cell targeted agents under development work through their own unique mechanisms. Accordingly, as these agents become available, clinicians will need to take precautions against grouping safety and efficacy concerns, which is commonly done with anti-TNF therapies.

Current evidence suggests that combining biologic agents will not increase efficacy and results in more adverse events.38,39 Therefore, combining biologics is contraindicated pending further clinical trial data.
Answer: f

Case Four: When You See A Primary Anti-TNF Inadequate Response
John is a 48-year-old male with newly diagnosed RA. Clinicians utilized increasing doses of methotrexate from 12.5 mg to 20 mg weekly and prednisone 5 mg daily over a period of three months. He experienced a minimal improvement of pain and swelling in his pain and ankles. At a follow up visit, clinicians started the patient on etanercept 50 mg weekly.

Three months later, John is still symptomatic without notable improvement. A physical examination reveals swelling and tenderness in his MCPs, PIPs and ankles. John’s 28 tender joint count is 12 and his swollen joint count is 6. His lab results reveal a CRP of 2 mg/dl, an ESR of 28 mm/hr and hemoglobin of 10.5 mg/l. John’s CMP is normal and his DAS 28 score (5.75) reveals very active disease.

What management decision would likely result in the best clinical outcome?
a) Increase the dose of etanercept
b) switch to infliximab or adalimumab
c) discontinue etanercept and add rituximab
d) discontinue etancerpt and add abatacept
e) c or d

This case illustrates a primary non-responder to an anti-TNF agent. Switching to another anti-TNF is an option. However, registry data demonstrates that switching anti-TNF agents in primary non-responders is less effective compared to patients who are secondary non-responders.³⁷

Additionally, a recent study suggests that treatment with rituximab is more effective than switching to an alternative anti-TNF agent in patients with active RA despite anti-TNF therapy.⁴⁰

Abatacept and rituximab have proven beneficial in both primary and secondary anti-TNF non-responders.^27,32

In this case, changing therapy to a drug with a different mechanism of action is preferable to switching anti-TNF agents.
Answer: e

In Conclusion
There has been much improvement when it comes to managing RA. These improvements include the development of more effective therapies, the elucidation that treating early in the course of disease improves outcomes and the observation that using disease activity measures to guide treatment changes enhances disease control.

However, optimal RA management may still challenge the most adept medical practitioner. Ongoing clinical trials with newer agents and trials comparing currently available agents may help provide additional strategies to enhance patient care, addressing remaining clinical questions and unmet needs.

It will remain the rheumatology medical team’s responsibility to determine the best management strategies for individual patients based on available and upcoming clinical data.