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10 Articles in Volume 12, Issue #6
Carpal Tunnel Syndrome
Case Studies in New Daily Persistent Headache
Hormone Testing and Replacement in Pain Patients Made Simple
Management of Prenatal Low Back Pain
Managing the Diabetic Patient with Dementia
Myofascial Pain Syndrome: Uncovering the Root Causes
New Tools for Improving Patient-to-Physician Communication in Clinical Practice
Suicide and Suffering In the Elderly: We Must Do Better
Three Cases Highlight the Challenges Of Treating Rheumatoid Arthritis
Understanding the Sources of Morphine

Three Cases Highlight the Challenges Of Treating Rheumatoid Arthritis

Differential diagnosis and comorbidities, such as infectious diseases and malignancy, can hamper the ability to manage the patient with rheumatoid arthritis.

Theumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that can lead to considerable disability. It is found worldwide and is approximately three times more common in women than men. Although it may occur at any age, the peak incidence of RA is found in the 4th or 5th decade of life, and is present in almost 5% of women by age 70. This is in contrast to a 1% to 2% incidence rate found in the general population.1

The pathogenesis of RA involves inflammation of the synovial lining of the affected joints that can result in injury and damage leading to less function in patients. Much of the joint damage that occurs in RA is seen early in the course of the disease, usually within the first one or two years. It is therefore imperative that clinicians try to secure the diagnosis as soon as possible in order to start appropriate therapy (Table 1).

Frequently the diagnosis may be elusive, and only as we treat the patient do we find that the response to therapy is less than we desire. This may be due to a number of factors including resistant disease and other illnesses that may confound our ability to interpret patient response and even laboratory results.

In this article, we discuss three cases that have presented challenges in our practices, and how we proceeded in evaluation, treatment, and further care.

First Case:  60-year-old Woman with 3-month History of Joint Pain

History
A 60-year-old white woman presented with a 3-month history of joint pain, primarily involving the small joints of her hands and feet. She noted that she had swelling and stiffness in her joints that was worse in the morning, usually lasting over one hour. The stiffness gradually improved but returned towards the late afternoon. The patient also said that she was very fatigued despite sleeping what she thought was soundly.

Examination and Testing
The patient’s general physical examination was unrevealing. The joint examination was abnormal—there was synovitis noted in the first through third metacarpophalangeal joints (MCPs) in both hands and the patient had tenderness in response to squeezing across the metatarsophalangeal joints (MTPs) (squeeze test) in both feet, with swelling noted. The patient’s left knee was also swollen and her right elbow was held in 20° of flexion.

Laboratory data included an elevated rheumatoid factor and a markedly elevated anti-cyclic citrullinated peptide (anti-CCP) antibody. Both her erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were elevated (ESR=42 mm/h; CRP=3.9 mg/L). Plain radiographic (x-ray) imaging of her hands and feet suggested early erosions noted at scattered MTPs.

Diagnosis and Treatment
The patient was diagnosed with RA and started on methotrexate 10 mg weekly, advancing to 15 mg over the next few weeks, and eventually increased to a dose of 20 mg, given weekly in divided doses. In addition, she was given 1 mg folic acid daily and 10 mg of prednisone at bedtime (HS).

The patient experienced modest improvement in symptoms over the next 2 months, but both the patient and physician felt there was an inadequate response to her therapy. A biologic agent was added—adalimumab (Humira) subcutaneous 40 mg injection every other week—and within the next month there was considerable improvement in the patient’s symptoms. On follow-up physical examination, the patient clearly had less joint pain, diminished fatigue, reduced morning stiffness, and less swelling of her affected joints. The patient told the clinician that she had an overall sense of improvement and well being. A repeat of her laboratory tests was performed 2 months later, which showed the improvement in markers of inflammation and no change in other levels.

Increase in Symptoms
This pattern of improvement continued for about 3 months until the patient began complaining again of increasing joint pain, which was worse in the morning. She also noticed increasing fatigue, lower abdominal discomfort, and increased forgetfulness. Her feeling of improved health also was diminished. When she awakened each morning, she felt exhausted, as if she “had slept poorly, if at all.”

Table: Facts about RA

On physical examination, the patient had generalized pain with joint motion and increased tenderness including the joints and soft tissue regions between the joints. There was no increase in joint swelling and her repeated laboratory tests were unrevealing—the ESR and CRP were minimally elevated and unchanged from prior determination. Because the patient was on methotrexate, her liver function, complete blood count (CBC), and renal function were being monitored.2 All the tests were within normal limits. Her pain level was described as being “moderate to severe.”

How to Proceed?
Our concern was how to proceed. If, indeed, her RA was flaring—should she be switched to a different biologic? She had successfully tapered off her prednisone—should we add this again? Could there be another consideration not obvious at our earlier visits?

We expanded our laboratory testing, and obtained unremarkable results for basic metabolic profile (BMP), thyroid stimulating hormone (TSH), and 25-hydroxy vitamin D levels. Prednisone (10 mg orally) was added HS, but with a minimal response. The patient had been able to return to her job as a secretary for an insurance firm after she had initially improved, but felt the stress level that greeted her upon her return was increased and difficult to handle.

This presented scenario is not uncommonly seen. The diagnosis of fibromyalgia was reviewed with this patient and she was started on the serotonin–norepinephrine reuptake inhibitor (SNRI) duloxetine (Cymbalta) at 30 mg per day, increased to 60 mg per day, with gradual improvement as the dose was escalated.

Her pain level diminished, as did her fatigue—although it still lingered. Despite this, there was an overall sense of improvement and the patient was able to cope with her work situation and daily routine much better.

Discussion
Pain is the number one reason a patient seeks help at a rheumatologist’s office—and is also the primary reason for follow-up visits. Although it may appear simple to differentiate the pain of RA—where there are physical and laboratory findings that are commonly abnormal—from the pain of fibromyalgia, this may not be the case. In fibromyalgia there is no joint inflammation, and no objective findings of acute or chronic illness may be evident.

RA is associated with synovitis and potential joint injury, where fibromyalgia is thought to be a result of enhanced pain sensitivity, perhaps due to dysfunctional processing of pain stimuli. The other components of ascending and descending pain pathway abnormalities and other theories as to the origin of fibromyalgia are described in detail in our medical literature.3

We need to be vigilant in pursuing the correct etiology of our patients’ discomfort—as, at times, the etiology may be less than clear. Certainly, in this patient, the changing of her biologic agent or otherwise treating her RA more aggressively might have led to an undesirable conclusion.

Second Case:  Woman Developed RA When She Was 55

History
A 61-year-old woman with history of hypertension and osteoporosis developed typical RA at the age of 55 years, with symmetric distal synovitis of the hands, wrists, and feet. Laboratory findings were positive for rheumatoid factor and anti-CCP antibodies. She was placed on oral methotrexate 20 mg weekly along with folic acid, initially, with a good response with reduction in joint pain and synovitis. Within 1 year she experienced increased disease activity and was placed on the tumor necrosis factor inhibitor (TNFi) etanercept (Enbrel) 50 mg subcutaneously weekly with almost complete remission of her RA in 4 weeks.

Cancer Diagnosis
The patient was diagnosed with malignant melanoma (Clark level II-III) of the face and underwent surgical excision with adequate wide tumor margins. Post-diagnosis, etanercept was discontinued due to the theoretical risk of immunosuppression and risk of recurrence of malignancy.4 Even with the use of methotrexate, a severe flare ensued necessitating use of oral methylprednisolone (Medrol) at doses up to 12 mg daily orally to control the disease. The cumulative dose of corticosteroids was deemed unacceptable and the decision was made to proceed with rituximab (Rituxan), (standard dosing 1,000 mg intravenously repeated in 2 weeks), which binds to the CD20 antigen on B lymphocytes to mediate B-cell lysis in vitro.5

The patient had an excellent response with almost complete control of rheumatoid activity, and methylprednisolone was discontinued within 1 to 2 months. The patient continues to receive intermittent rituximab injections every 6 to 12 months in combination with oral methotrexate, with excellent control of disease activity.

Discussion
This case highlights the need to weigh the potential side effects related to the use of TNFis, which are the most common class of biologic agents used in the treatment of RA, with their benefits. The potential complications include risk of infections, demyelinating disease, lupus-like reactions, psoriasis, increased mortality in end-stage congestive heart failure, and risk of malignancy (ie, skin cancer and non-Hodgkin’s lymphoma).6-8 RA itself may increase the risk of non-Hodgkin’s lymphoma, colon cancer, and skin cancer (both melanoma and non-melanoma). Paradoxically, patients with RA may have lower rates of breast cancer and colon cancer (perhaps due to non-steroidal anti-inflammatory drug [NSAID] use).

As the US population ages, including patients with RA, the prevalence of comorbid illnesses such as serious infections and malignancy increase regardless of concurrent illness and medication. But since certain biologic agents have been implicated in these complications, the risk to benefit ratio will prove challenging for the continuation of biologic treatment.

At least for the patient described in the case study it was felt that restarting a TNFi was relatively contraindicated, given her history of melanoma. Even though there is a paucity of data, rituximab has some retrospective studies that do not link it to an increased risk of malignancy.6 The mechanism of action of rituximab with B-cell depletion also does not logically lend itself to increasing the risk of malignancy.

Third Case:  48-year-old Man with 6-month History of Joint Pain and Swelling

History
A 48-year-old man presented for further advice regarding treatment. Until 6 months ago, the patient had been well “all of his life”; then he developed joint pain and swelling in the MCP and MTP joints in both hands and feet. Laboratory tests were pertinent for elevated CRP (8.9 mg/L), ESR (42 mm/h), rheumatoid factor (1:80), and a positive anti-CCP antibody. Radiographic imaging (x-rays) did not reveal evidence of erosions in either the feet or hands.

He was diagnosed with RA and was started on methotrexate 15 mg per week and the NSAID ketoprofen 200 mg per day. While he improved clinically on this regimen, the patient continued to have persistent swelling in the MCP joints after 3 months of therapy.

Examination and Testing
On follow-up examination, the patient had synovitis in the MCP joints of both hands. There was mild tenderness, but no nodules. The remainder of the physical examination was normal. X-rays of the hands showed a new erosion in the third MCP of the right hand. A review of systems was negative for skin rash, fever, cough, and weight loss.

Biologic therapy was discussed and the patient agreed to proceed. He was counseled about the risks for reactivation of tuberculosis (TB) with biologic therapy and undergoes testing. A tuberculin skin test (TST) was planted and was read in 48 hours. There were 7 mm of induration. A chest x-ray was normal.

Latent TB Suspected
This case highlights the potential dilemma of latent TB in a patient with RA.9 The use of biologic therapies in RA is associated with immunosuppression of macrophage release of TNF and an increased risk for latent tuberculosis infection (LTBI). In addition, the reliability of tuberculin skin testing can be compromised in the RA patient due to treatment with biologic therapy as well as corticosteroids.10

The CDC has published guidelines for classifying positive tuberculin skin tests in persons at highest risk for LTBI.11 Patients at highest risk include “persons who are immunosuppressed for other reasons (eg, taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF-α).” A TST of 5 or more millimeters induration is considered positive in this high-risk group. For patients who have received Bacillus Calmette-Guérin (BCG) vaccination, it is recommended testing be performed using an interferon-ɣ-release assay (IGRA). Immunosuppressed patients with a negative IGRA or TST should be retested in 1 to 3 weeks as there is an increased risk of false negative results in this high-risk group. The patient, therefore, has a positive TST with a negative chest x-ray.

Discussion
The patient has LTBI and should be counseled regarding the risks and benefits of isoniazid (INH) therapy. The CDC currently recommends treatment of LTBI with 9 months of isoniazid. The patient cannot be treated with a biologic agent or corticosteroid for his RA until he starts INH therapy, as treatment could result in activation of TB. There are no published trials on when to begin biologic therapy once INH has been started. The American College of Rheumatology published a consensus opinion in 2008, which recommends continuing INH therapy for 1 month before initiating a biologic agent.6 This is a common sense approach founded on the need to ensure the RA patient with LTBI is compliant with INH therapy and is not experiencing untoward side effects before exposure to immunosuppressive therapy.

Summary
If untreated, RA can lead to joint destruction and considerable disability. The newer medications available, especially the biologics, have significantly impacted the way RA is approached and treated. The consideration of the use of these medications is not made lightly. There may be confounding diagnoses and co-existing illnesses that must be addressed prior to embarking upon treatment with these agents, and changes that are necessary if side effects or other complications arise. These three cases illustrate some of the difficulties that may be seen when diagnosing, treating, and caring for patients with RA.

Last updated on: October 5, 2012
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