Setting: office
CC: “My hands hurt.”
VS: normal
HPI: A 38-year-old woman with pain in her hands for the past year visits you at your office. She takes acetaminophen and over-the-counter nonsteroidal antiinflammatory drugs (NSAIDs) with some relief. The pain began in several metacarpophalangeal (MCP) joints of the hands with the thumb especially affected. Pain has started in the feet as well, affecting the metatarsophalangeal (MTP) joints. She has difficulty moving the joints when getting out of bed or after staying in one position too long. The pain is worse in the morning, but improves as she starts to move around over the course of the day over the next 1 to 2 hours.
PMHX: none
Medications:
Ibuprofen
Acetaminophen
PE:
Musculoskeletal
“Boggy” swelling of several small joints in each hand and foot symmetrically
Decreased grip strength of hands
One elbow minimally involved
Skin: no nodules in skin
Chest: dullness and decreased breath sounds at left base
Initial Orders:
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Anti-cyclic citrullinated peptide (anti-CCP)
Rheumatoid factor (RF)
x-ray of hands
Chest x-ray
The cause of rheumatoid arthritis (RA) is unknown.
Short-term steroid therapy can sometimes help acutely.
Chronic NSAID use: 20% chance of ulcer per year
The patient continues to use ibuprofen for pain with some relief.
Reports:
ESR: 68 mm/h
CRP: elevated
Anti-CCP: positive
RF: positive
X-ray of hands: normal joints
Chest x-ray: effusion on one side
What is the difference in the overall clinical value of CRP and ESR?
a. None
b. ESR is for diagnosis; CRP is for follow up.
c. ESR is more sensitive for RA.
d. CRP is better for predicting mortality.
e. ESR is more useful in response to therapy.
Answer a. None
There is no overall difference in the use of ESR or CRP in either diagnosis or the response to treatment. There is no clear area in which there is a definite benefit of one versus the other in testing, treatment, or prognosis.
Anti-CCP is the most specific of the tests for RA.
RF: immunoglobulin M (IgM) against the Fc portion of IgG
Which of these is essential to diagnose RA?
a. Abnormal x-ray
b. Nodules
c. Anti-CCP or RF positive
d. Anemia
e. Arthrocentesis
Answer c. Anti-CCP or RF positive
There must be some laboratory evidence of RA to establish a diagnosis. There is no one single test to establish a diagnosis of RA even though the anti-CCP is the most specific of the tests. An anti-CCP antibody result alone, without the involvement of multiple small joints, morning stiffness >1 hour, and a duration of several months is not RA. Normocytic anemia happens from the anemia of chronic disease and is completely nonspecific. Nodules are only present in 20% of patients, though they can be present in the lung and eyes. An abnormal x-ray is most certainly not essential for establishing a diagnosis of RA. The entire point of using disease-modifying antirheumatic drugs (DMARDs) is to prevent the development of an abnormal result shown on x-ray.
The “bogginess” felt on palpation during the examination is overgrown synovial lining.
RF is associated with
• Hepatitis C
• Cryoglobulins
• Endocarditis
• Tuberculosis
• Age
Positive RF does not equal RA.
Positive RF alone does not equal anything.
What is unique about the pleural effusion of RA seen in this patient?
a. High white blood cell (WBC) count
b. Low glucose level
c. High protein level
d. Negative Gram stain
Answer b. Low glucose level
For unclear reasons (like everything in RA), the etiology of low glucose level in RA pleural effusion is unknown. RA effusions do, however, have the lowest glucose level of any pleural effusion.
The patient is started on low-dose prednisone and methotrexate (MTX). She returns the following week and has marked improvement in pain, mobility, and morning stiffness.
• MTX takes 2 to 6 weeks to be effective.
• MTX is a folate antagonist.
After 1 month, steroids are stopped and the patient remains on MTX weekly and NSAIDs for pain. You must advise the patient against becoming pregnant while on MTX because it is teratogenic.
MTX-caused liver or lung fibrosis is a must know for the Step 3 examination !
MTX Folate Antagonism = Teratogenicity
Which of these should you use if MTX cannot be tolerated?
a. Leflunomide
b. Gold salts
c. Cyclosporine
d. Penicillamine
Answer a. Leflunomide
Leflunomide is an alternative to MTX as a DMARD in those who have liver or lung fibrosis. None of the others is ever the right answer. Gold salts are no longer used in RA.
The patient comes to the office a few months after the start of MTX and is feeling better. She would like to become pregnant, but knows that MTX cannot be used in pregnancy.
Which is the best therapy for RA in pregnancy?
a. Sulfasalazine and hydroxychloroquine
b. Tumor necrosis factor (TNF) inhibitors
c. Minocycline
d. Leflunomide
Answer a. Sulfasalazine and hydroxychloroquine
These are the safest in pregnancy. Minocycline is a tetracycline antibiotic and should be avoided in pregnancy. Leflunomide is both a teratogen and a carcinogen.
Leflunomide is a pyrimidine antagonist.
The mechanism of retinal toxicity with hydroxychloroquine is unknown.
The patient stops MTX therapy and switches to hydroxychloroquine for a few months while waiting for the MTX to wash out of her system.
What will happen to her RA activity during pregnancy?
a. Improve
b. Worsen
c. No change
Answer a. Improve
Most persons with RA improve during pregnancy. This was the original observation in the 1930s that led to the discovery of steroids.
In the ninth month of pregnancy, now off MTX, why is it important to tell the patient’s anesthesiologist and obstetrician prior to delivery that the patient has RA?
a. So they can order an x-ray of her neck
b. So they can give her bolus intravenous (IV) steroids
c. So they will not do a cesarean section (C-section) delivery
d. So they will stop hydroxychloroquine and sulfasalazine therapy
Answer a. So they can order an x-ray of her neck
Always inform surgical and anesthetic colleagues about RA because intubation is potentially dangerous because of C1 to C2 cervical spine subluxation (Figure 8-1). C-section is almost always done under epidural anesthesia so this is not dangerous. RA generally does not involve the axial skeleton, which is the spine and sacroiliac (SI) joints, but endotracheal intubation is especially dangerous. The hyperextension that is usually done can lead to cord compression.
Figure 8-1. The cervical spine in rheumatoid arthritis, showing atlantoaxial subluxation. A lateral view of the upper cervical region shows posterior displacement of the odontoid process. The preodontoid space measures approximately 8 mm (arrows). Normally, this measurement should not exceed 2.5 to 3 mm in an adult. (Reproduced with permission from McKean SC, et al. Principles and Practice of Hospital Medicine. New York: McGraw-Hill; 2012.)
Moving the case forward a month or two at a time, or waiting for your pregnant patient to deliver, you then restart the MTX therapy.
Which of the following is most likely to occur in the long term with RA?
a. SI joint involvement
b. Peritoneal inflammation
c. Carpal tunnel syndrome
d. Vasculitis
e. Pericarditis
Answer c. Carpal tunnel syndrome
Carpal tunnel can happen in 10% of patients. Pericardial involvement is rare (<1%) and usually clinically silent. Vasculitis is also much rarer than carpal tunnel.
The computer-based case simulation (CCS) and the Step 3 examination are very big on testing your ability to advise patients about prognosis. You have to know what to tell patients to expect. You should tell RA patients that they may get carpal tunnel. You do not have to tell patients to expect Felty syndrome (enlarged spleen and neutropenia).
A year after the delivery of the baby and restarted on MTX, the patient’s Interval History shows progression of joint pain and immobility.
Which of these medications should be added next?
a. Adalimumab or etanercept
b. Rituximab
c. Abatacept
d. Tocilizumab
e. Anakinra
Answer a. Adalimumab or etanercept
These are TNF inhibitors. It is clear that you should use the TNF inhibitors first as add-on therapy to MTX if the disease progresses.
Why do TNF inhibitors reactivate tuberculosis (TB)?
a. They suppress neutrophil function.
b. They remove CD20 cells.
c. TNF maintains granulomas.
d. They block interleukin-6.
e. They block interleukin-1.
f. They inhibit T cell costimulation.
Answer c. TNF maintains granulomas.
TNF inhibitors (adalimumab, etanercept, golimumab, certolizumab) “unlock” the old TB stored away in walled-off granulomas (Figure 8-2). This is why purified protein derivative (PPD) screening is needed before they are used.
Figure 8-2. Pathophysiology of rheumatoid arthritis. HLA-DR4, human leukocyte antigen DR4. (Reproduced with permission from Chandrasoma P, Taylor CR. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. © 1998 by the McGraw-Hill.)
Rituximab removes CD20 cells.
Anakinra suppresses neutrophil function.
Tocilizumab blocks interleukin-6.
Abatacept inhibits T-cell costimulation.
Case Summary:
After prescribing MTX first and adding a TNF inhibitor, you will not be asked which DMARD is used next, because it is not clear. The questions regarding drug mechanism of action, such as rituximab removing CD20 cells or tocilizumab inhibiting interleukin-6, have definite answers. It is not clear, however, which inflammatory marker, CRP or ESR, is generally to be used in rheumatology. It is clear that you do not need to wait for an abnormal x-ray result to make the diagnosis of RA. Use DMARDs to prevent deformity from becoming bad enough to be seen on an x-ray.