Someone
close to me was diagnosed with juvenile rheumatoid arthritis when she was 11
years old. She went to the doctor for a
camp physical, and the doctor said to her, “you look like an 80 year old lady
getting off that table.” Her mom said that she had been having a hard time
getting around lately and attributed it to growing pains. The doctor noticed symmetrical swelling in
her wrists, ankles, and balls of her feet.
The swelling tipped him off that it might be juvenile rheumatoid
arthritis, an autoimmune disease
causing swelling and damaging cartilage and bone around the joints.1
The
physical exam along with blood work confirmed his suspicions.
Since
nobody specialized in juvenile cases of rheumatoid arthritis (RA) in her town,
she went to a general rheumatologist who prescribed her an anti-inflammatory,
naproxen, along with cortisone shots in the affected joints. After a year and worsening symptoms like
having a hard time dressing herself, he referred her to a pediatric specialist
at the Denver Children’s Hospital. There
they put her on the Leflunomide (Arava) pill, a disease modifying antirheumatic
drug (DMARD) that inhibits cell cycle progression and promotes apoptosis.2 It did not work. The next step was methotrexate, a common
medication used in cancer chemotherapy, but also a DMARD. At
the doses used in RA, it does not have a significant anti-cancer or
immunosuppressive effect, but it does modify the abnormal immune processes that
cause RA.3
She
took methotrexate in increasing doses until some improvement was evident. It was the first drug that started to
alleviate symptoms. Unfortunately,
methotrexate caused the uncomfortable side effect of nausea shortly after
taking her pills. The knowledge that medication
would make her feel like “death” made it difficult to stomach the pills, but
she still had to take as many pills as she could stand. This led to an inability to maintain a
healthy weight, putting more stress on her body. While the methotrexate did help, she still
could not participate in any sports and her joints continued to deform.
Luckily,
Etanercept (Enbrel), a DMARD TNF-α inhibitor injected subcutaneously once a
week, came out in 1998.4
Etanercept finally reduced the inflammation, improved her range of
motion, and allowed her to resume her daily activities with less pain. The only downside is that it is an injection,
every week, indefinitely.
It
worked great for about seven years, with one year of complete remission. When symptoms came back, the Etanercept was no
longer as effective. She tried Adalimumab (Humira), another
DMARD TNF-α inhibitor.5 It worked for a few years and then stopped
working. When she tried Etanercept
again, it worked well.
She
is very susceptible to infection while taking it, and needs to be especially careful
of fungal infections. One fungal
infection, histoplasmosis, is especially dangerous in patients taking TNF-α
inhibitors because TNF-α is a key mediator of the immune response against the
culprit, Histoplasma capsulatum.6
Recently,
she has developed unexplainable neuropathies like numbness in her face, neck,
and arms, and her skin itches constantly.
The only explanation doctors have for her is that RA can manifest with
many strange symptoms. Her eyesight is
rapidly diminishing, and the damage to her joints, mostly from the early days
of her illness, is irreversible. She
will soon need a hip replacement, but is far better off than those who do not
benefit from biological DMARDs (Etanercept is $1,500/month without insurance)7
or who were not diagnosed right away.
References:
1 Panayi,
Gabriel. What is RA?. National Rhuematoid
Arthritis Society Website.
http://www.nras.org.uk/about_rheumatoid_arthritis/what_is_ra/what_is_ra.aspx.
Published July 2003. Accessed October
16, 2012.
2 Fox
RI, Herrmann ML, Frangou CG, et al. Mechanism of action for leflunomide in
rheumatoid arthritis. Clin Immunol. 1999;93(3):198-208.
3 Butler,
Robin. Methotrexate in Rheumatoid Arthritis.
National Rhuematoid Arthritis Society Website. http://www.nras.org.uk/about_rheumatoid_arthritis/newly_diagnosed/which_drugs_are_used/methotrexate_in_rheumatoid_arthritis.aspx. Published August 2006. Accessed October 16, 2012.
4Moots,
Robert. Etanercept (Enbrel). National
Rhuematoid Arthritis Society Website. http://www.nras.org.uk/about_rheumatoid_arthritis/newly_diagnosed/which_drugs_are_used/etanercept_enbrel.aspx. Published August 2004. Accessed October 16, 2012.
5Kirkham, Bruce. Adalimumab
(Humira). National Rhuematoid Arthritis
Society Website. http://www.nras.org.uk/about_rheumatoid_arthritis/newly_diagnosed/which_drugs_are_used/adalimumab_humira.aspx. Published October 2004. Accessed October 16, 2012.
6Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis
complicating immunotherapy with tumor necrosis factor alpha antagonists
infliximab and etanercept. Arthritis Rheum. 2002;46(10):2565-70.
7Ostrom, C. What's
behind the whopping price tags on the newest generation of drugs. The
Seattle Times. August 18, 2008.
http://seattletimes.com/html/health/2008120449_drugs18m.html. Accessed
October 16, 2012.
Rheumatoid arthritis is such a devastating disease especially for someone who was diagnosed so young. I was just wondering why an antifolate, methotrexate, is a drug commonly used to treat RA? I understand that inhibiting folate metabolism is important in treating cancer. From what I understand many cancer cells overexpress the folic acid receptor and have a high requirement for folic acid. Does folic acid have a role in the autoimmune disease? Also, wouldn’t inhibiting folate metabolism cause other conditions that result from folate deficiency such as anemia? I believe neuropathy results in patients with RA due to the inflammation of the blood vessels which can cause nerve damage. It is so unfortunate that there aren’t medications yet that can effectively treat RA without the symptoms ever returning and without terrible side effects.
ReplyDeleteKevin, thanks for sharing this story. It really shows how devastating autoimmune disorders can be. When I read one of the last paragraphs describing her new onset of neuropathies, like numbness in the limbs, I thought about my mother's MS diagnosis. She was having limb numbness and optical neuropathies. So, I looked to see if there was in increased risk for juvenile RA patients developing MS, because many patients diagnosed with one autoimmune disorder go onto develop another. In my mother's case she was diagnosed with MS and then seven year later diagnosed with myasthenia gravis. What I found was no where near conclusive, but one article:(http://www.sciencedirect.com/science/article/pii/S0014579311003899)
ReplyDeletelooked as GWAS (genome-wide associated studies) comparing RA (not juvenile) and MS and showed that they share a number of susceptibility regions, such as a cluster in the MHC regions. While the heritability of MS and RA is not definitively understood, the shared susceptibility was intriguing. Hopefully studies like this can further our understanding of autoimmune pathogenesis so better treatment modalities become available to patients like your friend and my mother.
Jasmine and DG, thank you both for your comments. Jasmine, I was also interested in the anti-inflammatory mechanism of methotrexate. Take a look at the review article below. The exact mechanism is still unknown, but it argues that it is unlikely due entirely to the anti-proliferation effect caused by inhibiting folic acid dependent synthesis of purines and pyrimidines. Instead, it attributes most of the anti-inflammatory effect of methotrexate to it indirectly increasing extracellular adenosine levels. Adenosine is an anti-inflammatory mediator.
ReplyDeleteCronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2):163-72.
DG, I agree that the neuropathies could be closely related to MS type pathology. She even had a head MRI done to rule out MS, which thankfully came back negative. There must be a link. I am sorry to hear about your mothers MS and MG diagnoses. I’ll keep my fingers crossed with you for new treatments.