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More Case Histories:
A elderly woman was referred to a rheumatologist for evaluation. She had a six-year history of bilateral pain in her
knees and wrists. RA had been diagnosed four years earlier,and 3 years of treatment with low doses prednisone (5mg /day) and
HCQ (plaquenil) had provided some improvment. She used no other medications. The patient complained of morning stiffness
that lasted 45 minutes but felt her ability to function had not been significantly impaired.
However,during her most recent visit to her family physician,it had become apparent that she had occasional warmth,tenderness,and
swelling in her second and third MCP joints bilaterally as well as her wrists and knees,and that she occasionally used wrist
splints for pain relief. The physician realized that she might not be doing as well as she thought and refferred her for a
possible adjustment in therapy.
Examination by the rheumatologist showed mild soft swelling and synovitis in both wrists. Their range of motion had decreased
to 45 degree of flexion and 30 degree of extension. There was mild tenderness and swelling of the MCP and PIP joints bilaterally
and evidence of mild effusions in the knees.
Laboratory studies showed a white blood count of 6,400/mm^3; hematocrit,39.17;platelet count,288,000/mm^3;BUN,13 mg/dL;serum
creatinine,1.6 mg/dL;ALT,21 U/L;RF,negative;ESR,25 mm/hr.
X-rays showed extensive bony erosions in MCP joints as well as erosive disease involving carpel bones of the right wrist,distal
ulna,and radius. In the left arm,there was foreshortening of the radius and significant erosion of the ulnar styloid.
This case illustrates why rheumatologists have become more rigourous in the follow-up of patients with RA. The patient
thought that treatment had brought significant improvement,and her family doctor,and possibly a previous rematologist,had
agreed. Because no one realized that her treatment was inadequate significant joint destruction had occurred.
The current evaluation provides clear-cut evidence that the patient's disease is still quite active,showing tender,swollen
joints with reduction in range of motion,joint space narrowing,and erosion. The radiographic changes are fairly significant,they
warn of potential future complications. Although the test for rheumatoid factor was negative,that is not always a predictor
of long-term outcome. The ESR is still within the normal range,but that may be misleading. It is possible that the predisone
and hydroxychoroquine have been able to decrease the ESR without suppressing the disease.
Decision:,the addition of another medication should be considered. Sulfasalazine is out of the question because of the
patient's sulfa allergy. The elevated serum creatinine level obviates methotrexate. She has slight renal impairement and using
methotrexate,especially,at high doses,is not a option.. That limits the choices to lefluonomide (Arava)or etanercept.
(Enbrel) Infliximab (Remicade) is used in combination with methotrexate or sometimes another disease-modifying drug.
Treatment: The patient was started on leflunomide,at a loading dose of 100 mg a day for three days,and then a maintenance
dose of 20 mg a day. She experienced mild diarrhea with the loading dose as instructed to take loperamide (1-3 mg) after each
loose bowel movement. The diarrhea resolved over the following 10 days,and she had no further complications. Disease signs
and symptoms improved during the next three months.
One possible strategy in this case would have been to replace HCQ with leflunomide. Since the patient pappears to have
had some benefit from HCQ and has been tolerating it well.
Serious complications are rare with leflunomide,unless a underlying liver disease is present. The physician should be
on the alert for rash,diarrhea or loose stools,and liver inflammation. The rashes tend to be reversible with either dose reduction
or discontinuation of the medication. To monitor for liver inflammation,patients are asked to return in two weeks for liver
function tests,and then every six to eight weeks thereafter. Rheumatologists often obtain intermittent complete blood counts
to make sure there have been no decreases,although they are rare.
Diarrhea is among the most common complications of leflunomide,altered bowel function occurs in more than 33 % of patients.
Diarrhea can develop at any point,but patients often experience it with the loading dose. It tends to be mild and self-limited
and can be treated symtomatically with loperamide,in most cases.
One of the attractive aspects of leflunomide is that dose escalation often is not required;the patient can simply be
started at 20 mg a day. However,when leflunomide is given in combination with other drugs,it is preferable to give 100 mg
daily for two days as a loading dose followed by 10 mg or 20 mg every other day. The dose can be increased later if necessary.
Should toxicity develop,the medication can be withdrawn or the dose cut in half. Cholestyramine can be given to bind the leflunomide
in the bowel and remove it from the body
The benefits of leflunomide often begin to appear within four weeks ( moreso with a loading dose-it appears),and most
patients who are going to benifit will see it within 12 weeks. The drug is expected to improve function and impede radiofraphic
progression. If it doesn't appear efficacious during that time period,it simply won't work ever, for that patient. Arava doesn't
work for everyone.
The second case illustrates the problems that can occur if periodic x-rays are not obtained. In patients with any evidence
of ongoing disease activity,a plain film of the most severely affected joints can be helpful. Had that been done, documentation
of progressive joint destruction would have permitted far earlier intervention with aggressive therapy.
Usually,the patients who are most prone to joint destruction are rheumatoid-factor positive,this patient was not. Her
hematocrit of 19.1 % is remarkably good for a patient with smoldering arthritis,but she may have been a smoker. Acute phase
reactnts (white blood cell coun,platelets,ESR,and C-reactive protein ) may not be elevated in patients with active arthritis,especially
in older patients. A sometimes useful strategy is to obtain and analyze synovial fluid,which should show features of disease
activity. The method used is often a decision based on the patient symptoms and medical history.
Physicians have many patients to look after and are constantly bombarded by cost cutting measures by their
peers,payees,and government,and sometimes, what should be done,is not done,in this pressure provoked and time-saving atmosphere.
Some tests deemed unnecessary,or non-essential in one patient may make a world of difference in another.
A middle-aged man was referred by his family physician for evaluation of refractory rheumatoid arthritis ( can't toleraate
conventional therapy) The patient complained of persistent pain and swelling to the joints of his hands and feet despite treatment
with methotrexate.
Symptoms had begun three years earlier with swelling,significant pain, warmth, and erythema of the second PIP joint of
the left hand. Not long afterward,the patient noted similar involvement of the PIP,MCP,and MTP joints occurred. Chronic pain
and swelling of those joints was accompanied by 30 to 60 minutes of morning stiffness.
The family physician had initially prescribed NSAIDs,with only modest benefit. A year later,he was referred to a rheumatologist
who prescribed methotrexate, initially at low doses and then rapid escalation to 20 mg a week,the patient experienced nausea,fatigue,and
lack of energy for the next two to three days.
The rheumatologis switched from oral to subcutaneous MTX and added folic and folinic acid,but the patient remained unable
to tolerate the higher doses.
Examination by the rheumatologist revealed marked bilateral synovitis and swelling of the PIP joints in a virtually symmetric
pattern.
The second and third PIP joints in a virtually symmetric pattern. The second and third PIP joints showed the greatest
involvement,with both swelling and mild deformity. There was also notable enlargement of the MCP joints,with mild ulnar deviation.
Examination of the feet revealed mild tenderness and swelling of the MTP joints.
Laboratories studies showed a white blood count of 4,900/mm^3;hemocrit,34 %;platet count,197,000/mm^3;BUN,21 mg/dL;serum
creatlinine,0.8 mg/dL; AST,27 U/L.;RF,positive;ESR,35 mm/hr;X-rays of the hands showed juxtra-articular osteopenia and small
erosions of the second and fourth PIP joints on the left and of the third MCP joints bilaterally.
This case represents a situation that rheumatoligists unfortunately see all to often-a patient that has received a timely
diagnosis and been given appropriate treatment but who neverthe less continues to have active disease. Although his disease
showed some response to methotrexate,the limit of its usefulness clearly had been reached. Fatiegue and nausea are not uncommon
with high doses of MTX, Swotching from oral to subcutneous administration often reduces the side effects and is more efficious,but
not in this case.
Hence,this patient is an ideal candidate fpr anticytokine therapy. cytokines are involved in the inflammatory cascade
of all autoimmune inflammatory conditions. Those considered the most important in mediating the swelling,pain,stiffness, and
radiographic destruction are TNF-alpha and interleukin (IL-)-1. Etanercept and Remicade are TNF inhibitors,have different
structures,but both bind to TNF-alfa,preventing it from binding to cell receptors.
Both etanercept and infliximab often dramatically reduce disease symptoms and signs after the first few injections. Dramatic
reductions can occur during the first four weeks of therapy,and retardation of radiographic progression can occur within a
year.
Since etanercept is injected subcutaneously,and this patient was already giving himself subcutaneous injections of MTX,etanercept
is the logical choice for him. He still has to visit the physician for an educational session,however,during which a nurse
shows him how to draw up the medication in a syringe,how to select and rotate injection sites,and how to give the injection.
Potential complications are explained. He also watches an educational video produced by the manufacturer.
For patients who cannot or refuse to self-inject,infliximab is a more acceptable choice. The drug is given intravenously,so
patients initially come to the government sponsored injection locations in Canada,if approved,for these medications,every
two weeks,then every eight weeks for the infusion.
The patient was started on etanercept,25 mg subcutaneously twice a week. He experienced mild erythema,itching,and swelling
at the injection site,but continued with treatment and within four weeks began to experience notable clinical improvement.
Over time,injection site reactions became less frequent ,then ceased entirely. Follow up x-rays one year later showed stabilization
of his disease.
Etanercept injection site reactions tend to be mild and self-limiting. Patients who continue the injections generally
find that they will self-resolve. Another potential side effect of etanercept is impaired eradiction of infection. Patients
taking etanercept do not appear to have an increased risk of infection,but if a significant infection does develop,etanercept
therapy should be stopped until it heals.
There have been some patients-typically those who are older or have comorbidities-who have had difficulty clearing an
infection if they remain on etanercept. Some patients do not respond to biologic therapy,period.
Since this patient is still taking methotrexate,he requires regular liver function studies,and occasionally a complete
blood count. Etanercept therapy does not require additional monitoring.
If a patient such as this shows a substantial response to therapy after six to nine months,one might consider reducing
the methotrexate dosage from 20 mg to 15 mg a week or less,or even stopping it entirely. Withdrawal should be done slowly
and carefully,over a period of six months,because is some patients, reduction of the methtrexate dosage results in disease
exacerbation.
This case illustrates the special problems associated with MTX therapy. A trial of subcutaneous MTX can be valuable,because
it often eliminates the gastrointestinal side effects seen with the oral route and,amazingly,is less expensive. (As noted
the patient probably should have taking folic acid from the star tof MTX therapy.)
This patient is a fine candidate for etanercept;infliximab would be equally satisfactory. The safety record for both
medications remains excellent,although there have been recent reports of reactivation of mycobacterial infections andmposibly,significant
cytopenia. Neuropathies may also be an issue. Just how long etanercept should be continued is not known,but it appears clear
that if the drug is withdrawn,the arthritis will flare.
The most formidle hurdle to management of arthritis in North America is cost. Insurance companies are,of necessity,wary
of unlimited authorization of the newer medications. In Canada a few provincial formularies will approve biological therapy,while
the majority,will not. In Ontario it is approved by "special access order",when conventional therapy proves ineffective.
It is becoming more clear that they are cost-effective-the follow-up expenses for a patient with improved function and
less or no pain are significantly less. Furthermore,it is expected that with new technologies,production costs of these and
other agents under investigation will be reduced, As time passes we will have a longer record of what these drugs can actually
do and what to expect from them on a longer time basis. With,methotrexate,physicians know what it can do,and expect on a long
term basis.
This is indeed a new era in the management of RA. But the government bureaucrats must get their health care in order
that none that needs biological therapy is not denied treatment because of cost. For example in Canada,Remicade is approved
for Chron's disease,but not for RA. HIV (aids)patients,high cost medication is paid by the government,but not RA. Special
access plans is not the solution.
I want to tell a story about a survivor of RA.the name is unimportant,lets call him Tim,but his story might be of value
to some. The lesson isn't always easily learned,Tim 35,began to cope when he learned to accept RA,he says,as "a part of me".
It's not entirely me,and I'll never be free of it". But instead of "dissociating" when he has a lot of pain,instead of seeing
his body as a enemy, he wants only to escape,Tim learned to stop turning out. He's come to understand his limitations and
gain some control over his life again.
"I used to think I was just this person stuck in a crippled body",Tim says,"I'd try to disconnect myself from the neck
up,all the time. I lived in a day-dream world,and the only time I was actually alive was when I was day-dreaming. I'd crawl
into my own head,where I could run and play ball and do all those things I couldn't do in the real world. And that's where
I liked to stay". the rest of the time,he endured a depression so black it came very near to being what a philosopher once
called a "sickness unto death."
Tim sits angled uncomfortably into one end of the living room couch. His neck is painfully stiff;he doesn't turn his
head if he can avoid it. There are scars visible on his left elbow and knee,below shirt-sleeves and shorts,evidence of two
of five operations that have left him with artificial hips and a plastic knee. When he walks,his stride is laboured and out
of site with his age. His hands,the knuckles deformed by disease,rest quietly in his lap as he brings back the years.
Recalling the past is a descent into darkness,and at times Tim's voice falters and his eyes mist. He agrees to to talk
about this only after much soul-searching. The thought of exposing his pain,especially now that he hopes and believes the
worst of it is behind him,wasn't easy.,but Tim feels a kind of obligation to speak. He believes that talking about his own
experience of illness and depression might help other people get through theirs.
His story isn't unique,though it is wrenching. For more than twenty years,he's been taking a beating from arthritis and,emotionally,he's
been down for the count more than once. What's important,though,is that he's gotten back on his feet. He knows he's never
going to lick his arthritis,but he's learning to hold his own,with the RA and depression. And after everything he's been through,it
feels like winning.
Tim was born in a Eas Coast mining village. It was there his ordeal began with a minor skiing accident,followed by the
flu. In a way,he never recovered. In the next months,most of his joints became inflamed,and he was initiated into the harsh
world of front-line anti-rheumatic drugs. He was eleven. Over the next few years,he went through "pure hell",a mental and
physical anguish sometimes intensified by others' lack of understanding. During an arguement one day,another boy slapped Tim
in the face. "It snapped my neck," he says,"and I blacked out. At that instant I realized how fragile I'd become. It hurt
my neck,but it broke my heart. The whole illness hit me".
The disease went into remission for a few months,after knee surgery,and Tim thought he had it beat. Then it came back.
This time he understood what was happening to him,he just totally gave up: " I lost all desire to live,Most of my prayers,for
a whole year,were that I would die. The pain was excruciating. "This," he thought,"is how I'm going to spend the rest of my
life".
At sixteen,both hips were replaced. Within months,the pain returned,and Tim drifted into alcohol and drug abuse. Can
you imagine having RA and drug abuse,to cope with ? It's hell-triple trouble. "I felt like I was walking alone and looking
into a window," he recalls,"like I never really belonged anywhere because I never had anyone my age to communicate with. No
one at school was sick".
Tim turned eighteen. One day in early fall,he was home alone reading in front of the fireplace. "To this day," he says,"I
don't know why this happened,but I got up to go to the kitchen. It'd just gotten dark,and I walked out to the porch and grabbed
a budket. The next thing I know,I'm sitting in front of the fireplace again with my wrists split wide open and my hands in
the bucket. When it dawned on me what I was looking at,it was like it wasn't even me that was there,I was just sitting there
looking at my wrists with big gaping slashes in them and blood pouring into the bucket.
"I don't know where the knife came from. I phoned my brother,who lived next door,and told him,"you've got to come over.
I did something really stupid. I slashed my wrists." When the reality of it started sinking in,I began to lose it. I could't
believe I'd actually done it. the scary part was not realizing I had done it it till after the fact. I still don't recall
actually doing it ".
Tim spiralled through most of the classic symptoms of depression,fellings of helplessness and isolation,lack of meaning
and prolonged despondency,modd swings and emotional outbursts,sleep disorders and lack of appetiate,significant weight loss.
Fuelled by drug abuse and alcohol,he developed a poor self-image and lost all will to live. His suicide attempt "was the climax
to a steady decline in who I rhought I was. From the time I got sick until that point,the disease not only ate away at me
physically but mentally as well. The only time I wasn't depressed was when I was stoned or drunk".
After the suicide attempt,a desparate cry for help,Tim was assigned a psychiatrist and admitted to hospital. It would
be years filled with more suicidal thoughts,more despair and physical suffering,before he learned to accept the fact of his
RA,and how to deal with depression in a real and lasting way.
Tim's arthritis didn't go away,but he go it under control. He got his weight up,got into better physical shape,and began
trining for a career in computers. He took up some of the resposibility for his sister's children and developed a special
relationship with an understanding woman. Most of the changes he was able to attribue to having "actually accepted the diseas
as a part of life". Depression didn't vanish from his life,but he learned to handle it,rather than letting it handle him.
Tim in his youth didn't get the proper couseling,or medical help,that is available to-day. Everyone with RA doesn't suffer
from depression.
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