Patients with Autoimmune Disorders

Patients with Autoimmune Disorders


>>So this morning Mike’s going to be double teaming
with Yvonne. Autoimmune diseases are the most
classical mixed pain states. And actually I want to
sort of really focus on the peripheral component. And then Yvonne — so I’m going
to hopefully set up Yvonne to talk about the
central component because both are
really quite important in managing our patient. So these are my disclosures,
none of them which are directly relevant
to the content of my talk. So who are my patients? So in Scotland, I’m
a rheumatologist. And we have a great bias
towards managing patients with inflammation
in their system. And this includes patients with
rheumatoid arthritis, lupus, axial spondyloarthritis, psoriatic arthritis,
and vasculitis. And in essence, all these
different disorders have different dysfunctional
immune pathways at play, leading to very different
phenotypes. However, if I was to ask my
various patient populations what their priorities are, invariably
pain ranks number one. It’s the biggest deal
for our patients. It has been a privilege being a
rheumatologist over the last 15 to 20 years because there
has been a transformation in how we manage pain and
manage the underpinning disease. And I’m going to
focus this talk — and I think Yvonne is
going to do the same — around rheumatoid
arthritis as a prototype for autoimmune disease. And I think many of the concepts that we’ll be discussing
are really transferable across the spectrum
of autoimmune disease. So I’m going to try and
exemplify the transformation that I’ve observed over the
years with a couple of cases. The first case is genuinely
the first patient I remember managing with rheumatoid
arthritis many, many, many years ago when
I was a resident. And at that time we had
a full ward of patients with rheumatoid arthritis
at any one time. Now I don’t have a ward
anymore and that sort of speaks to the change which we observe. So this patient, a
49-year-old ex-nurse, was referred in from clinic. She established diagnosis
of rheumatoid arthritis for five years and she’d gone to
a clinic to see her consultant, complaining of crippling pain
and progressive immobility. So she was referred,
as many people were, for an inpatient
assessment and sort out. So her past medical history, despite her relatively
tender age, included ischemic heart disease. And we now know that systemic
inflammation not just targets the joints. It can affect every system,
including the blood vessels, and premature vascular disease
certainly was rather prevalent in those days. The inflammation can
affect other organs as well, including the lungs. And she had sort of
interstitial lung disease. She was chronically constipated. And I’m sure everyone
can guess in this room, after the last couple of days of
talks, why she was constipated. And I won’t even go there. She had a right total
hip replacement. This is from really,
purely controlled, aggressive rheumatoid
arthritis causing damage. And she had diabetes. Again, that’s related
to a drug toxicity which I’ll go on to speak about. Socially, unfortunately,
medically retired, the impact of the disease
was greater than just to her. It affected her whole
family, leading to divorce. Her teenage daughter
was the main carer. So back then, rheumatologists
adopted what we called the [inaudible] approach. We did have medications
there, such as Methotrexate and sulfasalazine which could
get at the abnormalities in the immune system,
but we were so scared of these drugs then that
we’d only really used them when we were desperate
many years down the track after diagnosis. Instead, we would focus rather
ironically on medications that we now know are ten times
more toxic than these DMARDs. So this patient,
she was being stuck on morphine for many years. In my world, if there’s
anything worse than opioids, it’s steroids. And steroids are
associated with a whole host of adversities including
diabetes, hypertension, osteoporosis, severe
infections, the list goes on. Even nonsteroidal
antiinflammatories which have been around for a
while now — used chronically, they’re increasingly being shown
to damage the blood vessels and have higher associations
with ischemic heart disease and ischemic vascular
disease now. So we’ve been basically
poisoning her for a few years. In clinical examination, she
had knees which looked a bit like this which evidence
swelling, which has probably got an
inflammatory component to it but also a lot of
damage as well. And certainly her feet, as you
see, are clearly very deformed. And this is all damage,
accrued damage over many years of having this terrible
disorder. So what did we do for her
while she was in the ward? Well, I as the medic did
very little, to be honest. In those days, I injected
a couple of joints which provided some
short-term relief. The real good work was done by physical therapy colleagues
getting to mobilizing — the occupational
therapist going to her home and fitting in shower aids. We had belatedly given
her methotrexate. It clearly wasn’t working. And then we switched
to gold injections. And do you remember
gold injections, Dan? Or this just a Scottish thing? I still laugh at the fact
that I used to use –>>[Inaudible], so
yes, I did use gold.>>Ah, so it wasn’t just Scots. So that’s how desperate we were. And there is some evidence
behind gold injections, but not great. But that’s — we reach for
gold when we’re desperate and that’s what we did in
this patient back then. And ultimately she needed
her joints replaced, and we got orthopedic
surgery involved and she was wait-listed
for knee replacement. But overall, I mean, all
these factors together — she had a very poor prognosis. I don’t know what
happened to her, but my suspicion is she
would have an 80% risk of mortality within ten years. Studies have shown
rheumatoid arthritis is more than just the joints. The inflammation gets
everywhere, including the brain. But the hallmark
feature is pain. And the hallmark feature
is inflammation targeting the joints. You can see this inflammation
in this picture here — red, hot, swollen joints. You’re not surprised that
these are very painful for the patient. So what’s going on
inside the joint? Well, the normal joint
incorporates a natural shock absorber which is basically
the synovial fluid sac. And it’s here that
the immune system and the inflammation is
targeting, causing that red, hot swelling that you observed. But we need the inflammation
in our bodies. It’s there for a
reason, of course. We need the immune
system to protect us from infections and
other things. So very briefly, when our normal
immune system is how we deal with infections, as we have
an innate immune system which involves cells such as
neutrophils and macrophages which help controlled
infection in short term. And then we have the
adaptive immune system which incorporates
B cells and T cells which help eradicate infection. They also, very importantly,
produce antibodies to help protect us from any
infections down the track. But it’s these antibodies
which can go wrong sometimes. And in rheumatoid arthritis, what we believe is the
culprit is in those people who are genetically predisposed, an environmental insult comes
along — it might be a microbe, it might be a period
of stress — and this triggers
the immune system to generate aberrant
antibodies which go on to target things they
shouldn’t be targeting, including the cartilage
and the joints. And over time, this
inflammation ramps up to cause and generate this terrible pain. And over the last ten or 15
years, since that patient, there’s been amazing progress of very clever biologists really
parsing out what is going wrong in the immune system,
what are the pathways, in particular aberrant cytokines such as TNF-alpha [inaudible]
six have been identified. And from that, new drugs
have been developed. So it’s these cytokines
alongside the cells and prostaglandins which
are in that terrible milieu in the joint which
goes on to sort of stimulate the
mechanoreceptor nerves, the primary afferent nerves,
which then go to the spinal cord and cause sensitization there
and ultimately to the brain. And you heard yesterday from
Rick of the different modalities that we can use to
evaluate pain. And one of them, a
quantitative sensory test that you can see here, if
you squeeze those joints, patients have purer
pain thresholds. And Yvonne has shown that those
purer pain thresholds relate to measures of inflammation. So this is good evidence of
peripheral sensitization. But also, if you squeeze the
joints and you stick the patient in an MRI scanner
at the same time, you’ll see that the regions of
the brain which are culprits in pain also light up. So rheumatoid can cause
acute inflammatory pain. But over time, it needles away at the joint, causing
destruction. And it leads to nasty x-rays
like that, I’m afraid. And clearly that’s
another mechanistic route of peripheral pain generations. The mechanoreceptors
there are clearly going to be very unhappy,
leading to pain and ultimate joint replacement. So I alluded to the fact
that there’s been a change over the last ten or 15 years. And probably the first
breakthrough was for us to realize that we
should no longer be scared of these DMARD therapies which soften the
immune system response. This is nice data from Europe
which shows that if you get in early and you diagnose
patients within 12 weeks and you start treatment
at the beginning rather than at the end, you can
completely transform the number of erosions — that’s a
good measure of joint damage in the rheumatoid
arthritis joint. The number of joint erosions
is reduced significantly just by getting in there
with an early diagnosis. And I appreciate in this
audience there is a lot of you will see many patients
coming to you with joint pains. And you might be
the first contact. And you might be thinking,
hearing this talk, well, how can I pick out
those patients who have the more
inflammatory arthritis so that I can get them referred on to a rheumatologist
sooner rather than later to improve their
longer term outcomes? And I’ll very quickly go
through a few pointers to help, basically, establish distinguish
inflammatory peripheral pain from the more mechanical pain
which is far more prevalent, whether it’s osteoarthritic in
origin or centralized in origin. So inflammatory pain
tends to be worse on rest and better on movement. Patients report substantial
early morning stiffness relative to mechanical pain. But the key thing for me is
having a good look at the joints and looking for that
swelling and making sure that that swelling
isn’t hard swelling because hard swelling — and
many of you may have looked at your grandparents’
joints recently. I bet you half of them will be
quite hard and knobbly joints. It will come to us
all, I’m afraid. But what we’re interested
in here and in inflammatory arthritis
is the soft, spongy swelling which is pretty pathognomonic
of inflammatory arthritis. And us rheumatologists now have
fancy tools to help us quantify and diagnose this more. We have ultrasound which
shows this fire in the joint which is the inflammation. Some of us used to stick
needles in the joint and take out the fluid. And you can see that
the fluid in our joints, it should really look like a
gin color, whereas in the sort of inflammatory joints
it’s clearly angrier. And these days we have
remarkable progress in making early diagnosis because we can measure
somebody’s aberrant antibodies I was telling you about. And in particular, there’s
an antibody called anti-CCP antibody which I call the
super rheumatoid factor because this is highly specific, unlike rheumatoid factor
— so 90% specific. And it’s also prognostic
as well. If you have high CCP, you’re
likely to have purer outcomes. And now in Scotland, and
I’m sure in the US as well, this is widely available to
all primary care practitioners. And as soon as they
get a patient who they wonder has rheumatoid
and they do this blood test, we will see that
patient within six weeks so that we can institute
treatment. So, I’m glad to say I can’t
remember the last time I prescribed gold. There’s far greater
uses for gold. And again, because of the
amazing insights of a number of clever biologists over the
last years, we’ve now mapped out what’s going wrong
and now developed appropriate treatments. And essentially we can target
so many different elements of the immune system now
with these biological drugs. So we can manipulate the
T-cells that go wrong. We can manipulate the B-cells that produce the
aberrant antibodies. We can mop up the excessive
levels of cytokines. It’s been an amazing time
to be a rheumatologist. And these biologics have
been, most importantly, amazing for our patients. And you can see here
what they do to pain. But you can also see that
the pain doesn’t go to zero. And I think that’s an important
point as we move forward. Many people ask me, is
there a drug that’s better for pain relief in the context
of these fancier biologics? The truth of the matter is
they’re all much the same. There’s certainly different
individuals will respond better to certain drugs. Rheumatoid is a heterogeneous
disease. What the abnormal pathways are in one patient will be
different to another patient. But on the population level, these drugs are pretty
equivalent. These drugs are also
very expensive. And so this is data from 2012. I’ll remind you that rheumatoid
arthritis isn’t as common as heart disease and
diabetes, but of the drugs at the top three drugs in
terms of income generation for the pharmaceutical industry
are three biologics used for rheumatoid arthritis. So these drugs are far
more expensive than gold. And they don’t cure. Patients are on these
drugs pretty much forever. So this brings in
a lot of income. And an important
message to take away is that while these drugs have been
transformative, it doesn’t mean that some of the older
drugs like methotrexate and sulfasalazine aren’t
just as good if used early and aggressively in combination. And in Europe we’ve done lots
of trials to just evidence that. So I know practice varies
across this world, but certainly in Europe we would still wish to use
methotrexate-sulfasalazine first line because if you
look back at the cost of these other drugs,
I mean, what else? I mean, how many
physical therapists, how many occupational
therapists, how many psychologists could
we support our patients with if we could even have
a fraction of that money? Something that we’ve — we’re very proud of in
Scotland are doing trials around improving
outcomes in rheumatoid. It hasn’t just been
around early diagnosis but also intensive followup. So when we see a patient
and we diagnose a patient, we monitor them really closely, sometimes every couple
of weeks or so. And every time we
see the patient, we ask ourselves the question,
has the pain improved? Has the inflammation
disappeared? And if not, we ramp
up the treatment. We’re very aggressive. And by doing that, particularly
in the early stages, we can improve outcomes,
particularly pain. So that first patient
I referred you to, never [inaudible] had a
lot of joint replacements. I can’t remember the last time
I’ve had to refer a patient for a joint replacement
which is a great success. Patients still get damage to their joints despite these
more aggressive strategies but the number of
erosions that people get in their joints is really
small, comparatively. And actually, the
observational data when you relate these
x-ray changes to pain, they don’t show an association. So I suspect that this
current level of damage, that’s probably not enough to be contributing greatly
to the overall pain. And despite these fancy
therapies, I really want to emphasize the MDT was
a cornerstone back then and remains a cornerstone now. It’s just that we’re
more ambitious. And rather than encourage our
patients to get out of bed to the toilet, we are now
encouraging our patients to stay in work and to live a
completely normal life with great travels
around the world. That’s sort of our aims and that’s what we’re
trying to achieve. And together with the
MDT, we have been able to combine the pharmacological
approaches to reduce work disability. So it’s all been a
great success story. And I really hope that
in the years to come when I’m teaching
medical students about rheumatoid arthritis,
I’m trying to find patients with rheumatoid arthritis
in the wards to do some bedside teaching, that we will not hands
like this anymore. And if we do see hands
like this, it’s a failure of the rheumatologist of not
making a diagnosis early enough and not treating
aggressively enough. So let’s think about my most
recent rheumatoid arthritis patient now, then. So this is a 59-year-old
business woman, again a five-year history
of rheumatoid arthritis. Her presenting complaint
was pain, just like that patient
15 years ago. And also fatigue
and major concerns about whether she could
continue on her employment. Unlike the previous lady, she
had no joint replacements. She had no cardiovascular
disease. By better treating
the inflammation, we’re stopping all these
other complications of this condition as well. But the [inaudible] related
complication still remained. Depression remains
highly prevalent. Anxiety is very high. And she did struggle
with depression. But she remained in
full time employment. She was single. And it was valued
activities, her hobbies, which were still constrained. So her treatment did follow
this treat to target approach of diagnosing early,
monitoring very closely, starting a methotrexate
combination treatment, and then finally
getting on to biologics. And as a result, that’s
what her hands look like — so very different. There’s no swelling there. There’s no hot, boggy joints. So why, then, is she
reporting significant pain, pain that is enough for her
to reconsider her career and stop her doing her hobbies
that enthuse her so much? And she’s not alone. So this is data from our
UK Biologics Registry where we are very careful
to monitor every patient who has been started on one
of these expensive drugs. And it hones in on patients who have apparently completely
responded to these drugs. They have no swollen joints. They have completely normal
inflammation in their blood. And this is data asking on that
population level of thousands of patient what their
pain levels are. And it’s the SF-36
Bodily Pain Score. And it basically shows that 50%
of patients have a score of less than 40, and 40 is a greater than one standard deviation
level of pain compared to the general population. So there’s clearly other
mechanisms at play here. It’s not just about
inflammation. And despite making these great
strides, there’s a lot more that we should be
doing for our patients. And me and Yvonne and
others all sort of feel that there are central
pain pathways to explain this disconnect. I’m very pleased to hand over
to Yvonne to talk a bit more about those more
central aspects. Thank you very much. [ Applause ]

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