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How to know if Methotrexate is working


Reader comments are often very useful, and this one (link) from Local Girl needs a more detailed answer.

She asked:

Even though my Doc spent a nice long time going over things with me (much of it echoing your messages here) there was a burning question that occurred to me only afterwards… how does one know MTX is working? Is it a subjective measure such as my personal assessment of how less achey and stiff my body is. or my personal assessment of how it has not progressed further…? Or is there a objective measure such as a decrease in my anti-CCP from 250+ to something more reasonable?

There are a range of ways your rheumatologist may assess whether a medication is working.

Typically, the whole point of using Methotrexate (MTX) is to control disease activity. In Local Girl’s case, it’s being used for Rheumatoid Arthritis (RA) so how effective the medication is depends on how much it controls disease activity.

First, your rheumatologist will want to know if it is actually helping you lead a better life.

This will be assessed through the symptoms you report and questions he or she may ask you.

How are you going? Is there anything RA is preventing you from being able to do? How much pain or stiffness do you have? Are there symptoms waking you up? How long is the stiffness lasting? Is your fatigue improved?

Some of us may use a questionnaire to assess this. For eg, the RAPID-3 (read Maybe what my Rheumatoid patient reports is more useful than my tests?).

Next, the rheumatologist will try to work out how well controlled inflammation is. Inflammation in RA is typically the enemy. Less inflammation equates to less damage.

We will use blood tests to help, typically the CRP and/or ESR which are markers of inflammation. The actual titre of anti-CCP is not routinely used as there is debate around how useful this is given the level can fluctuate and depending on the lab assays used, it may not correlate with disease activity well.

We examine the joints looking for swelling, tenderness or loss of movement.

At times, we will supplement the examination with investigations such as monitoring with power doppler ultrasound or occasionally (as the cost is much higher), MRIs looking for degree and extent of inflammation (if it is not able to be determined by simpler ways). X-rays are not generally a sensitive way to monitor effectiveness of MTX treatment as the changes on X-ray take time to develop so you lose the opportunity to make early, targeted changes to reduce longer term damage.

Some rheumatologists will use a validated composite measure such as the DAS-28 or the RAPID-3 questionnaire to help assess disease activity.

Finally, and very importantly, your rheumatologist will want to make sure you are safe and that you do not have side effects.

You’ll need to report any ill effects you may be experiencing. In addition, the rheumatologist will order regular blood tests to monitor your blood counts and to screen for any abnormalities that may be occurring. We like to find these at an early stage where abnormalities are reversible with simple actions such as reducing the dose of MTX or swapping the medication to another at times.

I hope the above demystifies how rheumatologists assess whether MTX is working.

Please let me know if you have any thoughts about this.

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Paradoxical Psoriasis


It’s an unfortunate situation.

My patient has ankylosing spondylitis and he was very affected by it with severe pain and stiffness of his spine as well as recurrent inflammation of his eyes (uveitis). He was commenced on a TNF-inhibitor medication and responded very well. Symptoms improved greatly and the eye inflammation hasn’t recurred.

5 years on the TNF-inhibitor (TNFi) and his disease remains well controlled.

Then he develops this rash.

Paradoxical Ps 2

Paradoxical Ps 1

And the rash has worsened despite a variety of topical treatments the dermatologist has tried.

It’s quite severe psoriasis.

He never had this before and paradoxically, it’s likely caused by the TNFi medication he is using. Paradoxical because TNFi medications do actually work to treat psoriasis but one possible side effect is the development of psoriasis-like rashes.

What do we know about this side effect?

  • They’ve been reported in patients with rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, juvenile arthritis and spondyloarthritis.
  • They’ve occurred with all TNFi agents (infliximab, adalimumab, etanercept, golimumab and certolizumab).
  • Most commonly, the skin lesions are plaque and palmopustular psoriasis but some have also presented with guttate lesions (as in this case).
  • These psoriatic rashes can occur weeks to years after being on a TNFi.

What about treatment?

  • This can be challenging.
  • I would involve a dermatologist as a skin biopsy can be of value and a variety of topical treatments can be tried.
  • Other therapies include phototherapy, methotrexate, acitretin and cyclosporine. Of these, rheumatologists tend to be most familiar with methotrexate use.
  • If the reaction is severe, we need to discontinue the TNFi. This is obviously a big deal for both rheumatologist and patient as the underlying disease is likely to flare and some alternative treatment will be needed (if available).
  • If the rash is less severe , switching to another TNFi may help, and I’ve certainly tried this with success.

With this patient, we have stopped his TNFi use. The rash is sufficiently severe for him to be swapped onto a different biologic medication, one with a different mode of action. He qualifies (in the current Australian context) on the grounds of his dermatologic condition, for the use of Ustekinumab, an antibody against IL12/23.

Hopefully this will help the skin and hopefully, it will help control the spinal symptoms. Ustekinumab has not however been shown to be effective in treating uveitis.

Do you have any experience of paradoxical psoriasis?

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My lack of options with Psoriatic Arthritis


Ridging&OnycholysisThese patients are frustrated. I am too.

In the last week, I’ve been reminded how difficult it can be to treat this disease.

In some, it’s severe and hard to control with whatever we throw at it.

In others, it’s an irritating, grumbling disease where it’s hard to control with simple medication and yet, not severe enough to consider (or to access) stronger medication with potentially more risk of side effects.

In addition, medication may help one aspect of the disease but since psoriatic arthritis can present in so many other ways, it may not help the other manifestations.

Patient 1:
She has had 20-odd years of disease, and has patiently tried all conventional disease-modifying agents (DMARDS) and has now trialled 4 different TNF-inhibitor medications (read more about biologic medications in this section). The disease remains uncontrolled. Skin is worsening. Joints are tender with intermittent swelling. We’re not happy.

Patient 2:
He has a swollen right big toe and a swollen left 5th toe. They look like sausages. All blood tests are normal and he is otherwise well apart from some thickened psoriatic skin plaques on the shins. It’s however painful to walk.

Methotrexate, Salazopyrin EN, Leflunomide, a number of anti-inflammatory medication as well as steroid has been trialled without success. He does not qualify for subsidised TNF-inhibitor therapy in his current state. I’m also not too sure I would like to use these agents for 2 sausage-shaped toes, if there were better options.

Patient 3:
15 years of mild skin psoriasis but in the last 5 years of so, he has developed painful heels (plantar fasciitis), recurrent shoulder impingement symptoms, a bad back which is quite stiff when he sits too long or when he wakes up. And most irritatingly, ugly fingernails (read this post on psoriatic nail disease). Side effects occurred with Methotrexate and Leflunomide. Blood tests are all normal and again, on the basis of this range of symptoms, this patients does not qualify for subsidised
TNF-inhibitor therapy.

An irritating lack of options. I’ve not done an audit, so my educated guess is that up to 30% of those I see with psoriatic arthritis fall into this annoying space.

I do realise complaining about lack of access to newer medications available in other countries is a 1st world complaint.

Still, I would really like access to other agents for my patients caught in these difficult situations.

Apremilast, an oral medication and Ustekinumab, a subcutaneous injection are options which should become available soon-ish. And there are more options coming with different modes of action so the future at least holds some promise.

Are you in a similar situation? I’d love to hear your thoughts.

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Health Insights & being Patient-centric


It’s the 1st time I’m quoting a document released by a bank.

But this one, entitled Health In Focus peaked my interest. The full document can be accessed here (link).

We are working in an environment of mounting pressure with rising costs with a reduced ability to pay these costs by those who hold the purse strings. In Australia, that’s the government and the paying patient.

Worryingly, there is an inexorably ageing population consuming more and more health resources.

By the way, the numbers are so stark, I thought I’d quote verbatim:

“It’s no small wonder that aged care is widely expected to be one of Australia’s growth industries over the next few decades. The figures tell the story: in 1984 there were 120,862 Australians aged over 85; today there are five times as many and by 2045 there will be 14 times as many.

Put simply, the great cohort of Baby Boomers are getting older and people are living longer: 30 years ago life expectancy at birth was 75.8 years. In 2045 it is projected to be around 90.4, a 15-year increase in just 60 years.”

The report highlights our disconnected health ecosystem. With all the pressures mounting, the current systems are unsustainable. Change is needed.

“Misaligned incentives between state and federal governments on one side and the private and public sector on the other need to be addressed by significant reform and market deregulation. Additionally, information asymmetries in the patient-practitioner relationship often result in the inability of patients to take ownership of their health journey. And data isn’t always recorded or readily accessible to facilitate decision-making.”

I’m sure you all can relate to that.

Given BJC Health’s vision is to create best care for people with arthritis, and how we aim to achieve this is with our connected care approach, I really liked the following from the same document:

Future Connected Patient Design Principles

  • Make life easier and more convenient for me
  • Let me take ownership and empower me
  • Include and respect me in the relationship
  • Provide me with confidence along my journey
  • Keep me informed
  • Enable transparent access to my information
  • Give me the best care you can
  • Reduce my costs

Lots of good guiding principles to design health delivery around. Many are hard to provide without going out of the comfort zone and thinking outside the square.

Do you have any thoughts on this?

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Balancing odds of drug working vs chance of side effects

Courtesy: digitalart @ FreeDigitalPhotos.net

Courtesy: digitalart @ FreeDigitalPhotos


This is a conversation I thought I’d share as it seems to touch on very pertinent concerns.

As you know, I write a bit about Methotrexate as it seems to be quite a maligned drug. These posts are popular and this particular conversation took place on the comments section of Why Methotrexate is My Current Go To Drug in Rheumatoid Arthritis.

Rosiet is 8 months post-RA diagnosis and is at the point of contemplating Methotrexate.

Rosiet: “I am trying very hard to educate myself as I move through this disease. I am not sure yet if your words have comforted me to the degree of accepting the <Methotrexate> , but <at least, it has> given me more information.”

While there is so much information on the internet, it can be so confusing for someone faced with a chronic illness.

They can read scary things about the disease. They can read scary things about medication. They can read confusing and sometimes, contradictory info about a variety of treatments, potions, remedies and snake oils. They can also research medications, and get wildly different opinions.

I take this as a reminder that we rheumatologists need to keep improving information and resources for patients to access. Patient support associations also need to become more visible so that people looking online actually come across their services.

Rosiet: “And, what I am just figuring out is that none of these drugs have much of a ‘success’ rate nor longevity to them. I am understanding that odds for each drugs effectiveness are relatively low to a high chance of side effects and that after an amount of time they stop working . . . and, you have to spin the wheel again . . .”

I’m wrote back as I did not agree with that assessment but I can understand how someone trying to find information online can be led to that opinion.

Rheumatoid Arthritis is not one single disease that acts the same way in every patient.

There is variability of severity, there are different outcomes for different patients, there are differences in how well people respond to medications, and of course, side effects occur in some and not in many others.

So it’s not that easy to determine the likely success rate of a particular medication in any one patient. It’s also not easy to say with certainty whether a patient will have a side effect or not.

Rheumatologists do try to make these assessments as they weigh up the history, the findings on examination, other health issues the patient may have and various test results.

For Rheumatoid Arthritis, “success” depends on many factors. Some of these include:

  • the window of opportunity: earlier treatment leads to better outcomes
  • treating-to-target: use of medications & close monitoring of response with swapping of medications as needed to get a better response
  • poor prognostic factors: how aggressive the disease is, how many joints are affected, how much inflammation is present clinically or using imaging or blood tests
  • negative factors such as periodontal disease, smoking, excess weight, etc

As a guide, Methotrexate works best early in the RA disease course with a good chance to achieve a remission state – around 40% using Methotrexate as the sole disease-modifying agent (DMARD).

This does not mean 60% do badly.

They will not have as good control of the disease and to obtain better control, changes or addition in medication therapy need to be considered.

Rosiet: “So, you would say that I, as newly dx’d, have a decent chance for full remission considering the Plaquenil has given me some relief on it’s own. And, it is a matter of running through each drug to find a ‘tolerance to healing’ ratio? I will admit that after not being able to take the sulfasalazine and looking toward the MTX and it’s myriad of side effects I am feeling apprehensive, at best. Along the line of the ‘tolerance to healing’ ratio, in your opinion is there a gray area where side effects are accepted to a degree with good drug response?”

My response:

In general, Plaquenil would be considered a weak DMARD on it’s own. Most of us would start with Methotrexate as 1st line DMARD for Rheumatoid. I suppose there are occasions when rheumatologists would use Plaquenil at the start, for eg, if pregnancy was being pursued, or the prognosis of your type of Rheumatoid was considered very good (based on a range of features including those I listed previously).

There are of course gray areas.

Any treatment decision is a balance between the probability of a good result vs the possibility of a side effect.

Have you had similar worries to Rosiet you haven’t voiced?

Dr Irwin Lim is a rheumatologist and a director of BJC Health. You should follow him on twitter here.
BJC Health’s vision is to create best care for people with arthritis. Contact us.

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