Why are we Rheumatologists looking forward to Tofacitinib (Xeljanz) ?

Rheumatoid disease is a chronic disease predominantly involving the joints. We have come a long way as far as treatment & outcomes are concerned. We have been able to put life back into patient’s life.
However, not everyone is that lucky. We are still not able to achieve remission in each & every patient. Statistically, almost 20- 30% rheumatoid patients do not improve sufficiently with DMARDs & biologics. The retention rate of most biologics are low (retention rate is the proportion of patients continuing biologics on a long term basis). We have still not understood the rheumatoid pathogenesis completely. We have not yet located the master switch that can turn off the inflammation.

As Rheumatologists, we would like each & every patient to achieve remission & do well. That is precisely the reason why we are looking forward to further development in understanding of RA & new drugs to tame the inflammation.

Rheumatoid inflammation

Rheumatoid inflammation

In rheumatoid disease, immune cells in the synovium of the joints get activated. They secrete various chemicals called cytokines. These cytokines are absorbed in blood & circulate throughout the body. These in turn act on other immune cells; activate them. The activated immune cells start secreting more cytokines. Theses cytokines are responsible for the joint damage & other complications of Rheumatoid disease. So, our efforts are directed to block either these cytokines or the cells secreting them. This would not only reduce the chances of joint damage but also keep the inflammation in check by blocking activation of immune cells. We can block these cytokines & cells with DMARDs & biologics.

Let us consider an example to understand the rheumatoid inflammation & the mechanism of various medications. This is akin to the following plot.
Understand biologics, DMARDs & JAK inhibitors
There are 5 terrorists (cytokines ) who want to enter an island country (immune cell) to start a terrorist camp & train more terrorists (generate more cytokines). So, if they are able to enter this country, the number of terrorists will increase as also the chances of destructive activities. They can enter the country by air using multiple airlines ( Airline TNF- α, Airline IL-6, Airline B cell)

If a Rheumatologist is the police; using DMARDs is like using multiple contacts in various airlines asking them to block the entry to the terrorists. This may work if one has good contacts, but is not foolproof.

Biologics are more specific. They are like specific legal orders to specific airlines to block their entry. So if one blocks the TNF α Airline from carrying the terrorists, the island is safer. But then, this is not the only airline available. They can always take the other airlines & still manage to enter the country & succeed with their plans. The same way, a biologic works but then is not the final answer.

How about going a step further? One can also block their entry at the ports of entry. This will block the terrorists irrespective of the airline they use.
Blocking inflammation at cellular level

This is exactly where we are today.
We have taken the war against Rheumatoid to the ‘ port of entry- signal transduction’ level. Instead of blocking multiple different cytokines, we are now looking at blocking the cellular system that responds to multiple cytokines. This way, we can block the effect of multiple cytokines with a single medication & reduce activation of immune cells thus keeping the Rheumatoid inflammation under check.
Janus Kinase is an enzyme that works at the port of entry in the cell & helps the transduction of message (execution of the plot). We now have Tofacitinib (xeljanz), a Janus kinase blocker recently approved by FDA.

As we saw, this is clearly a step ahead in our battle against the Rheumatoid Disease. We would be looking how well this technological advance really translates in practice in the further blogposts.

Time, tide & inflammation waits for nobody…

I recently blogged about the ‘drug free remission’ in Rheumatoid Arthritis.
Aggressive treatment with DMARDs, biologics & a targeted approach can help one achieve this.
But, is it really that simple? For the best results, what would one expect from Patients? Positive approach & compliance……
But, why am I thinking about all This?

Last week, I was going through my OPD appointment list. One of the names looked familiar; Mrs. K, but I could not recollect the patient.
A lady in wheel chair, with most of the joints swollen was brought in by 6 of her relatives! She was unable to walk on her own. As I went through her file, history unfolded.

I had seen her some two years back. A lively young lady, a doting mother had consulted me for her joint complaints. She did have rheumatoid arthritis & was started on DMARDs. She was given three DMARDs due to the high disease activity. However, unfortunately she continued to have persistent joint inflammation even after 6 months of therapy.

The inflammation then started interfering with her personal & family life as well. Frequent leaves were ruining her professional reputation, her son was doing badly at school & there were frustration & fights at home.

We were slowly moving towards a decision of starting biologics. The entire issue, need of biologics, effects, side effects were discussed. The family was alright with the idea of a more potent drug to control the inflammation, but wanted to wait for some more time. We waited for two months, DMARD doses further optimized; but in vain.
After three months, I discussed the issue again. However, they were scared by a pharmacist relative about the side effects of biologics.

That was the last I saw her then. Now, she started telling me what happened after the last meeting. She & her family were scared of the side effects of biologics, decided to try alternative medicine, stopped all her allopathic medicines. The Result? It was staring at me……

A crucial mistake of stopping all DMARDs at a crucial juncture had done a lot of damage. Her knees were badly damaged & hands were deformed. Time, tide & inflammation does not wait for anyone…..uncontrolled inflammation had inflicted enough of damage already & quite a bit was irreversible.

Suppose you are caught in a similar situation wherein you have to decide regarding a biologic/ new therapy advised by your Doctor, how would you go about?

Decision making made easy

Decision making made easy for patients

A few points to remember —

1) When you go for a second opinion, if the second consultant confirms the proposed line of treatment, go back to your primary consultant who already knows you & your disease. The second doctor would take some time to understand your arthritis & establish his own treatment strategy.

2) Use the internet, get more information. Be judicious in the choice of sites. You can also use the social media to connect with specialists & other patients to learn from their advice, experience.

3) Never stop the ongoing treatment in the mean time. Never go for the radical option of stopping all the medicines without medical advice.

4) Always know when to put a ‘stop- loss’ order. What is this ‘stop loss order’? It simply means that, you should know when to stop wasting time in taking crucial decisions. Your decision & the plan should not take more than 4- 6 weeks (preferably).

Let us not realize that ‘Time, tide & inflammation does not wait for anyone’ the hard way.

Do you take your arthritis meds with fruit Juice?

Do you take your arthritis med with fruit Juice?

If yes, think again. Fruit juice may not let you achieve remission…..
And why is that So?

Many fruits, especially grapefruit juice & possibly orange, starfish, Seville apple juice affect the absorption of methotrexate from the intestine.

Methotrexate is absorbed in the intestine by a pump called OATP. These juices contain chemicals that block this pump & decrease absorption of methotrexate. Grapefruit also blocks CY 350 which affects other meds.

So now that we know about this, what can we do?

1) Avoid taking methotrexate with any fruit juice.
2) Keep a gap of at least 2 hours between methotrexate fruit & any fruit juice.

Rheumatoid Arthritis: The journey from ‘no treatment’ to ‘drug free remission’

Not bothered about me crying in pain,
That Physician with great name & fame,
Gave the disease he cannot cure,
A name!

Is this what Rheumatoid Arthritis treatment all about?
Are Rheumatologists just giving name to a disease for which they do not have any treatment & cure?
Mind you, these lines were penned almost 150 years back.

We have come a long way since then.
In the early years, symptomatic therapy (pain control & patient’s feeling of well being) was all that was available. We had aspirin & steroids. Slowly multiple other anti inflammatory meds became available; but the treatment concept remained the same.

Slowly, the destructive potential of rheumatoid arthritis was realised. This stimulated the search for means to modify the disease course. This is when DMARDs (Disease Modifying Anti Rheumatic drugs) came into the picture. Armed with evidence, Rheumatologist shifted gears from the ‘conservative wait & watch’ approach to the much more aggressive ‘early diagnosis, early aggressive targeted treatment’. This literally translated into ‘will not tolerate any harm’ approach. Biologics came in handy for Rheumatologists to achieve this goal.

The change in mindset coupled with effective medicines enabled us to aim for remission in a disease that was thought to be the one without effective treatment.  Recent studies have already shown that even ‘drug free remission’ is possible.

The existence of ‘drug free remission’ was discussed at length at this year’s American College of Rheumatology Conference. Doubts about its real world definition, longetivity, recurrence of RA definitely do exist.

Nevertheless, we have come a long way; from ‘no effective treatment’ to ‘drug free remission’ Collateral damage in the form of cardiovascular events, osteoporosis is also well recognised & prevention strategies are getting refined. Patients be rest assured that better things are in store for them.

Few years from now & you may find me tweeting & blogging about sustained drug free remission. All the very best & wish everyone remission……

A stitch in time saves nine…How early is early in Rheumatoid Arthritis?

Rheumatoid arthritis is a chronic autoimmune arthritis with destructive potential. It not only destroys joints but can also play havoc with one’s personal life, family life & career. As Rheumatologists, we have learnt over the last decade that the only way to conquer this deadly disease is to treat early & aggressively with DMARDs.

However, how early is early enough?

We are very much interested in knowing how early we should be treating RA with DMARDs for the best results. This period is the ‘window of opportunity’. Once missed, the prognosis would change drastically. Initially, this was thought to be 2 years from the onset of symptoms. Later, it was thought that diagnosis & treatment with DMARDs within 6 months from the onset of symptoms should be good enough to take care of the disease.

Michel PM van der Linden studied this ‘window of opportunity’ at the Leiden Early Arthritis Clinic. His group studied 1674 patients with RA over a period of 6 years for the level of improvement with DMARDs & joint destruction. They found that contrary to popular belief, 6 months is too long a period to be considered as the window of opportunity. 12 weeks was found to be the critical period. A delay of more than 12 weeks would mean a lesser chance of achieving a drug free remission & 1.3 times higher risk of joint destruction in the long run. What was very striking was the fact that the effect of the delay could not be nullified by a more potent medication strategy later. Treatment started in this phase had the best chance of inducing remission & reset the disease. The effect was seen for anti CCP positive as well as negative patients.

What this means is that any delay of more than 3 months form the onset of symptoms to the start of DMARDs would mean poor outcome in the long run. Where can this delay occur?
1) Patients taking time to seek help.
2) Time taken at the Family physicians level in diagnosing & referring patients to a Rheumatologists.
3) Time taken at the Rheumatologist level in getting an appointment.

The average delay in UK, Canada & the Netherlands was found to be 23 weeks, 17 weeks & 18.4 weeks respectively. A survey in the UK found that delay at the patient level was the main cause of delay. Hence, an earnest request from my side to anybody suffering from joint pain – please seek a Rheumatologist’s help at the earliest. You can take this quiz to know if you have early arthritis. Please do not underestimate any joint pain or swelling as a part of ageing or as rheumatism that would settle on its own. Seek an expert help & that could mean a whole new life for you in the long run!

1)van der Linden, M. P. M., le Cessie, S., Raza, K., van der Woude, D., Knevel, R., Huizinga, T. W. J. and van der Helm-van Mil, A. H. M. (2010), Long-term impact of delay in assessment of patients with early arthritis. Arthritis & Rheumatism, 62: 3537–3546. doi: 10.1002/art.27692
2)Bykerk, V. and Emery, P. (2010), Delay in receiving rheumatology care leads to long-term harm. Arthritis & Rheumatism, 62: 3519–3521. doi: 10.1002/art.27691
3)Kumar K et al Delay in presentation to Primary care physician is the main reason why patients with Rheumatoid arthritis are seen late by Rheumatologists. Rheumatology (oxford) 2007;46:1438-40
4)Feldman DE et al Rapidity of rheumatology consultation for people in an early inflammatory arthritis cohort. Ann Rheum Dis 2009;68:1790-1.