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

March 24, 2013

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.

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History Of Rheumatoid Arthritis- an infographic

January 27, 2013

History of Rheumatoid Arthritis


Time, tide & inflammation waits for nobody…

December 9, 2012

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.


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

November 15, 2012

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……


Stem cell therapy for Rheumatoid Arthritis

April 3, 2011

Rheumatoid arthritis (RA) is an autoimmune disease. For unknown reasons, one’s own immune system starts thinking that his/ her joints are foreign & attacks them. This results in inflammation of the joints. The routine treatment includes medications that modulate the immune system (DMARDs) or medications that block the cytokines (biologics).

We are in the age of organ transplant. Kidney transplant has become an established therapy for those with kidney failure. How about immunity transplant since RA is an immune dysfunction. This is precisely what led the scientists to try out stem cell therapy for RA.

Unlike kidney, the immune system is not a solid organ that can be removed; hence chemotherapy is used to ablate the marrow (organ where the immune cells are generated). This is followed by infusion of stem cells. The stem cells give rise to a whole new immune system that does not attack the joints.

Geoff McColl first reported a successful stem cell therapy in a man with resistant RA in the October 1999 issue of Annals of Internal Medicine. A 39-year-old man with RA who had failed standard RA therapy was treated with stem cells from his identical twin brother. The results were dramatic & the patient could swim, ride a bicycle & was free of RA symptoms even after 2 years of the therapy.

Richard K. Burt also reported about a successful stem cell therapy in a lady with resistant RA in the August 2004 issue of Arthritis & Rheumatism. A 52-year-old lady with treatment resistant RA was treated with stem cells from her sister. She remained in remission even after 1 year of stem cell therapy. Her rheumatoid factor disappeared & so did the rheumatoid nodules. The joint inflammation & the morning stiffness settled & the ESR normalized.

However, this is easier said than done. These stories sound fabulous. Studies were taken up to study this therapy further. A study from Netherlands included 14 RA patients. Of the 12 who completed the study, 8 patients improved significantly within one year of therapy. 4 patients failed to respond & those who had responded relapsed & required reinstitution of DMARDs within 2 years of therapy. Snowden J & colleagues analysed the registry data of 76 patients who received the therapy in different studies. In most patients, disease-modifying anti-rheumatic drugs had to be reinstituted within 6 months for persistent or recurrent disease activity.

Zhang-Huo li and a team of researchers from Peking university People’s Hospital have come with a new approach recently. They studied the umbilical cord mesenchymal stem cells. They found that these cells can suppress the inflammatory effects of RA related fibroblast-like synoviocytes and T cells in cultures. They also showed promising results in animal models of inflammatory arthritis.

All in all, stem cell therapy for RA is in a developing phase. We will have to wait for further studies with different medications/ designs for a definitive take on this approach.

References:
High-Dose Chemotherapy and Syngeneic Hemopoietic Stem-Cell Transplantation for Severe, Seronegative Rheumatoid Arthritis Geoff McColl et al October 5, 1999 131(7) 507-509

Verburg RJ, Kruize AA, van den Hoogen FH, et al. High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy. Arthritis Rheum. 2001;44:754-760.

Snowden J, Moore J, Passweg JR, et al. Autologous stem cell transplantation in rheumatoid arthritis. Blood. 2001;98:860a.

Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Liu Y et al Arthritis Res Ther. 2010;12(6):R210


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