Robert Fox, MD Article (Therapeutics for Sjogrens)

[markt]

https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=48&ved=2ahUKEwjuyo2h1ffeAhULvVMKHWAJDEA4KBAWMAd6BAgCEAI&url=https%3A%2F%2Frobertfoxmd.com%2FSjogrensByFox%2FRheumatic_Clinics_of_North_America-Therapy.pdf&usg=AOvVaw1rEwKY1oJJZarRw01FWGyJ

Just browsing the web, and found this perspective from one of the leading Rheumatologists on various treatments (Past, Present, Future) for Sjogrens. 

Found it interesting and just wanted to share.

- Mark

[Carolina]

Dear Mark,

The article is VERY interesting, probably because I have around 70% of the conditions addressed in the article.

The recommendations for the current ways to treat these conditions are consistent with my treatment protocols.

It was also of real interest to see the possible treatment modalities presented at the end of the article.  The new small molecule approach has various substances under study.  It is hard to name the category they fall in.  I guess small molecules, of various types.

It is exciting that there is research that may 'pay off' with new treatments.  Of course most of them are far from becoming accepted treatments.

And once again I am reminded that the treatment of each aspect of our Immune Disorders, does not yet include identification of and treatment for the basic CAUSES of the conditions we endure.

It is clear that my Immune System used cytokines to attack my body, rather than autoantibodies as in autoimmune disease.  But no mention is ever made of how those attacks can be stopped at the level of the Immune System.

I think this will occur in the future and there will be a way to 'heal' or 'treat' us so that our immune systems do not carry out the attacks that damage us in so many ways.

It is so important to fund the basic research that underlies all of these advances.

Regards, Elaine

[Sharon]

Thanks markt, a very interesting read and an excellent summary
of available and possible future treatments.

[markt]

It was also of real interest to see the possible treatment modalities presented at the end of the article.  The new small molecule approach has various substances under study.  It is hard to name the category they fall in.  I guess small molecules, of various types.

Hi Elaine,

Please take heart in knowing that the small molecule inhibitors are here now, and represent the new bow-wave of advances in immunotherapy.

Tofacitinib (Xeljanz), a JAK1/3 inhibitor of was the first approved for RA in 2012 I believe.  Human trials for Sjogrens never occurred, but evaluation in murine models occurred:
https://acrabstracts.org/abstract/tofacitinib-suppresses-lymphocytic-infiltration-in-the-salivary-gland-of-non-obese-diabetic-mice-the-animal-model-of-sjgrens-syndrome/
I trialed it for several months under sero negative RA, and actually preferred it to Rituxan.  I didn't realize how much it seemed to help keep me on a "even keel" with Sjogrens management until I stopped.  (My Rheum brought up the potential risk of Lymphoma... I have since decided to myself that it is very much worth the perceived risk, which is apparently unproven and comparable to other biologics previously studied).  I should have printed this article for having that discussion with him: https://www.medpagetoday.com/rheumatology/arthritis/68112/

Also approved for RA is Eli Lilly's Oumiant (Baricitnib).

Since Tofacitinib, other safer and more selective Janus Kinase inhibitors have been developed and are pending FDA approval are present for RA.  Filgotinib by Gilead, and its competitor Upadacitinib by AbbVie.  This go around, they are being concurrently trialed in Sjogrens based on pre-clinical data suggestive of efficacy (which Dr. Fox alluded to in the article in my initial post...).
https://www.conference-service.com/ICIS2017/documents/agenda/data/abstracts/en/abstract_0174.html


This paragraph is key, as it addresses effects of JAK/STAT inhibitition on the expression of BAFF and IP10 by IFNα in salivary gland cultures...
"...knockdown of interferon-stimulated factors revealed less expression of BAFF and IP10 by IFNα in salivary gland organoid culture. Filgotinib suppressed the differentiation of IL-21 producing T follicular helper (Tfh) cells when peripheral blood mononuclear cells were co-cultured with IFNα-stimulated pSGEPs in salivary gland organoid culture. Finally, Filgotinib (1.5mg/kg) or vehicle was intraperitoneally injected to NOD mice three times per week. Salivary flow rates of filgotinib-treated mice were greater than those of controls."

I suppose the lesson is... get an RA diagnosis for a quicker shot at benefiting from current therapeutics.  In the meantime, they are very much trying to figure out the safety, dosing, efficacy profiles for Primary Sjogrens.  Data from the Phase-2b trial of Filgotinib should be out this year, which should be interesting.

[Carolina]

Dear Mark,

Re: Tofactinib and Filgotinib. These drugs are both Janus kinase inhibitors, which must be the reason they have 'nib' at the end of their generic names.  From Wikipedia:  "Janus kinase inhibitors, also known as JAK inhibitors or jakinibs" so the jakinib is shortened to nib.

If other drugs in that category are developed, they will probably also be designated with 'nib' at the end.

When monoclonal antibodies are used in treatments for cancer,  the term 'mab' occurs at the end of the generic names.  Mab of course stands for monoclonal antibody.

And it is wonderful that drugs in both categories are now being used.  These drugs target specific modalities in the body which cause harmful conditions.

My husband has benefited from infusions of a monoclonal antibody which targets the specific mechanism that causes his type of leukemia.  This is so superior to the use of chemotherapy drugs which mainly target all cells in the body, which is why they make people feel so miserable.

Of course, for most of those that benefit, the mechanisms of the 'drugs', and derivations of their names, is of little importance.

Are you a scientist or a doctor, Mark?   I am neither, and struggle through these articles because they are so highly scientific. 

Regards, Elaine

[markt]

Are you a scientist or a doctor, Mark?   I am neither, and struggle through these articles because they are so highly scientific. 

Hi Elaine, Nope.  I am not in the medical profession (although I am married to a Nurse).  I am actually in the Navy (Aviation Maintenance Officer).

Regardless, since dealing with Sjogrens, I have found that I needed to become part Lawyer and part Doctor to get the best treatment possible.  (By that I mean learn the things to say to Drs. that challenge them and convince them to proceed with unconventional therapies that others would not).  As you know, it's very easy for them to pass us along and let us languish on the side as if it's no big deal.

Having a well rounded knowledge base and being aggressive with it has proven invaluable, as I have had to navigate and intelligently explain legal provisions and extent of liability to my Doctors regarding FDA Expanded Access law to advocate for my own treatment with investigational medications (being SS-A/B negative, I am excluded from trial participation).  This was my means of applying for such medication like Tears Solutions' Lacriprep. 

[Sharon]

I agree with Markt on doing all you can to get an RA diagnosis to gain access to better treatments.
It's exactly what I did...
Wondering about the Filgotinib possibly improving eye dryness as well?
The article mentioned only salivary flow and not tears...

[markt]

Hi Sharon,

For what it's worth, I have noted that the JAK inhibitors do have interesting secondary indications for inflammatory eye conditions (such as Xeljanz, aka Tofacitinib, with Uveitis). 

The paper below details some of the beneficial properties with regards to inflammatory dry eye / dry eye disease:

https://www.touchophthalmology.com/articles/immunomodulatory-effects-topical-ophthalmic-tofacitinib-cp-690550-dry-eye-disease

https://www.dovepress.com/new-drugs-for-the-treatment-of-dry-eye-disease-peer-reviewed-fulltext-article-OPTO

"Pfizer Inc. (New York, NY, USA) developed a selective inhibitor of the Janus kinase (JAK) family (tofacitinib, also known as tasocitinib and CP-690550). JAK is involved in the activation of immune cells, proinflammatory cytokine production, and cytokine signaling.77 Tofacitinib inhibits JAK1, JAK2, and JAK3.78 Tofacitinib was employed in a Phase I/II clinical trial (NCT00784719) in dry eye patients and the results have been published.79 This was an 8-week study in which several dosage levels of tofacitinib (taken once or twice per day) were compared to vehicle and cyclosporine ophthalmic emulsion. All doses of tofacitinib exhibited a good safety profile and were well tolerated. The trial demonstrated improvement in the signs and symptoms of dry eye. These results suggest that JAK inhibitors may be useful in the treatment of dry eye."

[markt]

On another note, isn't a shame that our medical professionals aren't making us aware of such information?

It seems their thoughts are limited to prescribing approved medications within the context of a defined "playbook" as insurers will allow.  No room for thought outside of that, unless you have a very A) unconventional B) empathetic C) motivated D) Rheumatologist invested in getting you well at a reasonable risk level.

Rant off   

[Sharon]

Now I'm kicking myself for not taking Tofacitinib to begin with!
My rheumy had originally allowed me to choose between it and Orencia for RA, and since there was such a buzz
about Orencia being trialled for SS at that time I opted for it instead.
The one thing Orencia hasn't helped me with is my eye dryness/inflammation and it is now my most
debilitating symptom.
I ask my rheumy every time I see him if there is anything else I can do for my SS eye symptoms and every time he says "no".
So yes, it is a shame that our medical professionals aren't making us aware of such information, but I'm beginning to believe they are simply not up to date on information themselves.
So to add to your list- A rheumatologist must be: E) Knowledgeable