Rheumination

Minocycline for Scleroderma

I'm an ordinary clinical rheumatologist.  Not an academic, not a researcher, just a run-of-the-mill rheumatologist who practices what I hope is good, standard rheumatology.  This practice does not include treating scleroderma patients with antibiotics.  Should it?

After a post of mine bemoaning the lack of treatment options for scleroderma patients, my site was deluged by visitors and commentors originating from a group I had not heard of before, the Road Back foundation. In respect to scleroderma, and I believe other diseases, the group believes that antibiotics, an in particular, minocycline, are an unrecognized, underused, but highly effective treament.  The comments have ranged from the informative, to the pleading, to the accusatory. 

From  what the commenters and their links have provided, I think the major points are:

- Dr D Trentham, from Boston, published a research letter in The Lancet in 1998 where he showed that 4 of 11 patients were in complete remission after 1 year of minocycline treatment.  2 others improved and 5 did not complete the study.

- Since the publication of the study, many (?hundreds) have received the same treatment with great success.

-Minocycline is still not an accepted treatment because, among other things, doctors prefer using expensive new drugs, and no studies are being done on minocycline because, being past patent, there is no financial advantage in studying it.  Other doctors are just ignorant.

I'm going to have to rebut a few of these claims here, but we'll return to whether I should be using antibiotics further on.  First of all, minocycline is a very interesting molecule.  It pops up in rheumatology all the time, not really for it's antibiotic properties, but because it does seem to have some immune modulating activity as well as metalloproteinase inhibition, which might be useful in preventing cartilage damage.  It also causes drug induced lupus, immunomodulation gone bad.  So rheumatologists are not put off by the suggestion that minocycline might be useful, and in fact there was a period in the early nineties when, following a few positive studies, that we, me included, gave it a try.  It didn't work, or at least,  didn't work nearly as well as methotrexate, hydroxchloroquine and other drugs. 

 The study by Trentham, you must admit, was tiny by any standards.  Eleven patients, five of whom didn't finish.  Two stopped because of a scleroderma renal crisis. Yikes. Of the six that finished, however, four were considered to be in complete remission. Interesting.  Two really bad results and four really good.  Doesn't matter though because the study was so small it doesn't really mean anything.  Here,  commenters have suggested that no further research has been done because big pharma isn't interested, and doctors prefer studying new, profitable drugs.  This may be true in some areas, but not for scleroderma.  Two of the biggest, more recent studies in the area have been with methotrexate and cyclophosphamide.  These are old-timer drugs.  No money to mine here.  Even more interesting is the fact that there has been further research into minocycline treatment, using the exact same protocol.  This study was small as well, only 36 patients, and it too was not controlled.  It had 12 patients drop out, ten because of worsening disease and found no significant improvement in the others. ( I could not find this article on the Road Back website)  I didn't find any further, better studies, but this is understandable.  Scleroderma is a very rare disease and if it is to be studied, most patients have to be registered in a few select studies.  Given the above two studies, I gather the trail did not look promising enough to go further.

So in summary, doctors are not averse to minocycline, use it when studies support it, have in fact studied it in scleroderma even though there was no financial gain in doing so, and have not been impressed.

So what am I to make of the many testimonials claiming improvement and cure with minocycline?  I'm not sure. I'm certainly intrigued.  I would love for it too be true, as would all rheumatologists, but why does only one rheumatologist continue to promote it.  There have been other stories of stubborn scientists with whacky ideas that have subsequently proven true, think H pylori or prions,  but why haven't we seen more evidence coming out of Boston if there are so many dramatic results.  Until rheumatologists, scientists all, see something more substantial than the Lancet study, minocycline will probably remain nothing more than a very interesting molecule.  

PS:  If anyone is aware of more data, published or not, coming from Dr Trentham's work, I'm all ears.

Travel Bugs

Been to Vancouver?
   

It used to be that a trip to Florida was a big deal, and a vacation in Europe a once in a lifetime occurrence.  No longer. Now it seems that every week I hear of patients packing up and flying off to climb Kilimanjaro or trek to Machu Picchu. There has been a recent surge in people heading off to Thailand and Vietnam.  All very exciting, but it seems few ever consider their medical condition before they book their exotic voyages.  They're are often disappointed and even mad at me when I suggest that more first-worldly destinations might be preferable.  Not long ago I had to convince a young woman who had just started on cyclophosphamide and high dose prednisone for a Wegener's vasculitis that Laos was not the optimal travel destination for her.  Three days later she called back to say he was going after all because he was feeling much better on the prednisone. 

There are many reasons for her and other rheumatological patients to be cautious in their globetrotting:

First of all, you are much more likely to get sick in a third world country.  30-50% of travelers to these places develop gastroenteritis and the risk is highest amongst the immunosuppressed . Even simple meds like proton pump inhibitors for reflux can increase the risk.  There are also many other nasty bugs out there, all more likely to infect patients on immunosuppressors.

You can't get all the vaccinations necessary if you are taking biologics or other immunosuppressors.  Yellow Fever, for example is a live vaccine and therefore contraindicated.  Fortunately, many countries deny entry without these vaccinces, preventing immunosuppressed patients from even getting in.

Tuberculosis.  As anybody who has taken a biologic knows, TB is a big concern and all patients are screened before treatment is started.  If their PPD test is positive, we treat them before starting.  This cures the infection that was there, but doesn't prevent a new infection from occurring, something that is a lot more likely to happen in a third world country.

If you do get sick, what kind of medical care is available.  I have no idea what the situation is in the vacation regions of Thailand.  It may be fine for all I know, but what I have noticed is that the traveling patients of mine don't know either.  

Even if there is medical care available, who's going to pay.  Some of my patients aren't aware that their insurance has specific clauses concerning prior illnesses.  Here, most insurances won't cover your illness or complications if there has been any modification in therapy in the three months prior to departure.

So now I include travel recommendations with my normal biologic blurb.  Florida sounds nice.  France is lovely.  Been to Vancouver?

Fox-The Lupus of News

Dr. Jon Stewart
 
 Strangely, immunology was put to good comedic use last night, and that's not something I get to say very often. Jon Stewart takes on Fox News, nothing new there.  He suggests that Fox has detected a liberal pathogen at the other news stations, but that their reaction to it is over the top.  They are producing way too many antibodies.  Fox is the Lupus of News

.TheComedyNetwork.ca - Online Time Well Wasted. 

The Stabbing Pain of Gout

Gout hurts.  I've never had the mispleasure of an attack but it apparently feels as bad as it looks.  Literature is rife with descriptions of the pain, but the most convincing I've heard to date came recently from a patient lying in the cardiac unit, foot red and swollen.  "I came in with a heart attack, I was bayoneted in the Korean war, but neither compares to the pain I'm having in that foot!"    

Colchicine Gouging. It Ain't All Bad.

  The FDA in the States continues it's purge of previously grandfathered drugs.  Quinine and Darvon first and now colchicine.  Colchicine had until now kept under the radar, possibly because it has been used, in some form or another , for hundreds or even thousands of years. For all we know, dinosaurs may have munched on the stuff for their gout. The FDA though, obviously not history buffs, would have none of it. But one company was on the ball. URL Pharma, in anticipation of the recall, undertook it's own studies of the drug and was able to acquire exclusive marketing rights for the drug.  Now rebranded as Colcrys, it will cost about $5 per pill, something like 10 times the regular price of the old stuff, and can continue to gouge users for 3 years.  Americans are not amused, with good reason, but there is a good side to this story.  The research done by the company actually produced important, treatment altering, and in the long term, money-saving information. (Cautionary note: I haven't actually seen the study published anywhere, but the results are available via the FDA)

Until now the time tested but obviously not scientifically tested dose of colchicine in acute gout was 1.2 mg, followed hourly until the patient got relief or developed GI side effects.  In a hospital setting this meant that nurses had to check on patients hourly to reassess the situation.  Not infrequently this was impossible and the dosing never actually took place. Even when successful, the prescribed endpoint was when the patient developed  diarrhea.  So often you had a elderly, lame patient in bed with severe diarrhea.  Not a good scene.  Half the time the colchicine wasn't even stopped, the diarrhea being ascribed to C difficile or other causes.  This new study, however puts an end to all that.  They found that 1.2mg followed one hour later by a second dose of .6 was all that was needed.  Nurses around the world are rejoicing.

A second important clarification was dosing in renal failure patients.  In those with a creatinine clearance of less than 30 ml/min, acute gout patients should not have a repeat dose within two weeks.  For dialysis patients, a single dose of .6mg is recommended.  Longer term treatment of renal patients is not discussed but FMF patients with renal failure are given a recommendation of .3 mg/day.

Lastly, it is noted that there is a very strong interaction with clarithromycin as well as lesser problems with other drugs metabolized by the CYP3A4 and P-gp systems.

So there you have it.  Short term pain, at least for Americans, or at least for Americans who don't live near the border, but long term gains for all.  

Chronic Fatigue Patients Not Welcome

Well I guess that they don't read my blog down at the Canadian Blood Services.  Back in February I bemoaned the fact that the exciting news of a viral cause of chronic fatigue syndrome (XMRV virus) and possibly fibromyalgia had been dashed by the inability of other labs to replicate the findings.  It seemed like a long shot anyway, but still it was disappointing.  But now we hear that the Canadian service responsible for blood collecting is the first in the world to put patients with CFS on their not-welcome list, specifically because they are worried about viral transmission of the disease through blood transfusions. Not terribly scientific but I guess it's hard to blame them for being a bit jittery.  Canada was a little slow with HIV/hepatitis C  testing back in the eighties, and many people were infected through blood product use.  In fact, the new Canadian Blood Services arose from the ashes of the previous collectors, the Red Cross, relieved of their duties because of those infections.  I wouldn't be surprised if the French do the same.  People there went to prison for the same reason.  At first I thought that this would mean a big drop in donations, given that so many people have CFS and fibromyalgia, or at least enough to fatigue to think that they may have the disease.  But then again, if you're dead tired all of the time, I don't think you're thinking of giving blood all too often.  And who knows, science seems to be making quick work of this virus theory anyway.  It might not be too long before the gang at the Canadian Blood Services can relax once again.

 

Rheumatologists: The Miley Cyruses of Medicine

Just saw the premiere of what promises to be a pretty bad medical drama, Miami Medical.  It's set in a trauma hospital where the best of the best trauma surgeons work.  We know that because the head nurse tells a newcomer that "trauma surgeons are the rock stars of medicine, and here, we have the Rolling Stones". Yikes!

Pretty traumatic start I'd say, but it did get me to thinking about what kind of musicians rheumatologists would be.  My first thought was Leonard Cohen, slower paced but much more intellectual.  Thoughtful and nuanced.  He also went bankrupt which states fairly well where rheumatologists fall on the pay scale of things.  But then I remembered, I really don't like Leonard Cohen.  

Besides, rheumatology isn't old and slow moving.  In fact, it's one of the youngest specialties around.  In this neighbourhood it only became a stand-alone internal medicine subspecialty in the 70's.  And it's exciting.  I don't think there is a specialty around that's seen the kind of progress we've seen in the last five to ten years.  So no, no Leonard Cohen.  Rheumatologists are the Mylie Cyruses of medicine.  Young, perky and adorable.  And I've got video to back me up.

More Stuff That Doesn't Work For Scleroderma

I hate scleroderma.  I think I may have mentioned this before.  It seems that nothing seems to work in this condition, not even for the non-life-threatening but life-sucking symptoms like digital ulcers and calcinosis.  In the fall, the ACR had two presentations on the use of imatinab (Gleevec).  One small study suggested some small but encouraging benefit while the second study was extremely small because the investigators called the whole thing off.  I decided to remain optimistic against all hope, but that all changed when I met one of the investigators from the second group at a recent conference.  She was not at all wishy-washy, telling me that these patients did not tolerate the drug at all, even at sub-targeted doses.  Forget it.  Move along.  

Well I have, and I've even found the next drug that probably won't work for scleroderma.  Perfenidone, a novel, not-sure-how-it-works anti-fibrotic drug has just received a rather non-ringing endorsement from the FDA advisory committee for the treatment of idiopathic pulmonary fibrosis.  In Vivo has an article on how one of the FDA referees voted no regarding safety and no regarding effectiveness but then voted yes for approval.  The logic, which sounds familiar to any scleroderma patient or treating physician, was that even if it didn't impress him, there really isn't anything better out there.  So I'm sure there are scleroderma trials underway trying to break the long streak of failures on record.  We can only wish them luck.  Lots of it.

Gold Therapy for Canada

from bodogBEAT
 

Posting has been a little light lately, largely because of the Olympics.  I spend the entire inter-olympic period telling anybody who will listen that it is all a waste of money, that we spend way to much attention to spoiled athletes who are patriotic for exactly two weeks every four years .  Then for exactly two weeks every for years I become extremely patriotic and have to watch every sport with any chance of medalling.  I renew my acquaintance with the nuances of curling, the fine detail of the half-pipe and of course, twizzles and lutzes.  No, I couldn't care less about combined Nordic, whatever that is, because Canada doesn't have a chance.  But hockey, now we're talking.  In fact, all the rest is just filler for the time between hockey games.  And this olympics was just perfect, hockey gold for both the men and women.  Even better, we trounced our old arch enemy, the Russians, and then beat our new, next-generation arch rivals, the USA.  Doesn't get any better.

Two Steps Back for Retrorvirus in Fibromyalgia

Well it did seem to good to be true didn't it.  Last year's surprising study showing remarkably high rates of XMRV retrovirus in chronic fatigue syndrome (CFS) has now been challenged by two British studies (1,2) which found absolutely no evidence of such an infection.  It's a transatlantic spat between a private research institute from the States and more regular academic folk from across the pond,who accuse each other of sloppy lab technique. The results are not even close, only one of them can be right.  Unfortunately, I'm leaning towards the skeptic's corner.  The breakthrough study was simply to good to be true.  As I mentioned in the previous XMRV post, I can't imagine such clean results in what is likely an untidy inhomogenous disease.  It's a real downer though, because the same group tantalized us with preliminary evidence suggesting that the same virus was found in fibromyalgia patients.  Still, the whole world laughed at prions and helicobacter, so while I vote with the skeptics, I cheer for the XMRVers.

As is often the case, this story unfolds at In The Pipeline.