Hydroxychloroquine, COVID-19, and Lupus

Researchers are taking seriously the use of hydroxychloroquine for COVID-19 therapy:

Both chloroquine and hydroxychloroquine inhibit SARS-CoV-2 in vitro, although hydroxychloroquine appears to have more potent antiviral activity [75].

I think saw a post somewhere that claimed it interferes with viral replication inside infected lung tissue but I can't find it now.

That's obviously great if it works out.

If it does work out though, it might be worth looking again at old (and still current) ideas that rheumatic disorders that response to hydroxychloroquine (esp. SLE, RA) are infectious in origin. Maybe an RNA virus ...

Bodies are weird, episode 26

My right wrist hurt the other day. A sudden sharp annoying pain. Maybe a tendon, maybe my arthritis acting up.

So I did my usual amateur self-therapy. I avoided the sharp ouch, but I moved with weights and resistance through a proximal path that was sometimes achy but not ouchy. I had lots of opportunities to load the wrist with weights, I am obliged to do CrossFit six times a week [3].

After about 4 or 5 days of this I noticed the wrist was pretty good. No more sharp pains.

It seemed … familiar. Eventually I remembered it happened before, back in Oct 2015, a bit before my formal Dec 2015 arthritis diagnosis. Resistance work was the fix then too.

This isn’t what we were taught in the medieval medical school of my youth. We were taught to rest sore joints, not to put them under painless load. We weren’t taught that running might make knee cartilage better.

Bodies are weird. Back in 2015 my knees were quite sore. I figured my CrossFit days were numbered; I even tried underwater hockey.

But then the knees got better. I continued my back squats and lunges and all the CrossFit rest. Maybe it was the exercise, maybe it was the hydroxychloroquine my atypical rheumatologist prescribed [2] maybe it was both.

Over the next four years I sometimes had knee and wrist effusions, sometimes not. Lots of things came and went. My hands got beat up, but they didn't bother me much.

Then this past summer came around. I felt weaker. My back was fragile in late July. I developed “pseudo-claudication” (look it up). I lost a bet with my daughter when I missed my birthday Bar Muscle Up. I figured age had caught up.

But then it turned out I had the pseudo-claudication was pseudo-pseudo. Probably a protruding disc. It got 80% better after 6-8 weeks of modified exercise and 100% better after 8-10 weeks. (Discs do that — it’s even in the textbooks.) I hit new lifetime best lifts in clean & jerk and back and front squat. Equaled some others. Got even closer to that elusive bar muscle up.

It’s not like I’ve stopped aging. I look a few years older than my age. I feel pretty old. Everything could fall apart tomorrow. So I’m not expecting to carry on like this. I’m just saying bodies are weird and “osteoarthritis” / “idiopathic arthropathy” [2] is weird. We do not understand. We might as well keep moving.

- fn -

[1] The process likely began with some rogue antibodies before 2010 and a single acutely inflamed distal finger joint in 2012.

[2] The one study I’ve seen on HCQ and OA says it doesn’t work. OTOH, I think “osteoarthritis” should be renamed “idiopathic osteopathy” to underscore our ignorance of what’s likely many different conditions with similar appearances. My mother did relatively well on it FWIW — before she went full RA.

[3] I leave it as an exercise for the reader to imagine why a sane person would actually need to go 6 times a week, even foregoing my ice hockey. It’s not for (my) health or training!

CHIP, immune disorders, osteoarthritis, and hydroxychloroquine

A footnote in my post on Kateva’s liver disease linked to a NYT article on CHIP (clonal hematopoiesis of indeterminate potential). Wikipedia calls it “Clonal hematopoiesis”. To put it mildly, this is a hot research topic (wikipedia, lots of 2017 edits) …

Recently, several independent studies have confirmed the presence of malignancy-associated mutations in the blood of individuals who have no clinical signs of hematologic malignancy.[4][5][6] In combination, these studies have demonstrated the widespread incidence of clonal hematopoiesis in the healthy adult population and have stimulated further efforts to broaden our understanding of clonal hematopoiesis in health and disease.

Whenever we discover something new about human biology we round up all the diseases we don’t understand and look for a connection. The main focus now is on CHIP’s role in atherosclerotic heart disease, but I assume all the immune disorders are being CHIP tested. (I couldn’t find any articles on this today, which only makes me more suspicious :-).

If you’re going to look at mysterious CHIP disorders, I’d nominate the weird flavors of osteoarthritis. “Osteoarthritis” is an age related disorder (like CHIP), it’s very diverse, some of it has autoimmune type features — feels kind of CHIPpy. (As of Feb 2018 Google and Pubmed found nothing on “clonal hematopoiesis” osteoarthritis [2]. So you might have read it first here, except we know Google isn’t what it once was. Anyway, I’ve created an RSS feed for “clonal hematopoiesis” osteoarthritis — be interesting to see what that link shows in a few months.)

As long as I’m having fun with medical speculation, I’d like to throw in a mention to one of my favorite medications — hydroxychloroquine (HCQ). HCQ started life as a treatment for malaria, but it’s most commonly used for SLE and RA — autoimmune disorders. More recently it’s being explored as an adjunct to chemotherapy.

HCQ was thought to have something to do with Toll receptors (somewhat hot topic), but research on its oncology use focuses on how it interferes with lysosomal mediated autophagy. Autophagy (self-eating) is important for cells, it’s how they recycle their constituents to make new things. Some cells depend on this more than others. Retinal cells rely on autophagy and it’s probably not a coincidence that HCQ can cause retinal toxicity [1].

Cancer cells rely on autophagy too — they don’t have normal cooperative nutritional inputs. Which is why HCQ is being tested for cancer treatment.

Which brings me back to CHIP.  We think CHIP is a kind of premalignant age related disorder of the stem cells that form blood. We think HCQ might impair replication of disordered cells. We know HCQ works for some autoimmune disorders. We wonder about CHIP and oddball autoimmune disorders …

So it would be fun to see if HCQ inhibits CHIP.

- fn -

[1] Worryingly the process can continue even after the drug is stopped.

[2] Actually they both returned results, but they were nonsensical results. I miss when Google used to actually work. It was funny to get a false positive from PubMed, it’s usually reliable.

Arthritis update (personal note)

My familial arthritis showed up in one finger a few years ago, but in December of 2015 it became a bigger deal [1]. It looked like an early and fast moving symmetric osteoarthritis (OA), but then so did my mother’s before it morphed into something like RA (which ate lungs, joints, etc). OA is really a junk drawer diagnosis so I ended up calling it “familial arthritis”.

After a bit of personal research I ended up with an eclectic rheumatologist who suggested hydroxychloroquine (HCQ). This is a popular Lupus and RA med that started life as an antimalarial. It’s generally well tolerated with one minor side-effect — you can lose your vision. [2]

HCQ has been since tested experimentally in osteoarthritis — and it didn’t seem to do anything. [3] It did work for my mother’s RA though (where it is known to work), and her disease started out looking like mine …

So I’ve been on the HCQ for about two years.

Has it worked?

There’s no way to know, I can only present circumstantial evidence for one person. I have no idea what the disease would have done without treatment.

The joint deformity has not progressed much. To track joint changes I bought a ring sizing set and I use it to measure a selection of PIP (small, distal finger joint) and PIP (join in mid finger) sizes. There hasn’t been much change in joint deformity over the past two years; interestingly the worst measurements were the first set. That’s probably measurement error or some initial soft tissue swelling that’s diminished. 

I don’t have any finger joint redness or pain any more. Sometimes I forget to take the HCQ and I imagine I have some hand stiffness and joint aches — but that seems too fast to be a med effect. I think it’s my imagination. (Though we don’t have a good story for how HCQ works, so who knows.)

My knees aren’t worse; they are better than they were before I started the HCQ. I still do 230 lb CrossFit deep back squats. (I’m a wimp. Average strong guys do well over 350 lb.)

And, yes, I’m still doing the CrossFit. The rheumatologist approves. I thought I’d have to take up underwater hockey instead but I put that one off for now. 

It’s only been two years though. I’ll be more impressed if this is still true in two more years.

- fn -

[1] When I search the blog I see a few prior posts on knee and wrist exercise related aches that were, in retrospect, part of the arthritis.

[2] There are eye exams to try to spot this early, but we know in animal models that the chorea disease progresses for some time after the medication stops. We don’t know the real frequency of this complication — there’s at least a 1/20 chance I’ll get it.

[3] OA, like autism and schizophrenia, is an ill defined collection of things that’s damnably hard to study.

Aspirin, NSAIDs, cell death and the treatment of arthritis and interstitial cystitis

While doing some research on interstitial cystitis Google uncovered an extraordinary claim by the Cleveland Clinic’s Raymond Rackley:

Microsoft Word - Transcript for IC Video.doc

… exposure to TNF−α produces a dysfunctional activation pattern in IC urothelial cells that leads to cellular apoptosis…

Aberrant NF−κB signaling activation may be responsible for the imbalance of apoptotic and survival mechanism of the bladder epithelium that gives rise to the pathogenesis of IC … asking all IC patients to avoid aspirin or aspirins like products such as NSAIDs that block normal NF- B signaling …

I can’t tell when this transcript was created, there’s no date information on the PDF. As of Feb 2016 Rackley has 71 publications, but the only one that might lead in this direction was from 2011. I don’t think there have been any publications out of this particular video presentation.

The claim is extraordinary for two reasons. The first is that interstitial cystitis is a common cause of significant suffering, we have no good treatments (see also), and patients often use NSAIDs or even aspirin (which acidifies urine, for some that might help). If this claim were true those people should all switch to acetaminophen.

The other reason, of course, is that the transcript notes that aspirin and NSAIDS (ibuprofen, etc) have a significant effect on the mechanisms that influence cell death (apoptosis). This is mentioned as though it were common knowledge, but it was a surprise to me. Perhaps it shouldn’t have been, I know here has been a suspicion for at least 10 years that NSAIDs slow tendon injury healing. I’m also aware of epidemiology studies of an inverse association between colon cancer and aspirin use, and recently the USPSTF added colorectal cancer prevention to its draft aspirin use guidelines.

I suppose, in retrospect, if aspirin reduces the risk of colorectal cancer it may well do so by empowering our cellular level anti-cancer controls (vs. say, altering the microbiome). One way to empower those controls is to bias our cellular monitoring systems towards more aggressive cellicide (apoptosis) — and away from healing.

This has occurred to researchers. A search on apoptosis and aspirin returns 181 results starting in 1995 and accelerating in 2008 (NSAIDs) with a flurry of publications in the past few years. So among researchers, the idea that aspirin and NSAIDs shift our cellular systems away from healing and towards apoptosis (for better or worse) is probably not so surprising.

For clinicians however, this is potentially significant. We use aspirin for heart disease of course, but only in modest doses. More importantly, we use NSAIDs extensively for arthritic conditions where we may want more rather than less healing. (Not to mention interstitial cystitis).

It would be good to know how real this effect is. As Emily reminds me it is perilous to extrapolate from basic research to clinical practice. Even so, I would suggest people suffering from interstitial cystitis may want to consider acetominophen, assuming their liver is in good health.

Heberden's nodes deserve more respect.

Wikipedia has the party line description of these buggers. Emphases mine.

Heberden's node

Heberden’s nodes are hard or bony swellings that can develop in the distal interphalangeal joints (DIP) … They are a sign of osteoarthritis and are caused by formation of osteophytes (calcific spurs) of the articular (joint) cartilage in response to repeated trauma at the joint.

Heberden's nodes typically develop in middle age, beginning either with a chronic swelling of the affected joints or the sudden painful onset of redness, numbness, and loss of manual dexterity. This initial inflammation and pain eventually subsides, and the patient is left with a permanent bony outgrowth that often skews the fingertip sideways.

Heberden's nodes are more common in women than in men, and there seems to be a genetic component involved in predisposition to the condition.

Let’s deconstruct that narrative, looking for internal contradictions.

Here’s one: “Repeated trauma … but sudden onset of redness … inflammation”. Really? Trauma? From what - typing? If it’s repeated trauma, why the sudden inflammatory onset? Hmm.

Here’s another: “calcific spurs”. So why are they “nodes” and not spikes? Why are they rounded, like things that grow from an internal nexus? Why do they grow so quickly? Why don’t they keep growing? Why don’t we call these “Herberden’s tumors”? Why are they universal by age 80?

Lastly, how do they grow so quickly? I’ve seen the become prominent in 2-3 weeks. That’s tumor class growth.

Really, we could be a bit more curious.

See also:

• Genetic influences on osteoarthritis in women: a twin study | The BMJ 1996. Genetic influence 39-65%. “Although environmental factors have traditionally been thought to be the main influences, there are few data to support this.” (The “repeated trauma” is nonsense.)
• Yet more evidence that osteoarthritis is not a cartilage disease -- Brandt et al. 65 (10): 1261 — Annals of the Rheumatic Diseases. Many think it’s related to something in ligaments, not cartilage. So are Heberden’s nodes more from the ligament area?
• Heberden’s nodes and what Heberden could not see: the pivotal role of ligaments in the pathogenesis of early nodal osteoarthritis and beyond. - PubMed - NCBI “The earliest structural abnormalities in GOA may be evident in ligaments and the ligament-associated 'enthesis organ', where degenerative changes are evident. Ligaments also influence the expression of joint damage including Heberden’s node and joint erosion formation”
• Heberden’s Nodes: The Incidence of Hypertrophic Arthritis of the Fingers — NEJM 1940 “They syndrome derives its name from Heberden, who first described it in 1902 as “digitorum nod”: “… little hard knobs, about the size of a small pea .. hardly ever attended with pain”. Charcot “Usually the onset is very obscure; however, there are attacks of redness, heat and temporary swelling of the soft parts”… “often accompanied by asthma, migraine, neuralgia and muscular rheumatism … commonly seen in patients with cancer of the breast”.

That 1940 article is fascinating, I’ll have to see if I can get the full article. We certainly don’t think of them as associated with breast cancer today.

I’d like to toss a few nodes in a blender and mine the slurry for non-human DNA.

Medical knowledge diffusion: The osteoarthritis example

For personal reasons I’ve been doing a deep dive into current medical knowledge of osteoarthritis — particularly the relatively early and aggressive diffuse joint condition i’m enjoying.

It’s given me an opportunity to compare what’s in a current Internal Medicine textbook (Harrison’s 18th edition, 2012) vs. a current Rheumatology text (Hochberg, 6th ed, 2015) vs. the medical literature. 

There’s a relatively clear trend. Harrison’s has vestiges of the 1980s and 1990s view of OA, which focused on injury and “wear and tear” and treats OA as thought it is a single disorder. It is cautious about exercise and joint use. There’s no way to slow, much less reverse, disease progression.

Hochberg, the specialist text, deprecates “wear and tear” and focuses on genetics, but inflammation is mostly a secondary response to some relatively unspecified joint process. In this text OA is a “heterogenous disorder”, which is a pedantic way of saying it’s a whole bunch of things that need to be divided up better. Hochberg is keener on exercise. There’s still no way to slow, much less reverse, disease progression.

The literature, of course, is all over the place, but there’s a consensus for dividing OA up into more useful diagnostic categories. In general exercise is encouraged with little caution. There’s a movement to treat some kinds of OA as a primary disorder of the pre-vertebrate ancient innate immune system (vertebrates also have an adaptive immune system). There are experiments now with medications which act on the innate immune system, like H3 blockers. Of course to be effective these would need to start early in what feels to some like a fast moving disease.

Future versions of Hochberg may or may not incorporate the medical literature. Some quite nice studies have sown that the medical research literature is usually misleading or flat out wrong; most physicians are wise to avoid it. I am, however, a bit disappointed that Harrison’s seems to lag behind Hochberg — the authors are drawn from a similar pool of researchers. Maybe it’s simply that Harrison’s 19th edition is due out shortly, the one I read was probably written five years ago.

For a family physician, internist or geriatrician one lesson might be to stop reading the “generalist” textbooks and skip to the specialist textbooks. Harrison’s is famously unreadable, Hochberg is actually an easier slog. This assumes one has online access to both of course, these are very expensive references.

See also

• Gordon’s Notes: arthritis
• Inflammatory osteoarthritis treatments: is there anything to watch for? 1/2016
• Extremophiles and auto-immune disease 11/2015
• The impossible machine 11/2015
• Rheumatic syndromes remind me of pre-quark particle physics 10/2015 (or of psychiatric disorders)
• Fixing a painful wrist with high frequency weightlifting and wrist hyperextension. WTF 10/2015. I didn’t have a diagnosis then, this is my OA at work. Example of counter-intuitive action of exercise though.
• On knee pain and the state of medical knowledge (updated) 9/2015
• Why did medical progress slow after 1984? 12/2010 (interestingly, as I wrote this, innate immune system related articles started to hit clinical journals)
• Whatever happened to medical progress? 3/2008

Inflammatory osteoarthritis treatments: is there anything to watch for?

See also: Arthritis - the feeds and queries (reference post).

There’s something problematic about human tendons and cartilage. A wide range of infectious, auto-immune and idiopathic disorders land on them. I think dogs are no better, I can’t speak for other mammals.

We’ve tried to put boundaries around these disorders, to name them and attach treatments to the names. Some of our boundaries are better than others. Rheumatoid arthritis isn’t a bad tag. Osteoarthritis though, that label kind of sucks. It includes a wide range of clinical presentations at varied ages with diverse and poorly understood contributions of genetics, auto-immune activity, injury and healing, tendon and cartilage, inflammation and age. The one thing all of the diverse forms of osteoarthritis have in common is that there’s no useful treatment. We might as well call them the idiopathic untreatable arthritides (IUA).

Over the past 20 years or so IUA, or osteoarthritis, has had a few partitions. The biggest one so far was to carve out psoriatic arthritis; a history article claims it spun off in the 1960s (I thought 1980s, but maybe it took a while to make it into textbooks.) There have been efforts to split out “inflammatory osteoarthritis” (sometimes also called erosive osteoarthritis), but since there are no treatments (NSAIDs don’t count) IOA hasn’t quite launched.

I have something between psoriatic arthritis and inflammatory osteoarthritis, so I did a recent search of the UK’s Clinical Trials database for osteoarthritis + inflammatory, trials in UK, US, Canada and Germany and a similar search on the NIH ClinicalTrails.gov. The UK database draws on data from the WHO’s International Clinical Trails Registry Platform, but most of the trials were in the US. Of the two the UK database had the more interesting results.

These are the investigations for slowing disease progression that looked slightly interesting

• Hydroxychloroquine: This is an old antimalarial often used for Rheumatoid Arthritis and Psoriatic Arthritis. It’s something one could probably induce an adventurous rheumatologist to try. The most interesting possible mechanism of action is through inhibition of toll-like receptor (TLR) 9 family receptors, these are a part of the “innate immune system”. The role of the innate immune system in inflammatory osteoarthritis is interesting.
• ABT-981: Inhibitor of interleukin-1 (IL-1) alpha and IL-1 beta cytokines. More here.
• GSK3196165: HuCAL antibody, Granulocyte macrophage colony stimulating factor (GM-CSF) receptor agonist
• ABT-652: Histamine H3 receptor modulator. Targeting the H3 receptor is interesting because of a possible roll in Toll-like receptor activity and the innate immune system.
• Gevokizumab: monoclonal antibody inhibitor of interleukin-1 beta (IL-1 beta), a cytokine. 

The innate immune system connection is new to me, but a search in Google had an auto-complete….

Spooky AI world indeed. Here’s the PubMed abstract for the article The Goog is suggesting, emphases mine:

Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound?
Curr Opin Rheumatol. 2008 Sep;20(5):565-72. Scanzello CR1, Plaas A, Crow MK.

PURPOSE OF REVIEW:
Synovial inflammation is increasingly recognized as an important pathophysiologic process in osteoarthritis, but the stimuli and downstream pathways activated are not well defined. Innate immune system activation, best documented in responses to pathogens, likely plays a role in induction of inflammatory mediators and the specific cellular infiltrate seen in osteoarthritis. Thus, the Toll-like receptors (TLRs) and their signaling pathways are of particular interest. These innate pattern-recognition receptors are activated not only by pathogens but by endogenous 'danger signals'. In this report, we review evidence that certain extracellular matrix components of joint tissues (hyaluronan and fibronectin) may act as TLR stimuli, and summarize recent literature implicating TLR activation in osteoarthritis.
RECENT FINDINGS:
Convincing evidence exists that hyaluronan/TLR interactions drive responses to tissue injury. Evidence of a similar role for fibronectin is growing. TLRs are expressed and functional in the joint, and many proteases and cytokines that promote cartilage catabolism are dependent on nuclear factor-kappaB, a TLR-activated transcription factor.
SUMMARY:
Activation of TLR pathways seems likely in osteoarthritis and may play a central role in disease development and progression. A model of osteoarthritis as a chronic wound, in which the innate immune response is triggered by molecular signals of tissue damage, is presented as a framework for future study of inflammation in this prevalent joint disease.

Well, well, well. That feels like me. I particularly liked this followup article from 2 years later, note the reference to dividing “osteoarthritis" into subsets:

The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive
J Rheumatol. 2015 Mar;42(3):363-71. doi: 10.3899/jrheum.140382. Epub 2015 Jan 15.

Although osteoarthritis (OA) has existed since the dawn of humanity, its pathogenesis remains poorly understood. OA is no longer considered a "wear and tear" condition but rather one driven by proteases where chronic low-grade inflammation may play a role in perpetuating proteolytic activity. While multiple factors are likely active in this process, recent evidence has implicated the innate immune system, the older or more primitive part of the body's immune defense mechanisms. The roles of some of the components of the innate immune system have been tested in OA models in vivo including the roles of synovial macrophages and the complement system. This review is a selective overview of a large and evolving field. Insights into these mechanisms might inform our ability to identify patient subsets and give hope for the advent of novel OA therapies.

So now I need to research currently FDA approved medications that are thought to be TLR antagonists, like H3 receptor antagonists. Ciproxifan could be ordered from suspicious Chinese suppliers. Ok, Am I feeling lucky?

Probably not.

Exploring the “similar articles” and “citing articles” streams for the 2008 Scanzello et al article is quite interesting. Maybe we’ll make some progress. I’ve added some of those articles to my Pinboard arthritis stream, quite a few have free full text and are PubReader viewable. (yay NLM — the only good thing GWB ever did). I have some reading to do.

PS. As of Jan 2016 there are no interesting hits on “Heberden’s Nodes” and “Innate Immunity”. 

Update 1/21/2016

While discussing this with post with Emily something she said led us to a discussion of the curious history of the “H2 blockers”, particularly cimetidine (Tagamet). We remember when those drugs were introduced for gastric mucosa injury, as was common in OA patients taking NSAIDs.

The H2 blockers have an odd history with immune disorders. I recall eosiniphilic fasciitis had a curious response to cimetidine. Cimetidine is a physician-folk remedy for recurrent “cold sores” (usually ascribed to herpes simplex infection), which are now considered to be an innate immune response disorder. Cimetidine and ranitidine are also sometimes used to treat warts. As long ago as 1989 it was considered an immune response modifier, but researchers lost interest in the 00s. I did find a 2003 Japanese publication on cimetidine activity in suppressing rat adjuvant-induced experimental arthritis and a 2011 article suggesting sedating first-generation antihistamines and H2 blockers (cimetidine) impair innate immune responses to bacterial infection in mice.

On the other hand, there are some studies suggesting Cimetidine increases NK cell activity. I could easily see how shifting H2/3 balances would worsen osteoarthritis. I’m not quite ready to start taking a nightly cocktail of over-the-counter cimetidine and chlorpheniramine.

Update 1/21/2016

If you Google on Cimetidine and Osteoarthritis you’ll find a factmed page titled “Is Osteoarthritis a side-effect of cimetidine?” It says “Between January 2004 and October 2012, 78 individuals taking CIMETIDINE reported OSTEOARTHRITIS to the FDA…. of 2258 CIMETIDINE drug adverse event reaction reports”

I think what this group does is to dump the FDA FAERS files into Microsoft Access, then they generate web pages for each Drug - Condition pair and they sell ads off the pages. It’s a not-quite-criminal but not-quite-wonderful enterprise.

I doubt this is a meaningful finding, but if cimetidine truly does act on histamine receptors associated with NK activity and/or innate immunity it would not be surprising if it made some diseases worse as well as some better!

Update 1/23/2016

My intuition is not misplaced…

Antihistamines as treatments for autoimmune disease?
http://www.nature.com/nrrheum/journal/v9/n12/pdf/nrrheum.2013.169.pdf?WT.ec_id=NRRHEUM-201312
Jenny Buckland
Nature Reviews Rheumatology 9, 696 (2013) doi:10.1038/nrrheum.2013.169
Published online 29 October 2013

I’ve found articles on immune modulation activity of H1 and H2 antagonists, like chlorpheniramine, cimetidine and ranitidine dating back to the 1980s, including speculation on H1 and H2 receptor activity on human chondrocytes. Many starts and stops, but now we have innate immune system and the H3 and H4 receptors…

Update 1/24/2016

The Buckland article merely recapitulated an H4 blocker review — not worth paying Nature $8.

Meanwhile, I’ve started my own quixotic trial - Cimetidine 400mg/daily. A true shot in the dark, but it’s not like there are any alternatives. I’ll report out an ’n of 1’ observational result in 4-6 weeks one way or another. I reserve the right to terminate the trial if things go abruptly downhill but I’ll report out regardless.

Update 1/26/2016

Prion Disease and the Innate Immune System - mast cells in the brain play a role - of some kind. So what does cimetidine do there?

Upregulation of H2 receptors after cimetidine use - a risk of rebound with this experiment.

Update 2/1/2016

Cimetidine for chronic calcifying tendinitis of the shoulder, 2003.

Cimetidine decreases calcium levels and improves symptoms in patients with hyperparathyroidism… Cimetidine, 200 mg twice daily, was given orally for 3 months in 16 patients who did not respond to more than 6 months of conservative treatment… Calcium deposits disappeared in 9 patients (56%), decreased in 4 patients (25%), and did not change in 3 patients (19%) . Our results indicate that cimetidine is effective in treating chronic calcifying tendinitis of the shoulder; however, the mechanism by which cimetidine improves the symptoms is unknown.

Weird. I do have a long history of intermittent calcific tendinitis of the shoulders, though I’ve always managed it conservatively. There is only one article citing this study…The H2 blocker famotidine suppresses progression of ossification of the posterior longitudinal ligament in a mouse model. - PubMed - NCBI

Update 2/13/2016

This is peculiar …

Cimetidine in painful bladder syndrome: a histopathological study. - PubMed - NCBI

… Cimetidine is a useful medical treatment for bladder pain but the presence or absence of gastrin or histamine-like immunoreactivity does not explain its therapeutic benefit….

Arthritis - the feeds and queries (reference post)

I feel like I’m tied to a railroad track, and see the light of the train approaching. And I don’t know if it’s one mile away, or 500. 
Anonymous, a patient three years into leukemia remission.

Cancer will give many of us that oncoming train feeling, but of course the light is always there. We’re just good at denial. When we’re young and healthy the train is probably far away. When we’re 93 it’s pretty close. In between we try not to look.

There’s only one “train”, but there are lots of smaller hits along the way. Bicycles and cars maybe. One of them ran into me recently, so I’ve renewed an old interest in the so-called “rheumatic disorders” (misleadingly named after bodily fluid flow).

It really is an old interest. Before I figured out how to do medical school [1], I closely read the 1982 version of the Arthritis Foundation’s “Primer on the Rheumatic Diseases”. Within the broad bounds of unreliable memory I recall that osteoarthritis was a “wear and tear” disorder of aging, rheumatoid arthritis and a handful of other disorders were “auto-immune” diseases, gout and non-gout crystal deposition were relatively well understood, and many viral and non-viral diseases (Gonorrhea and, a bit later, Lyme) caused arthritis. Steroids (not the androgen variety!) worked very well on the auto-immune disorders, but the long term side-effects were horrible and inevitable. We had reasonable drugs for Gout, gold for Rheumatoid arthritis (some value [7]), and nothing for osteoarthritis. Okay, so we had NSAIDs like ibuprofen, but we already suspected they were a mixed blessing. We’ve kind of given up on them.

Things aren’t that much different 33 years later. Relatively recently we’ve realized that “osteoarthritis” covers a multitude of evils, some or all of which, like “psoriatic” arthritis, are more than “wear and tear”. We still don’t have any great treatments for Systemic Lupus Erythematosis, though we now do less harm with the treatments we have. Rheumatoid arthritis has seen the most care improvements, but, amazingly, we can’t actually cure it or any other auto-immune arthritis [3]. We still wonder about the role of infectious agents in creating or sustaining auto-immune disorders but we have few leads [2][6]. The most recent (2005) edition of the Primer on Rheumatic disease says of Osteoarthritis “It is clear that this … includes a variety of different conditions, but we have made less progress …”.

More recent publications have even undone old certainties; we’re no longer confident that the various flavors of psoriatic and osteoarthritis are primarily “arthritic” (greek: Arthron, joint). Disorders along the osteoarthritis - psoriatic arthritis spectrum may begin as diseases of the tendons. Some of them may be lifelong disorders of tissue healing; small injuries accumulate due to a healing defect, perhaps with later onset of an auto-immune component reacting to disordered tissues.

My medical school interest became personal as I watched my mother go through the arthritis experience for about 35 years, ending as “rheumatoid arthritis” (our classifications are imprecise). It wasn’t pretty.

Which is all by way of introducing this “reference post”; a blog post that I’m going to be revising and extending. It’s a post supporting my surveillance of our historically limited knowledge base. I’ll revise it periodically over the next year or two. Sometimes I’ll post/tweet about updates to this reference post, but most of the interesting results will appear in a pinboard RSS stream tagged “arthritis” [4].  

My surveillance relies on PubMed [5] (National Library of Medicine) RSS feeds. Anyone can create these, but I’ve never seen anyone but me write about them. I’ll list them by topic below, but first I’ll describe what I’m not monitoring.

I’m not monitoring care guidelines or the cutting edge of rheumatologic practice. I see a rheumatologist for that; that’s his job. If I want an update on current practices I’ll take a look at FP Notebook’s Rheumatology Book. I’m not interested in alternative or complementary therapies — that way lies madness. I’m only mildly curious about lifestyle factors; mostly because we know so little and very little research is going to get funded.

I am curious about tolerance induction — the Holy Grail of the rheumatic disorder treatment. We’ve been hammering on this decades, but we have new tools now. This is what we really want - a cure for at least some of these diseases. I’m looking for articles on disordered healing and secondary arthritic conditions, but I’ve yet to figure out a good search for that one. Likewise I’m looking for articles that relate loss of self-tolerance to a dysfunctional pseudo-neoplastic component of the immune system (yeah, this is definitely fuzzy). More concretely anything about the role of infections organisms in precipitating or maintaining arthritis.

Here are the RSS feeds and “similar articles” queries I’m revising and using for each of these topics. I wish there were RSS feeds for the “similar to” queries, as I learn the topics i’ll put create RSS feeds with similar results.

tolerance induction

• tolerance induction in arthritis (feed)
• peptide based immunotherapy (not limited arthritis, feed)
• T cell immunoglobulin-3 (Tim-3) therapy (query)
• tolerogenic dendritic cells

tendon injury (enthesitis) and arthritis

• enthesitis in psoriatic arthritis (query)

microbiome and role of infection in creating and maintaining arthritis

• microbial dysbiosis in rheumatoid arthritis (query)

Immune system and neural networks (because I figure the immune system is a form of neural network)

• Google scholar related article query

other

• psoriatic arthritis - natural history (not a query because this seems to be only article!)
• cimetidine and innate immunity (feed - because of this post)

- fn -  

[1] The way to do the didactic portion medical school is to maintain a relentless focus on examinations. If you’re doing well you may then indulge your passion and curiosity. 
[2] As a still distractible student I read the first speculative article written on an association between bugs living in the high acid stomach and gastric ulcer disease. Before then we thought the stomach was sterile; nothing could live in such a disagreeable environment. That probably contributed to my extremophiles and auto-immune disease post.
[3] Juvenile Rheumatoid Arthritis does resolve about half the time. Which is curious.
[4] Like all things Pinboard it has an RSS Feed: http://feeds.pinboard.in/rss/secret:c6ea18730310000211dc/u:jgordon/t:arthritis/. Sadly there are no RSS feeds for “similar article” queries and “My NCBI” doesn’t show feeds.
[5] My medical informatics career began in Family Medicine residence as a beta tester of the “Grateful Med” software. I believe the product manager, Rose Marie Woodsmall, was a dead head. I was among the last generation of medical students to use the paper Index Medicus to do journal research.
[6] I’d wondered years ago why we weren’t mining synovial fluid for foreign DNA. Turns out this was done in 2001 with interesting results, but the follow-up was limited until “microbiome” became a funding source.
[7] Gold was used to treat Rheumatoid arthritis from at least 1945 through the early 1990s. I seem to remember it was sometimes associated with extended remissions. I can find almost nothing on it written after 1965 or so, and nothing at all on how it worked. There’s very little on long term outcomes. Which is, you know, profoundly weird.

Update 12/18/2015

I have a hunch that whatever is afflicting me now is the end-stage of a congenital defect with soft tissue/tendon formation. I’ve always been prone to calcium deposits along tendons and to overuse tendonopathies. It would not be surprising that as I’ve aged my body’s ability to manage this problem, and heal from injury, has declined. That in turn could lead to some secondary auto-immune issues (prolonged inflammatory/antigen spill issues). I haven’t come up with a search criteria yet to explore this idea; it would probably show up in whole genome analyses. I would need to look for discovery of a gene associated with auto-immune arthritis/osteoarthritis that was important for tendon formation.

Extremophiles and auto-immune disease

The extremophiles are at home in near boiling water and the deep crust of the earth. Every ecological niche is colonized by life; and life forms everywhere work to change their ecology to suit themselves.

It is the inevitable logic of natural selection in action.

So then, why should the hot tissues of auto-immune disease be any different? How could there not be life forms evolved to that extreme environment? Life forms that might facilitate it, to defeat their enemies and extend their preferred environment. An ecology that, once created, will host competitors, some liking it hotter, some coder. An ecology with successor species, like any forest.

It seems inevitable.

The impossible machine

The immune system is an impossible, incomprehensible, machine. It is not even a ’system’ — evolution is not so modular. We name it as a thing so we can model it, but it is not made by a mind. It is made by evolution, so it is bizarre and emergent. Like a machine that pumps water and makes potato chips on the downstroke.

The thing we name, which is in truth not a bounded thing, allows us to exist, briefly, in a seething sea of self-organizing energy. Presumably its antecedents emerged with the bounded sack of water we call a cell. It has grown in complexity since then, a complexity that often resembles the nervous system. It is, after all, a processing machine. Brains must tell lies from truth, the immune system must distinguish friend from enemy from frenemy. It must often attack the non-self, except when the non-self is a fetus. It should not attack the parts of the self, except when those parts are broken or rogue. It ages as the body ages, but even as it grows frail the body grows more rogue.

Sometimes the non-self is a frenemy, at least for the moment. We are walking biomes, ecosystems in motion. Billions of microbes live within us, often helpful, sometimes the enemy of our enemy. Except when they turn on us. The immune system must manage this, even as the enemies and frenemies adopt the face of the self.

We created the idea of the immune system, and we created the idea of diseases of the immune system — though the boundary between disease and individual variation is not sharp. Some immune systems are poor at stopping some enemies — we usually die then. At other times the immune system confuses self and non-self, and it turns on the organism. We call this an auto-immune disease.

We can do very little about auto-immune diseases. System Lupus Erythematosis is a classic of this genre, our treatment has changed very little in thirty years. We have some newer treatments for diseases like rheumatoid and psoriatic arthritis, but our treatments don’t correct the error of the immune system, they merely induce selective immune dysfunction to slow the progress of disease. We know so little. We aren’t even quite sure that there isn’t some bizarre infection lurking in the tissues of affected people; maybe sometimes the immune system has the right idea but the wrong execution.

Auto-immune diseases are common. We used to think osteoarthritis was a disease of aging tissues, of wear and tear. Now we think this name we made contains multitudes, some related to aging, others to an attack of self on self (“erosive inflammatory OA”). We have no truly effective treatments for these conditions. We don’t even know if sleep and exercise are a good idea — what strengthens healing also strengthens the enemy within. The war on joints and tendons wears on the body, inducing metabolic syndromes and accelerating aging.

If we could reverse auto-immunity, if we could re-induce tolerance, we might be able to manage organ transplants and even stop the enemy within. Inducing tolerance is now an active research area — at least in rats. We have a very long way to go. I hope the next 30 years improves on the last 30, but we have had many false starts.

Related RSS feeds (for Feedbin, Feedly, etc).

• inducing self-tolerance in arthritic disorders.
• peptide-based immune tolerance induction
• Immune tolerance - therapy (very broad)

See also

• app.net thread: inducing tolerance might be rather like (re)training a neural network. The immune system as neural network analogy dates back to at least 1997.

Rheumatic syndromes remind me of pre-quark particle physics

This mornings board review included looking at the evolution of “inflammatory osteoarthritis” from 1970 to 2015. What was once described as an acute “inflammatory” (suddenly red and painful) form of osteoarthritis was later reformulated as “erosive osteoarthritis”, “psoriatic arthritis” and some vaguely described disorder that gradually morphs from osteoarthritis to rheumatoid arthritis — not to be confused with seronegative arthritis.

Bah. Humbug. It’s as bad as our mushy and obsolete classifications of neuropsychiatric disorders.

Unlike the neuropsychiatric disorders (autism, schizophrenia, etc) though, the rheumatic syndromes remind me of pre-quark partial physics. Lots and lots of fermions (neutrons, protons, etc etc) with mysterious distinctions; understanding the composing quarks brought a sort of sense to the world. Perhaps one day we’ll learn that seemingly distinct rheumatic syndromes are combinations of underlying simpler pathologies that in different contexts (microbiome, immune system etc) seem to make up different disorders...

Ok, not a great analogy. Just a thought. Classifications are powerful though, and that means they can be misleading — and harmful.

Update: On a quick literature scan it looks like psoriatic arthritis treatments (TNF inhibitors) haven’t worked that well for erosive osteoarthritis, which does suggest that inflammatory arthritis split is clinically meaningful...

Fixing a painful wrist with high frequency weightlifting and wrist hyperextension. WTF.

In the spirit of my medical anecdotes, I present my left wrist.

Late Monday afternoon, while typing, I developed sharp pains in my left wrist. It hurt! I couldn’t type, though changing wrist position with a gel pad helped. Maybe, I thought, it was something with some recent mountain biking. Or maybe it was the high intensity CrossFit cleans I was doing. Whatever, it was obnoxious.

So I sort of splinted it with my weightlifting wrist wraps and then I waited to see what it would do.

It kept hurting, but another mountain bike ride didn't make it worse.

Maybe, I think, it’s an inflammatory arthritis of some kind. I’ve a family history and some intermittent personal history to worry about. Who knows.

I go to my morning CrossFit anyway. (Hmm. I wrote that one at 54. Now I’m 56…) Today the workout is muscle cleans and push press — about 180 of em. Great. That’s gonna hurt. I do the first 80-90 with a straight wrist, which is extra work. Then, between sets, I realize my wrist isn’t hurting any more. I do the next 90 with the usual wrist extension.

There’s some mild aching as the endorphins fade, but then nothing. Twelve hours later it’s slightly sore with unusual motions. [1]

If a patient came into my office with wrist pain back in the 90s I might have recommended ice, a splint at night, and some gentle range of motion exercises. Today somebody smarter might suggest something like the Dynaflex Pro. I don’t think anyone would recommend high intensity high repetition wrist extension weightlifting.

That’s what helped though.

I do not understand my increasingly aged body, and I don’t think I’m the only mystery. I suspect nobody really understands joints and backs. Once upon a time we recommended bed rest for sore backs, then we recommended activity and exercise;  I personally did well with relatively intense weight and flexibility training. More recently, mountain biking made my anterior knee syndrome slightly worse, but deep squats seemed to have no effect and conventional rehab seems to have helped. Today there’s the wrist.

Pity the poor physician who has to make a recommendation for someone’s sore wrist. It doesn’t work to say “I really have no idea”. It would be nice to know what’s going on though.

[1] I can make up a theory. I have reason to suspect I’m prone to dumping calcium into sore tendons and tissues — a counter-productive response that promotes inflammation. Bad genes I guess. Maybe the vigorous activity promoted clearance of some local calcium deposits. Maybe a stuck tendon sheath loosened up. Maybe the gods had mercy...

Update 5/1/2023: Almost 8 years later I can see this was probably the start of wrist involvement in my mixed-type arthritis. It became an on and off problem over the next 8 years. I'm on HCQ to slow progression and the symptoms seem to be dose responsive. It's annoying but not bad. When it's more bothersome I do "true pushups" or ring pushups or more reps at lower weights.

On knee pain and the state of medical knowledge (updated)

One of the interesting things about being old (45+, sorry to tell you that) and active and is that we develop conditions that we then get to read about.

That's typical. But if you're old and active and a physician there’s a twist. You get to compare the medical textbooks (and web references to your personal experience, and because of the old-part this reading is further informed by a finely tuned bullshit detector.

The bullshit detector is first developed in medical school. No, it’s not when we learn that following the exam preparation advice of professors is suicide — that’s the betrayal and pit-of-knives detector. For me it was the illuminating moment when I realized my 1986 renal physiology professors really had no idea how the kidney really worked. In their hearts they knew this, but there were exams to write and textbooks to teach to — so they faked it.

Later we run into seemingly erudite residents and medical students who we sooner or later realize are just spinning during medical rounds. Attendings varied in their response, I think some were hapless while others found it amusing. Or not amusing.

Much later, sometime after the first few years of practice, we realize that most journal articles are rather like those residents. (More recently reproducibility studies have made this rather more apparent.) We begin to spot the handwaving in textbooks — and to treasure the few that are relatively honest about ignorance.

Which brings me to my the pain below my left patella (knee cap). It could be related to the patellar tendon, to the “fluid-filled sacs” (bursa) that are usually said to be [1] under and around various tendons and neighboring bones, or the knee joint (cartilage/arthritis).

The cause is important to treatment. There’s nothing much to do for arthritis except rest and general muscle strengthening. Patellar tendonosis is treated with knee extension exercise starting at 90 degrees, but something (I’ll get to that) called “patellar-femoral syndrome” is treated with knee extension exercise starting close to full extension. So it’s good to differentiate those two.

The differentiation turns out to be relatively simple. If pain hurts coming down stairs (down > up) it’s likely “patella-femoral syndrome”; you won’t be able to do resisted extension at 90 degrees of flexion but you’ll be fine doing it at at 10 degrees of flexion. Also, “patello-femoral syndrome” is much more common than patellar tendonpathy. A related characteristic is that discomfort is maximal between 15 and 35 degrees (stair descent) — so I have no discomfort extended or in a deep squat.

The medical knowledge/bullshit detector bit comes with reading about "patello-femoral syndrome”. As far back as 1990 one of our texts, “Practical Orthopedics” by Lonnie Mercier, refreshingly admitted that this might as well be called something like “sore knee syndrome”. It’s probably a bunch of things involving some degree of irritation of the bursae and tendons (patellar, iliotibial) beneath and below the patella along the course of the patellar tendon. We used to think it had something to do with the cartilage below the patella, but as far back as 1990 Mercier’s text suggested that “chondromalacia patellae" was relatively infrequent, not clearly related to symptoms, and ought to be carved out as a separate diagnosis.

Reviewing a 2007 AAFP article it looks like nothing fundamental has changed [2]. So points to Mercier.

I wasn’t able to find a persuasive evidence-based treatment program for “sore knee syndrome”; I liked Dr Lee Cohen’s PDF for its guide to resuming exercise [3]. Basically I’m avoiding what hurts (flexing knee on stair descent), doing what doesn’t hurt (high rep, low pressure cycling and swimming), doing near-full-extension quad cybex-style weight. I'll increase extension range as the knee improves, and I’ll try some of Dr. Cohen’s routines. I don’t like NSAIDs because of repeated studies showing they delay tendon healing, so not doing those.

Once I can do squats with 50 lbs or so (very light) and run a mile or so without discomfort I’ll go back to CrossFit...

- fn -

[1] human anatomy is more variable than the diagrams suggests

[2] I don’t particularly recommend that article btw. It reminded me a bit of 1986 renal physiology.

[3] Low intensity mountain and road biking feels fine, so I’m doing that. I’m “on leave” from CrossFit until I can do squats without pain or swelling — one of the great things about contract-free CrossFit at our gym is they’ll stop fees if we’re out for 2 weeks or more.

Update 9/12/2015: Occurred to me that I should change to flats on my mountain bike until the knee is done healing (it’s improving well). Normally SPD cleats allow a lot of lateral mention, but sometimes my mountain pedals get jammed with sand. That’s a formula for worsening my knee problem. So flats for now (which, these days, work pretty well anyway).

Update 11/24/2015: I learned a few more things, which really ought to be in a textbook. 

My own knee did get better after a few weeks of CrossFit abstention, a bit less mountain biking (week off), and quad strengthening. Subsequently, however, I found CrossFit didn’t bother it much at all, but heavy mountain biking could be annoying. Since mountain biking season ended I have been mostly doing CrossFit and ice hockey — and it is now better. I ended up thinking the mountain biking was probably the greater aggravating factor.

Ahh, but there’s a twist as well. I have since learned that what mountain biking and stairway descent have in common is 15 degrees of flexion, which is when the patella is most in contact with the femur. At greater degrees of flexion strong quadriceps pull the patellar undersurface away from the femur — which is why my strong quadriceps limited the pain. Alas, the clinical presentation cannot distinguish inflammatory arthritis (idiopathic, as in OA involving primarily the synovium), from psoriatic arthritis (less idiopathic, with tendon involvement). In my case other clinical findings point to more chronic conditions - psoriatic arthritis or idiopathic inflammatory arthritis (aka, erosive osteoarthritis). So I’ll write a bit more about that sort of thing over time.

Blood donation false-positive HTLV I/II test interpretation. Update - a single case of later onset auto-immune disorder

After decades of blood donation I was rejected in 2010 because of a false positive HTLV I/II test.

I was annoyed, but not too concerned. I forgot about it until I came across old papers today, and a Google search showed that this has been a problem for others. So I'll explain here what I know of this topic, and why I wasn't worried.

This is a bit hard to explain -- even physicians have trouble with testing concepts. One way is by a simplified analogy made for this situation. Suppose you were looking for a killer and you knew they blue eyes and a unique DNA marker that's expensive to test for. Blue eyes would be your imperfect screening test; it has lousy accuracy but it's cheap. Next you test the blue eyed people with the expensive (and perfect) DNA test and you find your killer.

You could test everyone with the perfect "DNA Marker" test, but that would cost a lot of money. So the "blue eye" test is used first to save money.

In my case I tested positive on the cheap ("blue eye) screening test but negative on the good (but expensive) test.

So you'd think I could still donate blood -- but one problem is I may continue to test positive on the inaccurate screening test. That means each time I give blood the expensive test would have to be repeated. That's too much money to spend since we have enough blood donors. (We use far less blood that we used to.)

There are other procedural workarounds, but they all introduce cost and complexity. On the other hand, I'm still a listed bone marrow donor; in that case the economics justify the expensive test.

There's a reasonable discussion in Transfusion 2011 - Human T-lymphotropic virus antibody screening of... [Transfusion. 2011] - PubMed - NCBI. There were 130,000 false positive US donors between 1995 and 2008.

There's a better screening test on the market now so this problem should become less common. Blood centers may eventually decide to reinstate people previously rejected for HTLV positivity and rescreen, but that's probably more trouble than its worth.

If you think about this a bit, there are some other issues to consider. I wasn't much bothered by my false positive test because I'm a physician who works with these topics -- but I bet most of those 130,000 people were quite anxious. Money was spent on follow-up visits with expensive specialists and unnecessary retesting. Some may have had insurance problems. Arguably blood donors should be warned about the risks of false positive testing prior to donation -- so they have informed consent prior to the procedure.

Update 11/26/2015: It helps to have some long term followup on these strange happenings. In retrospect this might have been an early indicator of an auto-immune disorder. Two years later, in 2012, I developed acute inflammation of a distal (near nail) joint of one hand. Five years later (2015) it involved 3 joints and I have sub-patellar arthritis on both knees. In addition to an inflammatory arthritis along the psoriatic-osteoarthritic spectrum I've features of metabolic syndrome despite a low BMI -- including slowly elevating glucose.

My (newly acquired) rheumatologist and I suspect this was a sign I was pumping out lots of antibodies, part of a dysfunctional immune system activation. Though there has also been a relationship between HLTL-1 infection and polyarthritis that doesn't seem to resemble mine, and of course the follow-up testing showed I didn't have the infection.

If someone has a false-positive HTLV-1/II test when donating blood it obviously doesn't mean they are in the early stages of an auto-immune disorder. This is just one odd case. Still, it might be worth a retrospective study.

Why did medical progress slow after 1984?

From 1910 to 1984 medical progress was extremely swift. After 1984, not so much. As I wrote in 1998 ...

Gordon's Notes: Challenges to medicine and science – medication invention hits a brick wall

... I can vouch for the lack of progress. I’m wrapping up a review of roughly the last 7 years of changes in medical practice.

To put it delicately, progress has sucked. If you put a good physician to sleep 7 years ago, and woke her up today, she’d be reasonable competent on day one. A week later she’d be fully up to speed.

My med review conclusions are:

• Lots of new combinations of old drugs, maybe due to co-pay schemes Many new drugs have suicidal ideation as a side-effect.
• Lots of failed immune related drugs re-purposed with limited focal impact on a few disorders. Probably some improvements in seizure meds.
• Lots of new Parkinson’s and diabetes meds, but they’ve had limited value. (metformin was a home run, but that was more than 7 years ago).
• Really lousy progress in antibiotics; there are fewer useful therapies now than 7 years ago. Actually, fewer every year...

Twenty-five years ago it was reasonable to criticize physicians for failing to keep up with a rapidly expanding medical literature. I used to lecture on that topic in residency and beyond, teaching "Grateful Med" [1] use with MEDLINE [2] before the internet went public.

By 1992 though I was getting suspicious. Many exciting journal findings were being reversed within 2-3 years. I planned out a small research study, looking at ten year success measures for novel therapeutic recommendations published in leading journals.

I never did that study, instead I moved from academic to industry. Later John Ioannidis did something similar [3]. Writing in 2010, he demonstrates that modern medical progress is slow with many reversals and lateral moves. The era of rapid progress in medicine is over.

Some of the consequences of slow progress are obvious. Nobody in 1984 would have predicted that by 2010 we still wouldn't be able to cure or prevent multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, or diabetes mellitus. Even as recently as 2000, nobody would imagine the near total failure of clinical genomics. Such negativity would have been considered irrational pessimism.

Other consequences are less obvious. True innovation produces bigger results for less effort. In the absence of innovation there's only raw effort. That translates to more money spent on health care to achieve smaller results. Without genuine innovation, health care cost control is exquisitely painful.

So why has medical progress slowed so much?

One can imagine a lot of cultural explanations, but it's not just US health care innovation that slowed. It slowed everywhere.

I suspect it's more like what happened to aeronautical or automotive engineering or cars or, with the death of Moore's Law, CPUs. The period of medical progress from 1910 to 1984 was an anomaly, an explosive renaissance arising from a "perfect storm" of emerging technologies and cultural receptivity. It was wonderful, but it's been over for a while. The gasoline engine gets a little better every year, and so does medicine.

One day there will be another renaissance in medicine. We just can't predict when.

There's a silver lining of course. Physicians needn't feel guilty about not keeping up with the literature.

See also:

• Lies, Damned Lies, and Medical Science - Magazine - The Atlantic (Story of John Ioannidis, Nov 2010)
• Big Think Interview With Peter Thiel | Peter Thiel | Big Think - innovation is failing in multiple domains
• Earning My Turns: No low-hanging fruit left? (9/18/10)
• Venter on what medical benefits have come from the Human Genome Project: “Close to zero to put it precisely” (8/9/10)
• An end to psychiatric drug development? | Follow Me Here… (8/21/10)
• Gordon's Notes: Challenges to medicine and science – medication invention hits a brick wall (7/2008)

-- footnotes

[1] A terrific DOS and Mac Classic app, named by a terrific National Library of Medicine project leader who was also a Grateful Dead fan. It was the successor to today's PubMed, but I think it was, in several ways, better than PubMed. Grateful Med was a graphical shell over a terminal interface; in 1996 Internet Grateful Med took over. The 1993 version was the best though.

[2] I am just entropic enough to remember the vast shelves of paper-bound "Index Medicus"; dozens of yards of books listing research publications.

[3] Thinking is easy. Doing is hard.

The ideal of medicine - realized in mice

The goal of modern medicine is not to extend life. It is to extend wellness.

Sirtuin activators, enhanced versions of Resveratrol, can do that for mice:

Hoping Two Drugs Carry a Side Effect - Longer Life - NYTimes.com

...Mice on the drugs generally remain healthy right until the end of their lives and then just drop dead...

Yep, that's the medical ideal. The only caveat being that we'd like a month or so of disability, so family members get to say good-bye. Dropping over suddenly is not so good for families.

Ironically, since there's no FDA approval process for compressing debility, the goal of current Sirtuin drug studies is to show a delayed onset of some chronic condition. Of course compressing debility ought to do that, even if life itself does not lengthen. If nothing else, delay the onset of diabetes and osteoarthritis.

Alas, I'm a pessimist. I suspect we'll find that these drugs reduce the onset of some diseases, while increasing others -- probably cancers. Just a hunch.

Of course I might be very willing to personally trade a 3 fold increase in pancreatic cancer risk for a 3 fold reduction in dementia risk, but the FDA isn't set up to allow this kind of swap.

Whatever happened to medical progress?

By an odd bit of synchronicity I'm simultaneously engaged with leading edge research in "Translational Bioinformatics" and refreshing my very dusty knowledge of family medicine.

How dusty? It's been about ten years since I took care of a patient, though other work has kept me somewhat connected to clinical practice. My medical school ended in 1986, so we're talking antique knowledge with dust on it.

Problem is, my old knowledge is more topical than it should be.

In 1983 I wrote a friend an enthusiastic note boasting of how quickly medical knowledge was moving. I was sure that the future was bright for treating and preventing diabetes, the "Haitian disease" (later HTLV, then HIV), rheumatoid arthritis, ALS, autoimmune disease, osteoarthritis, lupus, hypertension, heart disease, migraine, asthma, schizophrenia, dementia, viral and bacterial infections, multiple sclerosis ...

Ok, so I was a tad naive -- but the twenty years from 1962 to 1982 had been amazing. Infectious disease, nutritional disorders, thyroid disorders, insulin, hypertension, angina, -- we were doing great. All we had to do was keep up the pace ...

Splat.

We hit a wall. Now we're relearning how to fear bacterial infections, and the antibiotic pipeline is dry. We can't even treat menopause any more -- estrogen is a bad word. Lipitor and Glucophage are great, but we thought Diabetes Mellitus would be cured by now. We can slow the progress of HIV, but we still don't have a vaccine. Our progress against everyday medical conditions has been lousy over the past twenty years. Mostly we've learned to stop doing silly things, like given people with heart oddities antibiotics prior to minor dental work.

Forget the propaganda about zillions of articles being published -- that's not translating to big changes in people's lives. Yes, we do make progress -- but automobile-style progress, not computer-storage type progress. No wonder we're expecting to spend 99% of our GDP on health care -- we're not getting any big productivity boosts from breakthrough treatments.

Which brings me back to the "translational bioinformatics" stuff. This is the dream that we can apply enormous progress in computational power, and basic science breakthroughs in genomics, to the intractable diseases that have been jeering at us for 20 years.

I'd really like to see us knock off just one of those suckers before I retire. Multiple sclerosis would be a good start. Make my 20 year old knowledge completely obsolete. Please!

Not your father's immunology - and odd implications thereof

Nor your father's definition of the human.

In the past few weeks we've read of toxic viral payloads in sometimes commensal bacteria, we're read of viral infections that are a critical part of placental formation in at least one mammal, and we've read about T-Reg cells, such as:

• mice without T-Regs developed a fatal inflammatory bowel disease -- not due to autoimmune attacks on bowel cells, but rather due to immune attacks on normally tolerated bowel bacteria
• the best response (mice again) to some parasite infections is to keep a few of the buggers around so the immune system stays tuned. T-Regs help with that.
• T-reg activity may increase in pregnancy in some women to manage tolerance of the foreign fetus
  

This must be starting to at least make its way into medical school infectious disease lectures, and of course there are lots of implications for a range of auto-immune diseases (Is ulcerative colitis an auto-immune attack on GI bacteria, why do parasite infections seem to suppress UC, what's the relationship between cutaneous T-Reg cells, vitamin D, sunlight exposure and multiple sclerosis, etc).

Eventually we'll change the way we treat infections, and probably abandon the idea (still persisting) that patients need to take all their antibiotics to kill all the pathogens. We may eventually move to the long mooted concept that managing infections is about managing the "human" (meaning nuclear DNA, mitochondrial DNA, bacterial DNA, Viral DNA, a few prionic forms and lord knows what else) superorganism and its ecology rather than the traditional view of an attacking "pathogen".

Hmmm. What could this approach imply about managing terrorism?