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….

Smartphone Calendaring: survey results

Our family loves our Google Calendars. Today, looking at Calendars 5.app on my iPhone, I see that our 5 (human) family members own 8 calendars and I’m currently subscribed to 7 organizational calendars and 3 or so related to weather, holidays and the like. We’ve been doing this kind of coordinated calendaring since I got our family (free then!) Google Apps about 9 (!) years ago. The early days were painful, but now it’s smooth — Google hasn’t done any recent damage.

So I was looking forward to talking about Calendaring in my special needs smartphone book (working title: Smartphones for all: Supporting independence with iPhone and Android.). Then I started writing … and ran into a wall. What we did works, but it’s far too geeky. I needed “The Apple Way” (iPhone) and “The Google Way” (Android and iPhone) to be understandable. 

The first step to that was learning what normal people do. So I wrote up a Google Form 2.0 survey (now closed) and promoted it on app.net (mostly geeky) and Facebook (not geeky) and my blogs (sort of geeky). Today I dug through it.

I received 74 responses, about half from experts and half from my target group.

 

Of this group of 74 about 1/6 didn’t use any personal calendars on their smartphone. I didn’t ask this group any further questions, so my survey data is about smartphone users who have personal calendars - about 5/6 in this case.

Among the 5/6 who did calendaring the iPhone was more common than I’d expected - 87%!

Since most smartphones in the US are Android devices, that’s an unexpected result. I suspect some of that is an app.net effect (it’s pretty Apple-centric), but I wonder if many Android users don’t do calendaring. I did notice in the survey that Android users were disproportionately “expert users”, maybe Android users fall into an expert group and a web/messaging/youtube only group. I’m speculating there, but I think the non-expert responders to my survey are a lot like my book audience.

I looked briefly at my 33 expert respondents. Almost half had both personal and employer calendars, most had Google Calendars (many had both), and many viewed and edited multiple calendars. The only surprise was how many iPhone using experts made do with the native iPhone Calendar.app - 2/3 of them! Since most view multiple calendars they must be using Google’s obscure calendar sync web page.

Of my 28 non-expert Calendar few used an employer’s calendar and only 3/28 used Android. Of the 25 that used iPhones about 1/3 were using either Google’s Calendar.app or some other Google Calendar client (Calendars 5.app, etc) and 2/3 used iOS Calendar.app. Most of the iPhone users of Google’s Calendar service used multiple calendars and sent event invitations. iPhone non-experts who didn’t use Google Calendar also didn’t access more than one calendar and most had never sent an invitation. Many were unsure if their iPhone Calendars sync’d to iCloud (the default setup).

Despite obvious limitations with my sample I came away with some useful working conclusions for my book:

• I can’t assume my readers have ever looked at the Calendar app.
• I need to explain the relationship between the phone calendar and the “web” calendar and that changes made to one will show up in the other.
• Many iPhone Calendar users are not aware that they sync their Calendars with iCloud and that there’s a web view of their iCloud calendar. Many use their iPhone Calendar like a paper datebook or the original PalmPilot Calendar.
• Calendar sharing is effectively limited to Google Calendar users. It’s not only that subscribing to public calendars is basically a Google-only thing, it’s that most iPhone/iCloud users never make use of Apple’s relatively obscure iCloud shared Calendar overlays.
• I need to explain what sending an invitation does.
• Calendaring is not an Apple strength.

How to probe medical knowledge gaps -- and get a useful pub

I researched alcoholic myopathy the other day. The results were appalling. There’s been very little research in the past 25-30 years, fundamental questions are unanswered, repeated references are made to the same old prevalence numbers, etc.

It reminded me again of the big gaps in our medical knowledge base. Some topics get a lot of research, others seem to be forgotten. So I wondered about a way to characterize the gaps.

I think this would work, and it would be a nice paper for someone:

1. From medicare data get list of most often used 1,500 ICD-9 codes (still 9 for US).
2. For the “other” codes map them to the parent level in hierarchy.
3. For this set obtain ICD long names (optionally, use the better structured SNOMED names using ICD to SNOMED maps).
4. For each string run a pubmed query using the NLM’s API.
5. For each results count which are reviews, randomized controlled studies etc. (standard NLM metadata).
6. Analyze the results for outliers with few reviews, studies, etc. I’d expect 50-100 would be neglected.
7. Publish.

Medical history: What CT did to neurology, MRI has done to sports medicine

Few remember this now, but once neurologists were proud of their ability to localize brain injuries based on complex and detailed examinations. They could, for example, find a tumor or a stroke based on an examination.

Then CT scans came along, and we discovered that those exams didn’t, actually, work.

More or less the same things happened with cardiac auscultation and cardiac anatomy. I remember our cardiology teachers and my fellow medical students could hear “S4s” that somehow I could never hear.  I assumed it was because I was tone deaf. Then cardiac ultrasound took over…

I think the same thing happened with sports medicine. Once we had all kinds of specific shoulder tendon diagnoses we made based on examination. Then MRI showed things were messier. We used to talk about various hip soft tissue disorders like “piriformis” syndrome, not it’s just “deep gluteal pain syndrome”.

There’s a lesson in this somewhere.