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The recent newspaper and television publicity about PPS (Pentosan Polysulfate Sodium) is inevitably raising the discussion about treatment of arthritis. But what is it?
PPS has been shown, in a few papers, to be of some benefit in a specific form of virus-related arthritis, and is used by veterinary surgeons in treating horses and dogs with osteoarthritis (though by subcutaneous or intramuscular injection rather than into the joints). There is no clear indication of how a drug previously used for treating blood clots and bladder complaints might help in osteoarthritis pain, but we have been introduced to patients who have had dramatic symptom improvements with PPS treatment.
Is it the end of joint replacements for osteoarthritis?
Best we look at the evidence to date. All we have from the recent news is a so-far-unpublished case study, reported primarily by NewsCorp Health Reporter Sue Dunlevy (http://www.heraldsun.com.au/lifestyle/health/a-breakthrough-treatment-for-osteoarthritis-could-delay-the-need-for-hip-and-knee-replacements/news-story/07b6142b4440b1d1316fcac066183c82 ). Apparently there were 30 patients involved, getting 6 injections over 3 weeks, and 70% of the patients had significant reduction in arthritis pain. The Herald Sun article continues “there has been no double-blind placebo controlled trial of the medicine”. Which seems to ignore a 1996 abstract publication (Footnote 1), but does at least note that evidence is incomplete.
There is, according to the same newspaper article, a planned Phase 2 (Footnote 2) trial shortly to start.
What about the individual patient that we saw on the news, walking with her horse?
We know nothing about the lady’s xrays and the severity of her OA; we know nothing about whether the decision to offer a knee replacement, which she apparently now no longer needs, was reasonable. But she says that the injections cured her, so there must be something in it?
Here, we need to go back in time a little to the famous Moseley trial, published in NEJM in 2002 (http://www.nejm.org/doi/full/10.1056/NEJMoa013259#t=article). In this study, patients with knee OA were randomized to arthroscopic surgery (washout or active debridement) or placebo surgery, and to cut it short there was no difference between the groups. There is a very good full hour documentary “Placebo: cracking the code” (https://www.youtube.com/watch?v=QvbQnMvhQFw and a shorter clip from a BBC documentary on placebos https://www.youtube.com/watch?v=HqGSeFOUsLI ). In both of these films patients from the Moseley study were interviewed, describing the improvement in their knee pain. Would you be surprised to hear that these patients were in the placebo arm, and had no surgery beyond having minor cuts in the skin to mimic the arthroscopic surgery?
The Moseley study, and subsequent studies, have led to a marked reduction in the number of arthroscopic knee operations across the world.
What does this mean for patients now?
Of course this is all complex, and it is not easy to deal with the individual with knee pain who wants to try PPS, because it "helped a person on the TV news". And of course the placebo effect is still an effect. Nevertheless, we need to be both scientific and honest with patients: PPS might work, but there is as yet no real proof that it does, and we should await proper randomized, placebo-controlled trials before promising them relief from their pain by a miracle injection. There is still much else that we can do to help without rushing to surgery, which is the last resort.
But I won’t be giving up joint replacement surgery just yet.
Footnote 1:
The earliest human use of PPS that I could find was an abstract published in 1996 by the same Dr Ghosh who was in the news this week ( Rasaratnam, I; Ryan, P; Bowman, L; Smith, M; Ghosh, P (1996). "A double-blind placebo-controlled study of intra-articular pentosan polysulphate (Cartrophen) in patients with gonarthritis: laboratory and clinical findings". Osteoarthritis Cartilage. 4: vi-vii. doi:10.1016/s1063-4584(96)80025-2. ). Abstracts published in this form represent summaries of papers presented at conferences, and are not subject to the same peer review scrutiny as full papers. When studies presented as abstracts don’t subsequently appear as full papers, you do wonder if that was because they did not withstand the peer review process.
Footnote 2:
We are told that there will be a Phase 2 study about the start, which sounds impressive. It suggests that the process had passed the first hurdle and is moving on to more important testing. In fact, Phase 2 studies are for formal testing of efficacy - does it have an effect? For Phase 2 studies, the drug is not yet presumed to have any therapeutic effect https://en.wikipedia.org/wiki/Phases_of_clinical_research ).
PPS has been shown, in a few papers, to be of some benefit in a specific form of virus-related arthritis, and is used by veterinary surgeons in treating horses and dogs with osteoarthritis (though by subcutaneous or intramuscular injection rather than into the joints). There is no clear indication of how a drug previously used for treating blood clots and bladder complaints might help in osteoarthritis pain, but we have been introduced to patients who have had dramatic symptom improvements with PPS treatment.
Is it the end of joint replacements for osteoarthritis?
Best we look at the evidence to date. All we have from the recent news is a so-far-unpublished case study, reported primarily by NewsCorp Health Reporter Sue Dunlevy (http://www.heraldsun.com.au/lifestyle/health/a-breakthrough-treatment-for-osteoarthritis-could-delay-the-need-for-hip-and-knee-replacements/news-story/07b6142b4440b1d1316fcac066183c82 ). Apparently there were 30 patients involved, getting 6 injections over 3 weeks, and 70% of the patients had significant reduction in arthritis pain. The Herald Sun article continues “there has been no double-blind placebo controlled trial of the medicine”. Which seems to ignore a 1996 abstract publication (Footnote 1), but does at least note that evidence is incomplete.
There is, according to the same newspaper article, a planned Phase 2 (Footnote 2) trial shortly to start.
What about the individual patient that we saw on the news, walking with her horse?
We know nothing about the lady’s xrays and the severity of her OA; we know nothing about whether the decision to offer a knee replacement, which she apparently now no longer needs, was reasonable. But she says that the injections cured her, so there must be something in it?
Here, we need to go back in time a little to the famous Moseley trial, published in NEJM in 2002 (http://www.nejm.org/doi/full/10.1056/NEJMoa013259#t=article). In this study, patients with knee OA were randomized to arthroscopic surgery (washout or active debridement) or placebo surgery, and to cut it short there was no difference between the groups. There is a very good full hour documentary “Placebo: cracking the code” (https://www.youtube.com/watch?v=QvbQnMvhQFw and a shorter clip from a BBC documentary on placebos https://www.youtube.com/watch?v=HqGSeFOUsLI ). In both of these films patients from the Moseley study were interviewed, describing the improvement in their knee pain. Would you be surprised to hear that these patients were in the placebo arm, and had no surgery beyond having minor cuts in the skin to mimic the arthroscopic surgery?
The Moseley study, and subsequent studies, have led to a marked reduction in the number of arthroscopic knee operations across the world.
What does this mean for patients now?
Of course this is all complex, and it is not easy to deal with the individual with knee pain who wants to try PPS, because it "helped a person on the TV news". And of course the placebo effect is still an effect. Nevertheless, we need to be both scientific and honest with patients: PPS might work, but there is as yet no real proof that it does, and we should await proper randomized, placebo-controlled trials before promising them relief from their pain by a miracle injection. There is still much else that we can do to help without rushing to surgery, which is the last resort.
But I won’t be giving up joint replacement surgery just yet.
Footnote 1:
The earliest human use of PPS that I could find was an abstract published in 1996 by the same Dr Ghosh who was in the news this week ( Rasaratnam, I; Ryan, P; Bowman, L; Smith, M; Ghosh, P (1996). "A double-blind placebo-controlled study of intra-articular pentosan polysulphate (Cartrophen) in patients with gonarthritis: laboratory and clinical findings". Osteoarthritis Cartilage. 4: vi-vii. doi:10.1016/s1063-4584(96)80025-2. ). Abstracts published in this form represent summaries of papers presented at conferences, and are not subject to the same peer review scrutiny as full papers. When studies presented as abstracts don’t subsequently appear as full papers, you do wonder if that was because they did not withstand the peer review process.
Footnote 2:
We are told that there will be a Phase 2 study about the start, which sounds impressive. It suggests that the process had passed the first hurdle and is moving on to more important testing. In fact, Phase 2 studies are for formal testing of efficacy - does it have an effect? For Phase 2 studies, the drug is not yet presumed to have any therapeutic effect https://en.wikipedia.org/wiki/Phases_of_clinical_research ).
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