Next Round of Tanezumab in Osteoarthritis

About a year ago I’ve written about tanezumab in osteoarthritis [1]. Two years earlier I’ve already voiced my concerns about the substance [2]. My conclusion in 2018 had been: “Until further notice I’ll stay skeptical about tanezumab in osteoarthritis.”

And now there’s a study by Th.J. Schnitzer and colleagues [3]: “Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment [PGA] of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial”. The authors described the significant improvement in pain and PGA as “moderate”. Under results we find: “Rapidly progressive OA occurred only in tanezumab-treated patients (2.5 mg: n = 5, 2.2%; 2.5/5 mg: n = 1, 0.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab, 2.5 mg; tanezumab, 2.5/5 mg; and placebo groups, respectively.”

In conclusion the study shows an analgesic effect of tanezumab, but only against placebo. What about naproxen, celecoxib, or oxycodone? Or even paracetamol? “Rapidly progressive OA occurred only in tanezumab-treated patients”, and therefore the incidence of total joint replacements was higher in the tanezumab groups.

To sum it up, I’m even more skeptical about seeing tanezumab as a drug in osteoarthritis than I had been before.

Links:

[1] https://rheumatologe.blogspot.com/2018/03/tanezumab-in-patients-with-knee-or-hip.html

[2] https://rheumatologe.blogspot.com/2015/12/tanezumab-in-osteoarthritis-at-acr-2015.html

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Lutikizumab in Osteoarthritis

Lutikizumab (ABT-981) is an anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin. I’ve once discussed bispecific antibodies with Prof. Burmester as I have concerns about the fact that each part is as strong as the other and this might not reflect the need of each compound. Prof. Burmester had a more practical approach as you don’t have to apply for two different drugs in studies and later in looking for approval by agencies such as the FDA or EMA. I remain skeptic.

There has been a study by R.M. Fleischman and colleagues [1]: “A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis.” The authors found only a limited improvement in the WOMAC pain score and a lack of synovitis improvement with lutikizumab. The concluded further that “together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.”

M. Kloppenburg and colleagues published a study [2]: “Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis.” The had chosen as primary endpoint a “change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints.” The authors concluded: “Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA [erosive hand osteoarthritis] compared with placebo.”

I said: I remain skeptic. I don’t see a niche for lutikizumab in the treatment of osteoarthritis. Bye bye!

Links:

[1] https://www.ncbi.nlm.nih.gov/pubmed/30653843

[2] https://ard.bmj.com/content/78/3/413.long

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Methotrexate in Knee Osteoarthritis Revisited

There had been an article on methotrexate (MTX) in knee osteoarthritis (OA), which had been published in 2014. As it had been a double-blind, randomized controlled trial, I had had a closer look at the article back then (1). Abou-Raya and colleagues submitted and published: "Methotrexate in the treatment of symptomatic knee osteoarthritis: randomised placebo-controlled trial". I had been critical about the article and the results of the study. Today I revisited the article, as I wanted to know more on subsequent trials.

I was quite surprised that the article had been retracted. The Annals of Rheumatic diseases discussed the decision (2). They listed eight points of “great concern”. And the Investigation Committee’s report concluded: “There is an unintentional mistake in the statistical process, with errors in collection of data in some groups”.

Let’s hope that Sarah R. Kingsbury and colleagues fare better with their study: “Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase III trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial”. (3) Discussion: “The PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA.” The follow-up should have been completed by December 2016, so we should get results during 2017. Allow me already to voice some doubts. MTX is an immunosuppressant and any reduction of pain is due to this mode of action (4). Chronic low-grade inflammation is thought as a major driver of joint degradation in osteoarthritis (5); and it's unclear if MTX suppresses this kind of inflammation. “Despite the clear role of inflammation in OA, recent trials of potent anti-inflammatory therapies, including use of systemic and intra-articular biologic agents to inhibit TNFα and IL-1β, proved disappointing [Hunter, 2008].” 

But let’s wait for the publication of the PROMOTE study, which I’ve just misspelled as PRO MORTE. 

Links:

http://rheumatologe.blogspot.de/2015/05/methotrexate-in-knee-osteoarthritis.html (1)

http://ard.bmj.com/content/early/2016/06/08/annrheumdis-2013-204856 (2)

http://rheumatologe.blogspot.de/2015/05/methotrexate-in-knee-osteoarthritis.html (3)

http://rheumatologe.blogspot.de/2014/01/methotrexate-mode-of-action.html (4)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638313/ (5)

Fish oil in knee osteoarthritis?

“Fish oil in knee osteoarthritis?” is an interesting question. I’ve already mentioned a study here on this blog:

Fish oil and knee OA

Poster #2147: Fish oil doesn't have an effect on structural progression of knee OA. They used 9 g, which would be 18 cps. in Germany.

29.10.2013

The researchers sit predominantly in the area of Adelaide (University of Adelaide) and I’ve been in contact with them. In different groups they research fish oil in rheumatoid arthritis and other diseases.

Now, they’ve published two year data on Fish oil in knee osteoarthritis (OA). 202 patients with knee OA were randomised 1:1 to high-dose fish oil (4.5 g omega-3 fatty acids) 15 ml/day or low-dose fish oil (blend of fish oil and sunola oil; ratio of 1:9, 0.45 g omega-3 fatty acids) 15 ml/day. “The primary endpoints were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score at 3, 6, 12 and 24 months, and change in cartilage volume at 24 months. Secondary outcomes included WOMAC function, quality of life, analgesic and non-steroidal anti-inflammatory drug use and bone marrow lesion score.” Results: “…the low-dose fish oil group had greater improvement in WOMAC pain and function scores at 2 years compared with the high-dose group …” Other endpoints didn’t reach statistical significance. The authors concluded: “In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation.”

Maybe, maybe not. The study didn’t have a placebo arm. Maybe omega-3 fatty acids like in fish, fish oil or flax oil will have a place in the treatment of rheumatoid arthritis or other auto-inflammatory diseases, but knee osteoarthritis might not benefit. However, I don’t want to sound too apodictical – please go on with your research.

References:

http://rheumatologe.blogspot.de/2013/10/acr-meeting-2013-in-san-diego.html

CL Hill et al.: Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose. Ann Rheum Dis. 2016 Jan;75(1):23-9. doi: 10.1136/annrheumdis-2014-207169. http://www.ncbi.nlm.nih.gov/pubmed/26353789

Hyaluronic Acid Injections at the ACR 2015 Meeting in San Francisco

There have been two publications on hyaluronic acid injections at the ACR 2015 Annual Meeting in San Francisco.

Kevin Ong and colleagues analyzed retrospective data: “Hyaluronic Acid Injections in Knee Osteoarthritis Patients Are Associated with Delay to Knee Arthroplasty”. They concluded: “Our analysis of elderly knee OA patients showed a significantly longer delay to KA [knee arthroplasty] for those who were treated with HA [hyaluronic acid].” The authors presented a retrospective, observational study, which cannot take into account the placebo effect of an injection. It lacks a control group. Or do we have a control group?

Astrid in “Fringe” asked Dr. Walter Bishop: “What’s this?” And Walter answered: “A watermelon as a control group.”

I don’t see the two groups comparable; the second group isn't a control group. The time intervals are differently fixed: one with the treatment and the other one arbitrarily.

There may be other reasons as well: different coping attitudes (one trying to avoid arthropasty and the other wishing an arthroplasty), waiting for therapeutic effect or others.

All in all, I don’t think that this study has a good point to convince us of using hyaluronic acid in delaying the time to knee arthroplasty.

Gurjit S. Kaeley and colleagues also used retrospective data in their study: “Utilization of Viscosupplementation: 2011 – 2013”. The authors wanted to estimate and compare the prevalence and cost of Viscosupplemention utilization as recent “ American Academy of Orthopedic Surgeons (AAOS) guidelines have strongly recommended against use of hyaluronic acid because of lack of clinical improvement compared with placebo.” The authors concluded: “This study highlights the significant cost of VS [viscosupplementation ] in the Medicare population. […] In view of the negative recommendations by the AAOS [American Academy of Orthopedic Surgeons] against the use of Hyaluronic acid joint injections, the current trajectory of use of Hyaluronic acid may not represent optimal value care.”

Hyaluronic acid in knee osteoarthritis hasn’t proven efficacy like clinical improvement compared with placebo or delaying the time to knee arthroplasty. Therefore guidelines recommend against using it.

In Germany hyaluronic acid injections aren’t covered by the compulsory health insurance system, so patients have to pay for injection and medication.

I would not use hyaluronic acid in knee osteoarthritis.

References:

Ong K, Anderson A, Lau E, Niazi F, Fierlinger A, Kurtz S, Altman R. Hyaluronic Acid Injections in Knee Osteoarthritis Patients Are Associated with Delay to Knee Arthroplasty [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/hyaluronic-acid-injections-in-knee-osteoarthritis-patients-are-associated-with-delay-to-knee-arthroplasty/. Accessed November 16, 2015.

Kaeley GS, Thway M, Dodani S. Utilization of Viscosupplementation: 2011 – 2013 [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/utilization-of-viscosupplementation-2011-2013/. Accessed November 16, 2015.

Methotrexate in Knee Osteoarthritis

I've been pondering about an article on methotrexate (MTX) in knee osteoarthritis (OA), which had been published in 2014. As it had been a double-blind, randomized controlled trial. It’s well worth to have a look at it. The article had been published in the Annals of Rheumatic Diseases (Ann Rheum Dis doi:10.1136/annrheumdis-2013-204856).

A. Abou-Raya and colleagues:

"Methotrexate in the treatment of symptomatic knee osteoarthritis: randomised placebo-controlled trial". Methods: "One hundred and forty-four patients with primary knee OA were randomised in a 1:1 ratio to receive up to 25 mg/week oral MTX (n=72) or placebo (n=72) for 28 weeks." Conclusions: "MTX significantly reduced pain and improved synovitis. There was a significant improvement in physical function. MTX may be a therapeutic option in the treatment of pain and inflammation related to knee OA."

If you closely at the methods in the abstract, you don't see the flaw (maybe it isn't a flaw - we'll look closer into it later). The objectives, however, already give us a hint: "To assess the efficacy of methotrexate (MTX) in decreasing pain and inflammation in symptomatic knee osteoarthritis (OA)." If you look it up in the whole text, you see, that randomization took place after an entrance exam and patients were not consecutive in the manner of reflecting patients with "symptomatic knee osteoarthritis", instead we're looking at a subset of patients, most of whom were overweight women in their mid-60s with advanced knee OA and clinical evidence of synovitis. The text doesn't explain if any are suffering from concomitant rheumatoid arthritis.

What does the study really say? There might be a subset of knee OA patients, who might benefit from MTX. Then why not say so clearly? The headline doesn’t tell exactly, what the study is about. I think, we're far from using MTX in knee OA patients in daily practice; but as were lacking drugs to alter the course of osteoarthritis, some more scientific effort is warranted. If MTX turns out to be a drug for even only a subset of knee OA patients, we're indebted to A. Abou-Raya and colleagues.

Knee Osteoarthritis - what do I prescribe?

When Dr. Irwin Lim posted "Knee Pain? I prescribe diet & exercise" a couple of months ago, I asked myself, what do you yourself prescribe. Not the same, but much the same. It comes down to three points:

·        exercise

·        diet

·        drugs

I come back to these three in a moment. What I don't prescribe is:

·        chondroitin

·        hyaluronic acid

·        MSM

·        supplements in general

And I use patient education.

Exercise

There are lots of studies on exercise. Some people can't fulfill a whole program, which we with in-patients: a combination of aquatic, aerobic, and strength exercise. In general I also recommend these for out-patients, but would have to tailor my recommendations due to availability. For some patients exercise might mean walking on flat ground.

Diet

Diet is important to reduce weight in obese patients as it reduces weight load on the knees. Diet alone won't be too successful; but we already talked about the necessity of exercise. I advocate lots of veggies (easy as I'm vegetarian) and studies are in favour of a diet rich in antioxidants. I always stress that diet does the trick and not supplements. There's a study by Y. Wang and colleagues addressing this issue: " Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: a cross-sectional study." The author's concluded: "The present study suggests a beneficial effect of fruit consumption and vitamin C intake as they are associated with a reduction in bone size and the number of bone marrow lesions, both of which are important in the pathogenesis of knee osteoarthritis. While our findings need to be confirmed by longitudinal studies, they highlight the potential of the diet to modify the risk of osteoarthritis." Link: http://www.ncbi.nlm.nih.gov/pubmed/17617909.

Also reducing arachidonic acid in the diet may be beneficial.

Drugs

How about drugs? I keep a low profile with drugs. I counsel patients to be very critical about opiates, being a cause for falls. I use paracetamol or novaminsulfon instead, if not successful NSAIDs.

Patient education

I think it's important to educate patients on therapeutic goals and do so right away while they 're in the consultation. As there isn't enough time I recomment both evening talks, which I and my colleagues do on various topics at the hospital, and information texts I've put on my blog. As our center has once been the navel around which the evaluation of an educational program on RA was turning, I know for sure that education will increase the adherance rate of patients to therapy.

Link: http://bjcconnectedcare.com/2013/10/knee-pain-i-prescribe-diet-exercise/

Hyaluronic acid injection for Knee Osteoarthritis

Rheumatology News has an article on a study telling us “Hyaluronic acid injection for knee OA as effective as NSAIDs in short term” (Links are listed below).

The study is from Japan. It’s a multicenter, randomized, open-label, parallel-group, non-inferiority comparison study. One group received a weekly injection injection into the (one?) knee for five weeks and the other group received three times 60 mg of loxoprofen, which is an NSAID of the same group like ketoprofen or ibuprofen. Loxoprofen is only available in Japan, Mexico, Brazil, Argentina, and India. The primary endpoint was the percentage change in the patient-oriented outcome measure for knee OA, the Japanese Knee Osteoarthritis Measure (JKOM) score. Rheumatology News tells about the secondary endpoint: “and their percent change from baseline in pain as rated on a 0- to 100-point visual analog scale (VAS, secondary endpoint).”

Results: "The difference in the percentage changes of the JKOM score between the two intervention arms (IA-HA; - 34.7 % (P < 0.001), NSAID; - 32.2 % (P < 0.001)) was - 2.5 % (95 % confidence interval (CI): - 14.0 to 9.1), indicating IA-HA was not inferior to NSAID. The frequency of both withdrawal and adverse events in the IA-HA group were significantly lower than those in the NSAID group (P < 0.026 and 0.004, respectively)."

The study tells us, that after five weeks of treatment the effects of hyaluronic acid injection for knee OA is equal to an NSAID. How about the first two weeks? Is hyaluronic acid working or the injection itself? Invasive manipulations have a high percentage of placebo effect, but we do not have a placebo control group. We don’t even know if the control group is disappointed not getting their injections and therefore have less pain relief. Withdrawal in the NSAID group had been higher, but the use of gastro protective agents has only been allowed and not been mandatory.

The study has been perfectly done, but it fails to prove that hyaluronic acid injection for knee OA is the road to follow.

Links:

Article on Rheumatology News - http://www.rheumatologynews.com/index.php?id=8844&tx_ttnews[tt_news]=235121&cHash=04c039bf543c2984f1ad4aa5f1b6af91&utm_medium=twitter&utm_source=twitterfeed

Abstract of the study - http://arthritis-research.com/content/16/1/R18/abstract

Loxoprofen on Wikipedia - http://en.wikipedia.org/wiki/Loxoprofen