Pentosan polysulfate sodium for Ross River virus-induced arthralgia: a phase 2a, ... double-blind, placebo-controlled study, 2021, Krishnan et

[Hutan]

Lara J. Hererro and Paul Griffin contributed equally to this work and should be considered joint senior author.

Abstract
Background
Alphaviruses, such as Ross River (RRV) and chikungunya virus (CHIKV), cause significant global morbidity, with outbreaks of crippling joint inflammation and pain, leaving patients incapacitated for months to years. With no available vaccine or specific therapeutic for any alphaviral disease, and a growing economic and public health burden, there is a serious need for the development of specific therapies.

Methods
This study evaluated the safety and efficacy of pentosan polysulfate sodium (PPS) in subjects with RRV-induced arthralgia in a double-blind, placebo-controlled trial. Twenty subjects were randomized 2:1 to subcutaneous PPS (2 mg/kg) or placebo (sodium chloride 0.9%) twice weekly for 6 weeks. Safety evaluation included physical examination, concomitant medications, and laboratory findings. Efficacy assessments included change from baseline in joint function (hand grip strength and RAPID3) and quality of life (SF-36) at Days 15, 29, 39 and 81 after treatment initiation. Inflammatory and cartilage degradation biomarkers were exploratory endpoints.

Results
PPS was well tolerated, with a similar proportion of subjects reporting at least one treatment-emergent adverse event (TEAE) in the treatment and placebo groups. Injection site reactions were the most common TEAE and occurred more frequently in the PPS group. Dominant hand grip strength and SF-36 scores improved with PPS at all time points assessed, with hand grip strength improvement of 6.99 kg (p = 0.0189) higher than placebo at Day 15. PPS showed significant improvements versus placebo in adjusted mean relative change from baseline for RAPID3 Pain (p = 0.0197) and Total (p = 0.0101) scores at Day 15. At the conclusion of the study overall joint symptoms, assessed by RAPID3, showed near remission in 61.5% of PPS subjects versus 14.3% of placebo subjects. Additionally, PPS treatment improved COMP, CTX-II, CCL1, CXCL12, CXCL16 and CCL17 biomarker levels versus placebo.

Conclusions
Overall, the improvements in strength and joint symptoms warrant further evaluation of PPS as a specific treatment for RRV-induced and other forms of arthritis.

 

[Hutan]

I thought this paper was interesting given the discussions we have had about whether there might be a spectrum of post-viral conditions ranging across ME/CFS, fibromyalgia and overt arthritis resulting from chikungunya.

Arthritogenic mosquito-borne alphaviruses, such as chikungunya virus (CHIKV), Ross River virus (RRV) and o’nyong nyong virus (ONNV), can cause severe acute musculoskeletal inflammatory illnesses that may lead to significant muscle and joint damage. These illnesses can last months to years causing considerable pain and suffering for the patient and a significant cost to society [1].

The pathogenesis of chronic alphaviral arthritis in humans is not well understood. The isolation of viral antigen in leukocytes from joint effusions and viral RNA from synovial biopsies [2] suggest that persistent infection or viral antigen may play a role. Other evidence suggests a more independent post-viral inflammatory or autoimmune response which clinically resembles rheumatoid arthritis, with various inflammatory and immunological pathways implicated in disease pathogenesis. Several studies have demonstrated that various immune mediators are also implicated, including macrophage inhibitory factor (MIF) [3], an important cytokine in the pathogenesis of rheumatoid arthritis, and interleukin-6 (IL-6)

It's also interesting to see Australian virologist Lara Herrero as an author, given her comments in a recent article.

Researchers looking into the lingering effects of the coronavirus have also begun to note the similarities between the experiences of people suffering from long COVID and chronic fatigue syndrome.
Griffin University virologist Lara Herrero is one of Australia's foremost experts on the Ross River virus.
Dr Herrero contracted Ross River herself at a family BBQ in Western Australia back in 2004.
It would change the course of her career and she soon pivoted from researching viruses mainly affecting children - such as hand, food and mouth disease - to mosquito-transmitted viruses.
"I was surprised about how little was known about Ross River and how little it was being studied," she said.
"I had a very understanding GP at the time but was told nothing could be done."

 

[Hutan]

Interesting re the placebo effect on subjective endpoints:

A limitation of our study is the potential impact a placebo effect may have on subjective endpoints such as pain and function. In a meta-analysis of pain and function placebo responses in patients with osteoarthritis, Huang et al. [38] calculated a “placebo response ratio” of 0.44 (where 0 means the placebo effect made no contribution to the response and 100 means all the response is due to placebo effect). Combining this with the subjective nature of evaluating pain may have resulted in our failing to achieve statistical significance in all but one of the patient-reported outcome pain measures used.

 

[Jonathan Edwards]

Interesting re the placebo effect on subjective endpoints:

That sounds like a new way of scratching around for an excuse for not getting any results doesn't it?

I am not impressed with the 'biomarkers' they chose to report - biomarkers of what? Why not give results for something we know a bit more about like CRP or ESR?

I suspect pentosan polysulphate is quite irritant so this may not be realistically blinded.

 

[Hutan]

Yes, the results for the treatment don't look very exciting. And the authors suggest that maybe they need to dose at a higher rate, which could also be a way of scratching around for an excuse for not getting any results in this experiment. Perhaps they will find something with that treatment eventually, although probably not.

But I thought it was an interesting paper due to the apparent acceptance that alpha viruses including Ross River Virus can cause joint inflammation and pain. (Whereas, the discussions here have been a lot less certain about that.). And we know RRV causes a post viral fatigue syndrome that can meet ME/CFS criteria.

I heard a young woman who has idiopathic juvenile arthritis, which she got after a virus, on the radio the other day. As well as a lot of pain, she talked about 'paying' for exertion on the days following, and life-limiting fatigue, in a way that sounded a lot like PEM. That together with the joint pain that my son had, and that I currently have makes me think that maybe there are some commonalities in ME/CFS and inflammatory joint conditions.

 

[Mithriel]

One of the symptoms of ME before CFS was joint pain which could affect different joints at different times.