Six Trials, 198 People, and Nobody Recorded How Long It Took to Heal

Read the list of what the trials did not measure, because it is shorter than the list of what they did.

Time to complete ulcer healing. Ulcer-free survival after treatment. Quality of life. Incidence of amputation. Harms.

None of those appears in any of the six randomized controlled trials that exist on treating leg ulcers in sickle cell disease. That is the Cochrane reviewers’ finding, stated in their own results section, in the 2021 update of a review they have been maintaining for over a decade.

The whole evidence base, in one paragraph

Six studies. 198 participants. 250 ulcers.

Every trial tested a different intervention, so nothing could be pooled: L-carnitine, arginine butyrate and isoxsuprine on the systemic side; Solcoseryl cream, an arginine-glycine-aspartic acid peptide dressing, and topical antibiotics on the other. No trial of a non-pharmaceutical intervention met the inclusion criteria at all — no compression trial, no dressing-strategy trial, nothing about offloading.

All six carried an overall unclear or high risk of bias. Drug companies sponsored four of them.

One intervention, arginine butyrate, reduced ulcer size against a control by a mean of 5.10 square centimeters, with a confidence interval running from 9.65 down to 0.55. The reviewers graded the certainty of that as very low, and noted the single trial report was inadequate. Three trials looked at complete closure. None reported a clinical benefit.

Their conclusion, verbatim in substance: given the very low quality of the evidence, we are uncertain whether any of the assessed pharmaceutical interventions reduce ulcer size or result in leg ulcer closure. The harm profile of all interventions remains inconclusive.

Who this happens to, and where

Sickle cell disease is inherited, and its distribution follows the historical geography of malaria — West and Central Africa, the Caribbean, the Mediterranean, the Arabian peninsula, parts of India. In the United States and the United Kingdom it is overwhelmingly a disease of Black patients.

The ulcers appear low on the leg, usually around the ankle bones. The reported frequency across the disease ranges from 2.5 to 40 percent, which is itself a statement about how little precise counting has been done. They tend to arrive in older patients rather than children. They last months to years. They recur.

They are painful in a way that gets under-treated, in a patient group whose pain is already under-believed by the system treating it.

Why they do not close

The mechanism work is better than the treatment work, which is a pattern this section keeps running into.

Chronic hemolysis produces a vasculopathy and endothelial dysfunction — the small vessels in the skin are not behaving normally before the wound ever appears. A 2016 study in a sickle mouse model went further and found that wound healing was severely impaired in old animals and normal in young ones, matching the human age pattern, and that the impairment was specifically a failure of blood and lymphatic vessel growth into the wound bed, with poor mobilization of endothelial progenitor cells from the bone marrow and low CXCL12 secretion by keratinocytes.

Injecting recombinant CXCL12 or progenitor cells locally rescued the healing defect in those mice.

That was published in 2016. It has not become a trial.

What is being tried instead

Topical sodium nitrite is the most-developed candidate. It donates nitric oxide, which is the molecule chronically depleted by hemolysis, and it has an antibacterial effect as a bonus. Its evidence is a phase 1 dose-finding safety and tolerability study at the National Institutes of Health: 18 adults, five concentrations, twice weekly for four weeks, three patients per cohort with an additional six added at the end.

A phase 1 dose-finding study is designed to establish that something can be given safely. It is not designed to show that it works, and the authors do not claim it did.

A separate prospective study of 17 patients using it for four weeks found physical quality-of-life scores improved from 34.5 to 39, and mental scores improved more in those aged 35 and under. Its own conclusion asks for randomized controlled trials to confirm efficacy. Those trials have not reported.

Elsewhere in the literature are a stem-cell pilot, hyperbaric oxygen narrative reviews, transdermal oxygen case studies, a photobiomodulation systematic review, and an observation that leg ulcers improved in patients taking voxelotor for the underlying disease. Every one of those is a hypothesis with a small number attached.

The comparison nobody makes out loud

Venous leg ulcers — the commonest chronic leg wound in white European populations — have one of the better evidence bases in wound care. Compression therapy has been tested to death, in large randomized trials, with healing rates and recurrence rates and cost analyses.

The most sensible advice available for sickle cell leg ulcers is, essentially, to borrow it. A 2020 treatment update says so directly: there are no official recommendations for sickle cell leg ulcers, only a few high-level-evidence studies exist, but many high-level studies exist in venous ulcers and sickle cell ulcers could benefit from those treatments, particularly where venous incompetence or edema coexists.

Which is a reasonable clinical position and also an admission. The best evidence for treating this wound was generated in people who do not have this disease, and the field’s honest recommendation is to apply it across and hope.

The reason usually given is rarity — there are simply fewer patients than there are with venous ulcers. That is true, and it does not explain the absence of quality-of-life endpoints, or harm reporting, or a single trial of a dressing strategy. Those are not expensive. They are choices about what was worth writing down.

What follows for somebody living with one

The first thing is that there is no guideline, and knowing that changes how you interpret confident advice. If a clinician tells you the standard treatment is X, it is fair to ask what X is standard for — because for this wound, in a randomized trial, nothing is.

The second is that the coexisting problems are the treatable part. Venous incompetence and edema have real evidence behind their management, and they are common alongside these ulcers. Getting the venous side assessed is the step with actual trials behind it.

The third is that this is a hematology problem as much as a skin problem. The mechanism is in the blood vessels and the red cells, not in the epidermis, and treatment of the underlying disease is the only route in this literature that has been observed to shift the ulcers.

And the fourth is a matter of who is looking. Assessing a wound bed, its edges and the skin around it depends on color judgments that the wound-care instruments were not built to make on dark skin, on legs that have often been pigmented by years of previous ulceration. If somebody tells you it looks fine, that is an eye, not a measurement — and in this particular corner of medicine, there is not much behind the eye to fall back on.

This article is educational and is not a substitute for care from someone who can look at your skin. Anything new, changing, painful or spreading should be assessed rather than researched.