From Diagnosis to Treatment: Key Questions in Immune-Mediated Small Fiber Neuropathy

Small fiber neuropathy (SFN) is increasingly recognized as an important cause of neuropathic pain, sensory dysfunction, and autonomic symptoms, yet many questions remain regarding its underlying mechanisms and optimal management. While established causes such as diabetes, hereditary amyloidosis, and metabolic disorders account for a proportion of cases, growing interest has focused on whether a subset of patients may have an immune-mediated or inflammatory form of the disease that could be amenable to targeted treatment.

At the 2026 Peripheral Nerve Society (PNS) Annual Meeting, held June 13-16 in Maastricht, Netherlands, Matthew Evans, BM, BCh, DPhil, presented a session titled "Immune-Mediated Small Fiber Neuropathy: Is it for Real?" The presentation examined the current evidence supporting autoimmune involvement in select patients with SFN, explored proposed antibody associations, and reviewed available data on immune-directed therapies.

In an interview with NeurologyLive^®, Evans discussed the clinical features that may suggest an inflammatory etiology, the challenges of establishing an objective diagnosis, and the limitations of the existing treatment literature. He also highlighted ongoing efforts to identify meaningful biomarkers, improve patient stratification for clinical trials, and better understand which patients may ultimately benefit from immunomodulatory approaches.

NeurologyLive: Your presentation asks a provocative question: Is immune-mediated small fiber neuropathy real, and what evidence supports its existence?

Matthew Evans, BM, BCh, DPhil: It's a purposely controversial title, I suppose, but the short answer is yes. I think it does exist. Most people would accept that it exists, at least in a subset of people with small fiber neuropathy.

What the thrust of the talk is really about is putting your finger on who has a potentially inflammatory cause and who doesn't, because that can be very challenging. Even when you identify someone who may have an inflammatory or autoimmune-mediated cause of small fiber neuropathy, the evidence base from randomized controlled trials for immune treatments is poor.

We're in a difficult situation where there may be a treatable cause in a subset of patients, but we don't really know who those patients are or what the best treatment strategy should be.

What clinical features may help distinguish patients with a potentially inflammatory form of small fiber neuropathy?

The three main groups we think about are fairly well described in the literature.

The first is patients who present with non-length-dependent neuropathy. Most peripheral neuropathies, including many forms of small fiber neuropathy, are length dependent, beginning in the feet and gradually spreading upward. Non-length-dependent neuropathies can present in a patchy distribution and affect the face, arms, and legs. Those presentations appear to be more strongly associated with autoimmune causes. Conditions such as Sjögren syndrome and sarcoidosis often produce this type of pattern.

The second group includes patients who present very abruptly, often after an infection or vaccination. Some have likened this to a small-fiber version of Guillain-Barré syndrome, where patients develop an acute or subacute eruption of pain and small fiber symptoms without the classic large-fiber involvement.

The third area involves emerging research into autoimmune antibody associations. There are several antibodies that have been linked to small fiber neuropathy, and while the evidence remains preliminary, they continue to generate significant interest as potential markers of immune-mediated disease.

What are the biggest challenges in diagnosing small fiber neuropathy and identifying potentially treatable causes?

The phenotype itself is often fairly recognizable. Patients typically present with burning pain in the feet, or in the hands and feet, along with abnormalities in pain and temperature sensation. Most neurologists can usually recognize that pattern relatively quickly.

The challenge is first identifying whether there is a secondary cause, particularly one that may be treatable. The second challenge is obtaining objective evidence that the small fibers are actually damaged or dysfunctional.

Current diagnostic criteria generally require three components. First, patients need characteristic symptoms and signs. Second, clinicians need to exclude generalized large-fiber neuropathy through nerve conduction studies. Third, they need positive evidence of small fiber dysfunction or damage.

The two primary approaches are skin biopsy, which evaluates intraepidermal nerve fiber density, and quantitative sensory testing, which assesses how small nerve fibers function across multiple sensory modalities. The difficult question is how extensively clinicians should pursue investigations beyond that point, particularly when considering inflammatory or autoimmune causes.

What have clinical trials taught us about immune therapies in small fiber neuropathy?

One of the key areas of my presentation was a systematic review we conducted examining all available literature on immune therapies for small fiber neuropathy.

We used very broad search criteria, including conference abstracts, case reports, case series, and randomized controlled trials. In total, we identified 65 publications. However, the vast majority consisted of conference abstracts or small case reports and case series. Only three randomized controlled trials have been performed.

One study evaluated IVIG in patients with length-dependent small fiber neuropathy and found no benefit across primary or secondary outcomes. Another small trial focused on patients with antibody-associated small fiber neuropathy and again failed to meet its primary endpoint. A third study examined IVIG in patients with postural orthostatic tachycardia syndrome who also met criteria for small fiber neuropathy and likewise found no benefit.

What's striking is the discrepancy between these trial results and the published case literature, where dramatic improvements are often reported. Understanding why that discrepancy exists is something the field needs to address moving forward.

Where do biomarkers currently fit into the small fiber neuropathy landscape?

People are beginning to study neurofilament biomarkers in small fiber neuropathy populations, although that work is not nearly as advanced as it is in conditions such as CIDP.

The antibody biomarkers are particularly interesting. Of the currently discussed antibodies, only a couple have shown evidence suggesting they may be pathogenic rather than simply bystanders. More work is needed before we can definitively establish their role.

One challenge is that some of these antibodies are found in a relatively high proportion of patients with otherwise idiopathic small fiber neuropathy. Depending on the antibody, prevalence rates can range from roughly 20% to 40%. That makes it difficult to conclude that they are directly causative in all cases.

At this stage, we're still in the early phases of understanding how these biomarkers should be interpreted and whether they can meaningfully guide treatment decisions.

What research priorities should the neurology community focus on over the next several years?

I think one major issue is that many patients with small fiber neuropathy never make it to neuromuscular specialists. Often, the diagnosis is made in general neurology clinics, some degree of workup is performed, and patients are managed symptomatically because there are currently no proven disease-modifying treatments.

As a result, specialists may not be seeing the full spectrum of these patients. We need larger, prospective, collaborative cohorts that allow us to collect data in a more standardized and controlled fashion.

We clearly need more randomized controlled trials, but there are practical challenges. Many of the therapies people want to study, such as steroids or IVIG, have little commercial incentive behind them. At the same time, newer immune therapies are emerging, and there is increasing interest in repurposing them for conditions that may have an autoimmune component.

My concern is that we're going to have an expanding number of potential therapeutic mechanisms without sufficiently rigorous evidence to guide us. We need better patient stratification, stronger biomarkers, and carefully designed clinical trials to determine which patients truly benefit from immune-directed treatment and which do not. Transcript edited for clarity.

Transcript edited for clarity. Click here for more PNS 2026 coverage.