Painful Small Fiber Neuropathy Associated With Teriflunomide: A Case Series and Literature Review Related to Teriflunomide and Leflunomide

Teriflunomide and its prodrug, leflunomide, are disease-modifying medications used to treat relapsing-remitting multiple sclerosis (RRMS) and rheumatoid arthritis (RA), respectively. Peripheral neuropathy is a rare side effect associated with both medications, although the incidence rate and exact pathological mechanism remain unknown. We present a retrospective case series of three patients with RRMS, who developed painful small fiber neuropathy at various timeframes (<6 months, one year, and four years, respectively) while on teriflunomide treatment (14 mg/day); we also engage in a literature review of small and large fiber neuropathy associated with teriflunomide and leflunomide use. All three patients developed small fiber neuropathy following teriflunomide exposure. Laboratory workup was negative for metabolic, infectious, vitamin deficiency-related, and autoimmune etiologies, except for one patient who had chronic metabolic syndromes (impaired glucose, hyperlipidemia) before medication intake. However, the patient developed neuropathy following teriflunomide treatment. Electrophysiological findings were negative for large fiber neuropathy in all three patients with positive skin biopsy, with reduced epidermal nerve fiber density (ENFD) in two of the three patients. Teriflunomide was discontinued in all cases, after which symptoms stabilized. Current literature on leflunomide supports a direct neurotoxic effect or buildup of toxic intermediates from uridine synthesis inhibition. Cessation of teriflunomide use in the described cases resulted in symptom stabilization. Early recognition and treatment may lead to good clinical outcomes in these patients.


Introduction
Peripheral neuropathy is a nervous system disorder with a broad spectrum of clinical manifestations, ranging from positive symptoms like pain, tingling, paresthesia, and dysesthesia to negative symptoms like numbness.It can be clinically categorized into large fiber peripheral neuropathy, loss of sensation, poor balance and weakness, and small fiber neuropathy, pain, tingling, burning, and cold sensation [1].Leflunomide is a disease-modifying drug typically recommended in active cases of rheumatoid arthritis (RA) and known to cause large fiber peripheral neuropathy.Its effects on both sensory and motor nerve fibers can be recognized based on an abnormal electrophysiological study [2].Cessation of drug use generally results in symptom stabilization or improvement, which further reiterates its role in instigating neuropathy [3].
Teriflunomide, the active metabolite of leflunomide, possesses similar immunosuppressant and antiinflammatory potential.It was approved by the FDA in 2012 for the treatment of relapsing-remitting multiple sclerosis (RRMS) [4].By inhibiting dihydroorotate dehydrogenase, it imposes a cytostatic effect on T and B lymphocytes, thereby mitigating their proliferation without severely compromising the immune system [5].Both pyrimidine synthesis inhibitors, leflunomide and teriflunomide, presumably pose comparable risks for large fiber neuropathy.However, while significant data is available on leflunomideinduced peripheral neuropathy, little is known about the effects of teriflunomide on the nervous system.Incidents of peripheral polyneuropathy were found in pooled data from the clinical trial database of the disease-modifying antirheumatic drugs and the FDA-reported post-marketing data.Still, no case reports have been published so far in the literature [6,7].
In this small, single-site, retrospective observational case series, we present three painful small fiber neuropathy cases following teriflunomide treatment at various timeframes.We also provide a comprehensive review of data on small and large fiber peripheral neuropathy associated with teriflunomide and its mother drug, leflunomide.

Case Presentation Case 1
A 61-year-old woman with an eight-year history of RRMS presented with neuropathy in her feet after four years of teriflunomide treatment.She reported a burning sensation in her legs from her calves down and tingling, sharp shooting pain in her feet.Before teriflunomide therapy, she had failed trials of diseasemodifying therapies (DMTs) due to various side effects, including injection site reactions with glatiramer acetate, liver enzyme elevation with interferon beta-1a, and nausea and vomiting with dimethyl fumarate.
Neurological examination showed features of small fiber neuropathy with reduced sensation to pinprick a few centimeters below the ankles down to her toes and mildly reduced sense of vibration distally in her toes with normal position sense.Motor examination was normal.Deep tendon reflexes (DTR) were normal (2+) in the upper and lower extremities.Serum protein electrophoresis and immunofixation showed IgG lambda monoclonal protein (<0.1 g/dL).Plasma cell dyscrasias were excluded following a negative skeletal survey and a 24-hour urine protein collection, and the patient was diagnosed with monoclonal gammopathy of unknown significance (MGUS).Electromyography (EMG) and nerve conduction studies (NCS) were negative for large fiber peripheral neuropathy.A skin biopsy revealed significantly reduced epidermal nerve fiber density (ENFD) in a sample taken from the left foot, consistent with small fiber neuropathy, and normal ENFD in the left calf (Table 1).Gabapentin was initiated with a 300 mg daily dose and titrated up to 600 mg three times/day due to poor pain control.The patient could not tolerate further dose escalation.Teriflunomide therapy was discontinued, and lower extremity pain and paresthesia stabilized without progression.

Case 2
A 54-year-old woman with a three-year history of RRMS presented with neuropathy in her feet after one year of teriflunomide treatment.She reported sharp stabbing pain and tingling sensation from the calves down to the feet.Before teriflunomide therapy, she had failed trials of DMTs due to various side effects, including injection site reactions with glatiramer acetate and severe leukopenia with dimethyl fumarate.
Neurological examination showed features of small fiber neuropathy with reduced sensation to pinprick a few centimeters below the ankles down to her toes and mildly reduced sense of vibration distally in her toes with normal position sense.Motor examination was normal.DTR was normal in the upper and lower extremities.Serum protein electrophoresis and immunofixation were normal.EMG/NCS was negative for large fiber peripheral neuropathy.Unfortunately, the patient did not undergo a skin biopsy for evaluation of small fiber neuropathy due to insurance-related issues.She failed multiple neuropathic pain medications, including gabapentin, pregabalin, and duloxetine, due to various side effects (dizziness, tiredness, and drowsiness), and reported partial improvement with venlafaxine 37.5 mg.
Teriflunomide therapy was discontinued, and lower extremity pain and paresthesia stabilized without progression.

Case 3
A 47-year-old woman with an eight-year history of RRMS presented with neuropathy in her hands and feet after six months of teriflunomide treatment.She reported numbness as well as tingling and sharp pain.Before teriflunomide therapy, she had failed trials of DMTs due to various side effects, including injection site reactions with glatiramer acetate, worsening depression and flu-like symptoms with Rebif, and severe leukopenia with fingolimod.
Neurological examination showed features of small fiber neuropathy with reduced sensation to pinprick in a stocking-and-glove pattern with a mildly reduced sense of vibration distally in her toes and a normal position sense.Motor examination was normal.DTR was normal in both the upper and lower extremities.Serum protein electrophoresis and immunofixation were normal.EMG/NCS was negative for large fiber peripheral neuropathy.A skin biopsy revealed significantly reduced ENFD in a sample taken from the lateral right thigh, consistent with small fiber neuropathy, and low-normal ENFD from the right calf (Table 2).The patient partially responded to the gabapentin 600 mg three times/day.Teriflunomide therapy was discontinued, and lower extremity pain and paresthesia stabilized without progression.

Specimen
In all three patients, repeat neuroimaging (including MRI of the brain, cervical, and thoracic spine with and without contrast with demyelinating protocol) revealed chronic demyelinating disease without new or active demyelinating lesions.

Discussion
We discuss the cases of three patients with clinical features suggestive of painful distal symmetric small fiber peripheral neuropathy after teriflunomide treatment.Since the medication's integration into the market in 2012 until 2022, the FDA's online database of adverse effects received 427 reports of peripheral neuropathy associated with teriflunomide [7].Additionally, the product's summary of characteristics discloses an incidence rate of peripheral neuropathy of 1.4% and 1.9% in patients receiving 7 mg and 14 mg of teriflunomide, respectively [8].Yet, there is scarce data regarding these patients in the literature.In contrast to teriflunomide, there is a growing literature documenting peripheral neuropathy associated with the mother drug, leflunomide (Tables 3, 4  The exact mechanism by which leflunomide may cause neuropathy remains unknown.Bonnel and Graham (2004) attributed the patients' neuropathy to the accumulation of toxic metabolites generated due to leflunomide's inhibitory effect on uridine production [3].By blocking uridine diphosphate (UDP)glucuronosyltransferases (UGT), leflunomide impedes the conjugation of endogenous compounds, xenobiotics, and toxic substances with glucuronic acid and thereby obstructs their excretion [16].On the other hand, Carulli and Davies (2002) suggested that the drug may provoke vasculitic neuropathy, which was confirmed by a sural nerve biopsy [13].Bharadwaj and Haroon (2004) reinforced this hypothesis by obtaining nerve biopsies from three leflunomide-treated patients presenting with peripheral neuropathy [17].
Epineural perivascular inflammation and prominent neovascularization established the presence of axonal neuropathy and vasculitis in them.
Several factors favor teriflunomide as the culprit in our patients.There was a temporal relationship between the initiation of teriflunomide treatment and the onset of the neurological complaints.Moreover, symptoms stabilized following drug cessation.Additionally, EMG results ruled out large fiber neuropathy, and biopsies performed in patients 1 and 2 revealed a reduction in ENFD, establishing a diagnosis of small fiber neuropathy.Laboratory investigations showed no evidence of primary or secondary vasculitis in any of the patients.Other possible neuropathy causes -including metabolic or immune disorders, vitamin deficiency, and concomitant use of neurotoxic drugs -have been ruled out in all three cases (Table 5).The patients had no history of diabetes or hypertension.Autoimmune workup was only positive for antinuclear antibodies (ANA) (homogeneous pattern 1:320), a non-specific finding since all other autoimmune labs were normal.HIV testing was not recommended for patient 1 as the patient had no risk for HIV contraction and yielded negative results for patients 2 and 3. Lastly, patient 1 had chronic metabolic syndrome long before teriflunomide use, and her neuropathy began after the drug intake.It is unclear if the MGUS diagnosis had any link with teriflunomide exposure, as the patient did not have any testing done for MGUS before the diagnosis of small fiber neuropathy was established.

Conclusions
Teriflunomide-induced neuropathy is not only underreported in literature but also underrecognized in clinical practice.In cases of suspected neuropathy following teriflunomide exposure, early diagnosis and prompt treatment cessation may result in better clinical outcomes.Failure to improve upon drug cessation could imply irreversible damage.Clinicians should thus discuss this rare side effect with their patients to ensure timely management of small fiber neuropathy and prevent its progression to large fiber neuropathy.Failure to do so will cause patients to resort to polypharmacy for the management of neuropathic pain,