Rethinking Sjögren’s Beyond Inflammation: Considering the Role of Nerves in Driving Disease Manifestations

Abstract

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease characterized by destruction of mucosal glands resulting in dry eye and dry mouth. Ocular presentations can be heterogenous in SS with corneal nerves abnormalities that are structural, functional or both. Some individuals present with corneal hyposensitivity, with a phenotype of decreased tear production and epithelial disruption. Others present with corneal hypersensitivity, with a phenotype of neuropathic pain including light sensitivity and pain out of proportion to signs of tear dysfunction. A similar correlate can be found outside the eye, with dry mouth predominating in some individuals while pain conditions predominate in others. Understanding how nerve status impacts SS phenotype is an important first step to improving disease management by targeting nerve abnormalities, as well as inflammation.

Introduction

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease which is characterized by lymphocytic infiltration of exocrine glands leading to a clinical picture of dry mouth and dry eyes. It can occur in isolation, termed primary Sjögren’s syndrome (pSS) or as part of other rheumatological conditions, termed secondary Sjögren’s syndrome (sSS).¹ pSS is the second most common autoimmune rheumatic condition after rheumatoid arthritis, and its prevalence is estimated to be 0.06% worldwide.² SS can lead to significant ocular and/or systemic morbidity. In one longitudinal cohort of 163 patients in the United States, 13% had vision threatening findings (e.g., corneal melt, cicatrizing conjunctivitis, scleritis) and 25% had extra glandular complications including neuropathy, interstitial nephritis, and autoimmune lung disease, among others.³ SS also imparts an economic and societal burden, with one US-based analysis of 12,717 patients with SS finding a mean yearly cost of $4,878 in patients with glandular disease only, and $14,387 with extra-glandular disease manifestations.⁴

Diagnostic criteria for pSS and missing gaps as they relate to nerve function

The diagnosis of pSS, using the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria, is based on a point system which includes the presence of (I) labial salivary gland with focal lymphocytic sialadenitis (3 points) (II) Anti-SSA (Ro) antibodies (3 points) (III) Ocular staining score of ≥ 5 (using ocular staining score described in Whitcher et al.)⁵ or van Bijsterfeld⁶ score ≥ 4 in at least one eye (1 point) (IV) Schirmer test without anesthesia of ≤ 5 millimeter/5 minutes in at least one eye (1 point) (V) Unstimulated whole saliva flow rate ≤ 0.1 milliliter/minute (1 point). The diagnosis of pSS requires a total score ≥4 and at least one symptom of eye or oral dryness (without the presence of several exclusions including a history of radiation, active hepatitis C infection, sarcoidosis, among others).⁷

As noted above, the diagnostic criterion focuses heavily on glandular manifestations of disease, and does not capture many other features that are often co-morbid with SS. In the aforementioned US-based cohort study, the prevalence for these comorbidities was 4.9% for interstitial nephritis, 2.4% for autoimmune lung disease, 1.2% for pericarditis, 14.7% for thyroid diseases, and 3% for MALT lymphoma.³ Also missing from the diagnostic criterion is an assessment of nerve status, despite the findings that nerves abnormalities, both in and outside the eye, are common in SS and can drive disease phenotypes. This review will discuss how nerve abnormalities in the eye and body can drive SS phenotypes. It will further examine relationships between SS presentations in the eye and body and discuss how incorporating nerve status testing in SS may improve treatment algorithms and lead to the development of novel therapeutics.

Heterogeneity of SS manifestations within the eye

Some individuals with SS have an ocular phenotype consistent with neurotrophic keratitis

SS often presents with an ocular phenotype of decreased tear production, ocular surface inflammation, and epithelial disruption. While destruction of the lacrimal glands by infiltration of lymphocytic cells was believed to be the primary driver of this clinical presentation, another possible contributor to aqueous tear deficiency is neuropathy, both at the level of the cornea and within the lacrimal gland.

Many studies have demonstrated that individuals with SS have decreased corneal nerves density on in vivo confocal microscopy (IVCM).^8,9,10 One Italian study found a lower number of subbasal nerve in SS (pSS and sSS, n=35) compared to controls (n= 20, 3.34 ± 0.76 vs. 5.10 ± 0.79 nerves per frame, p<0.0001).⁸ In fact, individuals with pSS (n=15) have been found to have lower subbasal nerve density compared not only to controls (n=15, 2.9 ± 0.8 vs. 5.8 ± 1.3 nerves per frame, p<0.001), but also to individuals with non SS associated DE (n=15, 2.9 ± 0.8 vs. 3.9 ± 0.5 nerves per frame, p<0.001).⁹ Beyond density, other nerve abnormalities have included increased nerve tortuosity, beading, and decreased corneal nerve thickness.¹¹ For example, in the Italian study, the SS group had more tortuous nerves compared to controls (2.62 ± 0.94 vs. 1.20 ± 0.70, p<0.0001, 0-4 scale).⁸

Structural nerve abnormalities have been found to correlate with signs of tear dysfunction.^10,12 A Chinese study noted that individuals with pSS (n=22) had increased corneal staining, lower Schirmer scores, and lower nerve density compared to 20 individuals with non-SS DE. In this study, corneal staining negatively correlated with nerve density (r= −0.54, p=0.01) and number of nerves (r = −0.49, p=0.03), suggesting that corneal epithelial disruption (a common sign in DE) was related to nerve density.¹⁰ Nerve density has also been related to ocular symptoms. One US study examined 23 individuals with SS, 12 with non-SS DE, and 7 controls. Individuals with SS had lower nerve fiber density and higher tortuosity compared to controls. Notably, significant correlations were found between nerve density and Ocular Surface Disease Index (OSDI) scores (r = −0.92, p<0.001)¹³, indicating that individuals with more severe symptoms had lower nerve densities.

In addition to these structural changes, individuals with SS have also been found to have functional changes in their corneal nerves, often presenting with hyposensitivity.^12,14,15 One Spanish study noted increased detection thresholds using the Belmonte noncontact esthesiometer (indicating decreased sensitivity) when comparing patients with pSS (n=11, 147 ± 21 mL/min) to younger (n=10, 78 ± 12 mL/min, p<0.001) and older (n=10 106 ± 21 mL/min, p=0.024) controls.¹⁵ Nerve sensitivity has also been shown to be related to ocular phenotypes. In a retrospective Canadian study of 18 subject with SS, corneal sensation (measured with Cochet Bonnet) inversely related to corneal fluorescein and lissamine green staining scores (r= −0.35, p=0.03 and r= −0.37, p = 0.03), with decreasing sensation relating to higher staining scores.¹⁶ In this study, corneal sensitivity was not significantly related to symptoms, supporting the premise that some SS phenotypes can mimic manifestations of neurotrophic keratitis (NK). Tear production has also been related to corneal nerve sensitivity. A Japanese study examined 15 individuals with SS and 26 controls. Individuals with SS had lower corneal sensitivity (measured with Cochet Bonnet) compared to controls. In SS, a positive correlation was noted between Schirmer scores (r=0.46, p<0.05) and tear function index (r=0.44, p<0.05) and sensitivity; that is, individuals with lower sensation had decreased tear producton.¹²

Altered innervation of the lacrimal glands may also contribute to SS manifestations.^17-19 One study examined mice deficient in the autoimmune regulator (Aire) gene, as they spontaneously develop a T cell-mediated exocrinopathy and aqueous-deficient dry eye and thus serve as a model for SS. In addition to reduced corneal nerve density in Aire-deficient mice, lacrimal gland nerve density was also reduced when compared to wild type mice (0.05±0.005 vs. 0.04±0.002, unitless normalized values measured using immunofluorescence, p=0.04). Beyond density, abnormalities in nerve function have also been found within the lacrimal gland. This paper also examined acetylcholinesterase activity in the lacrimal glands (required for termination of neurotransmission) and found a ~2-fold decrease in acetylcholinesterase activity in Aire-deficient compared to wild type mice (243.96±35.89 vs. 427.89±19.12 mU/mL, p=0.02), indicating that mice with an SS phenotype have altered nerve function along with reduced innervation.¹⁹ While human studies of lacrimal gland innervation are lacking, findings in mice suggest that inflammation in SS may lead to denervation and reduced neurotransmitter activity within the lacrimal gland, leading to a phenotype of aqueous tear deficiency (ATD).

These studies suggest that many of the DE signs noted in SS occur as a consequence of neurotrophic keratitis and abnormal lacrimal gland innervation. In fact, one Dutch study found that a diagnosis of SS was related to DE discordance, with a phenotype of signs out of proportion to symptoms. The study included 648 participants with DE who underwent symptom evaluation via the OSDI and sign evaluation using Schirmer test, tear break up time, and staining. Both symptoms and signs were converted into a common unit ranging from 0 (minimal symptoms/signs) to 1 (maximal symptoms/signs). The difference between the composite symptom and sign scores was taken as a measure of discordance (with −1 corresponding to minimal symptoms and maximal signs, and 1 corresponding to maximal symptoms and minimal signs). This group found that the diagnosis of pSS (n=184 patients with pSS, β= −0.17, p<0.001) was predictive of greater signs than symptoms in this cohort.²⁰ In patients with a phenotype of decreased nerve sensitivity, abnormal sensing of the environment may contribute to inappropriate reflex tearing, ocular surface instability, and epithelial breakdown due to abnormal distribution of growth factors on the cornea. This is supported by a study which found a positive relationship between tear epidermal growth factor concentration and Schirmer scores (r=0.47, p=0.004) in a population which included individuals with DE (n=35) and controls (n=17).²¹ Applied to SS, this may explain why some patients have significant ocular surface disease, with a less severe symptom profile.

Some individuals with SS have an ocular phenotype consistent with neuropathic pain

However, not all studies have found decreased density and sensitivity in individuals with SS. And some patients with SS have symptoms out of proportion to ocular signs. This points to heterogeneity in ocular phenotypes that may be driven by nerve status. For example, some studies found that individuals with SS have normal nerve density compared to controls.^22-24 One Finnish study found similar nerve densities between 20 individuals with pSS and 10 controls (5.9 ± 2.2 vs. 6.1 ± 2.5 nerves per frame, p=0.78). Notably, this study also found evidence of corneal hypersensitivity, rather than hyposensitivity. This group measured corneal mechanical detection thresholds via a Belmonte non-contact esthesiometer and found significantly lower detection thresholds (indicating higher sensitivity) in pSS (n=20) compared to controls (n=10) (54.5 ± 40.1 vs. 85.0 ± 24.6 mL/min, p=0.04).²⁴

Corneal sensitivity may be related SS phenotype. In this Finnish cohort, corneal sensitivity was related to ocular surface signs, with corneal staining negatively correlating with detection thresholds (r=−0.51, p<0.05), implying more staining in those with increased sensitivity. A similar relationship was observed with ocular symptoms (r=−0.46, p<0.01), implying more severe symptoms in those with increased sensitivity. Together, these results may explain the SS phenotype characterized by hypersensitivity. Although this phenotype is not described in the literature, in our experience, these patients often have neuropathic symptoms which include burning and sensitivity to wind and light.²⁵

Studies outside the realm of SS may also often insights on relationships between corneal sensitivity and ocular pain. A US study examined 129 individuals with a wide range of ocular pain symptoms (none to severe) and characterized corneal mechanical thresholds with Belmonte esthesiometer and neuropathic ocular pain (NOP) symptoms with the Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E).²⁶ In this cohort, lower detection thresholds (indicating higher corneal sensitivity) correlated with increased neuropathic pain symptoms on the NPSI-E (r= −0.23, p=0.01) and ocular surface symptoms on the OSDI (r=−0.18, p=0.04)²⁷, suggesting that neuropathic mechanisms underlie corneal hypersensitivity in some individuals. This may offer a framework through which to evaluate SS patients with hypersensitivity and a suspected neuropathic component to their symptoms.

Notably, ocular surface and corneal inflammation (characterized by dendritic, antigen presenting, or Langerhans cells on IVCM) has been found in all pSS sub-types (low⁹ and similar²⁴ corneal nerve densities when compared to controls), suggesting that inflammation can contribute to all ocular phenotypes. Furthermore, studies have supported a relationship between inflammation and nerve dysfunction outside the purview of SS. A Turkish study found lower corneal nerve branch densities in individuals with lupus (n=39) compared to controls (n=30) (reported as median and interquartile range: 50.0 (39.6-68.7) vs. 64.6 (51.6-95.8) number/mm², p=0.003) along with greater mature Langerhans cell density (2.1 (0-12.5) vs. 0 (0-2.1) number/mm², p=0.002). In this cohort, total and mature Langerhans cell density correlated with decreased corneal nerve branch densities (ρ = −0.32, p=0.05, and ρ = −0.33, p=0.04, respectively) which supports the premise that inflammation contributes to nerve dysfunction.²⁸ Similar finding were noted when examining individuals with rheumatoid arthritis (RA).²⁹ The demonstration of corneal inflammation and nerve changes in other rheumatological diseases further implicates inflammation in the structural and functional nerve changes seen in SS.

The above noted heterogeneity within the SS population with respect to ocular phenotypes and nerve status may give insight to the heterogeneity in the clinical presentation of SS outside the eye.

Heterogeneity of SS manifestations outside the eye

Dry mouth is a common non-ocular phenotype in SS

Dry mouth is a common complaint in patients with SS and is attributable to poor function of the salivary glands. It can contribute to difficulty swallowing or tasting as well as dental decay and mouth infections. In a US study of 169 SS patients, 93.5% reported dry mouth, with 25.4% also endorsing difficulty swallowing and 16.6% endorsing difficulty chewing.³⁰ Despite this high incidence, not all individuals with SS have dry mouth as a prominent feature of the disease. In fact, some have a phenotype more predominated by pain.³¹

Some individuals with SS report pain as a predominate feature of disease

A proportion of individuals with SS have pain as a significant feature of disease. One US based prospective study of 108 individuals examined all pain complaints in patients with pSS and found that a higher frequency (69%) of subjects reported chronic pain (defined as daily pain for greater than 3 months), with 38.0% displaying neuropathic features based on the Neuropathic Pain Questionnaire (NPQ.³¹ More specifically, the experience of pain in SS can be driven by a peripheral^32,33 or central abnormalities.^34,35

Peripheral nerve abnormalities as determinants of pain in SS

Peripheral neuropathies can present with a variety of symptoms which include pain (described as burning, tingling, pins and needles, and/or tightness), numbness, weakness and ataxia. A variety of peripheral neuropathies have been found in individuals with SS. One Japanese study sub-divided 92 patients with pSS-associated neuropathy (patients who met pSS criteria and were evaluated as having symptoms of neuropathy by at least one neurologist) into categories. Some individuals presented with peripheral pain, and 18 were diagnosed with painful sensory neuropathy without ataxia (characterized by superficial sensation of pain without impairment of deep sensation or position sense). Fifteen patients were diagnosed with trigeminal neuropathy, characterized by parasthesias ± numbness along the territory of the trigeminal nerves. Other participants in the cohort had non-pain neuropathy, most notably sensory ataxic neuropathy (ataxia with preserved motor function, n=36).³³

Many individuals with peripheral pain in the setting of SS have a small fiber neuropathy (SFN). SFN is characterized by painful, burning parasthesias which present in a non-length-dependent manner (do not necessarily affect distal body parts prior to proximal ones).³⁶ In SFN, skin biopsies are often used to confirm the diagnosis, and reduced intraepidermal nerve fiber density (NFD) is a consistent feature of the disease.³⁷ Some patients with pSS have symptoms consistent with SFN as well as evidence of disease on skin biopsy.^38,39 One French study evaluated 40 individuals with pSS and symptoms suggestive of SFN, and found burning pain (90%, n=36) to be the most common feature, followed by pins and needles (72.5%, n=29), electric discharges (70%, n=28), and painful cold sensations (37.5%, n=15). Skin biopsies were performed in 17 individuals, and 13 were found to have reduced NFD based on normative data from prior studies (< 7.6/mm from the distal leg or <12.8/mm from the thigh).³⁸ This suggests that some individuals with pSS have objective evidence of peripheral nerve dysfunction underlying symptoms.

Overall, one systemic review (49 papers, n=5617) found the pooled prevalence of peripheral neuropathy (painful and non-painful, variably defined) in pSS to be 15.0% (95% CI: 10.7%-20.7%).⁴⁰ The diagnosis of pure SFN was estimated to be 9.2%. This suggests some individuals with pSS can present with clinical and anatomic evidence of peripheral nerve dysfunction and clinical findings of neuropathic pain.

Central nervous system abnormalities as determinants of pain in SS

Central nervous system symptoms are often co-morbid with SS. Headaches are a well described complaint of individuals with SS. One English study found that 46% (16 of 35) of individuals with pSS experienced migraines.³⁴ These results were replicated in a Turkish study of 133 patients with pSS and 97 healthy controls which found a higher frequency of migraine (49%, n=65) in pSS compared to controls (19%, n=18, OR: 7.72 95% CI: 3.90 – 15.29).³⁵ These results suggest that patients with pSS experience migraine with greater frequency than individuals in the general population. Individuals with pSS have also been found to have structural central nervous system abnormalities on brain imaging, such as white matter abnormalities.^41-43 One Spanish study examined neuroimaging findings in 51 individuals with pSS who had undergone imaging for suspected neurologic disease. 25 had white matter lesions, of which 21 were classified as vascular pathological changes.⁴¹ A Greek study found similar results in 53 individuals with pSS and 25 matched controls. Individuals in the pSS group had a higher frequency of white matter hyperintensities compared to controls (71.7%, n=38 vs. 48.6%, n=17), p<0.001).⁴² In rarer cases, CNS abnormalities such as cortical atrophy and hemiparesis have been observed in SS.⁴⁴ Together, these data suggest that pain in SS can be driven by CNS abnormalities in some individuals (Figure 1).⁴⁵

Figure 1. Sjögren’s syndrome and the functional circuit.

This figure portrays the previously described “functional circuit” in Sjögren’s Syndrome (SS), in which local blood vessels, glands, and the mucosal surface interact with lacrimatory and salivatory nuclei (which in turn communicates with higher level cortical processing centers) to regulate the ocular and non-ocular local environments in SS. Glandular and mucosal disease is well described as drivers of SS symptomology, however central sites of processing such as the midbrain and brain cortex warrant additional consideration as sites of nerve dysfunction which can contribute to SS symptoms, including pain. Adapted with permission from R.I. Fox (Lancet, 2005).

What can eye findings tell us about systemic nerve status in SS?

Ocular findings in SS may align with systemic presentations of disease (Figure 2). For example, individuals with DE signs (e.g., ATD, epithelial disruption) often have co-morbid dry mouth. One Dutch study correlated ocular and salivary measures in 80 individuals with SS (both pSS and sSS), and found that Schirmer test scores positively correlated with secretory flow rates of submandibular and sublingual glands (r= 0.29, p<0.01), suggesting a link between ATD and dry mouth.⁴⁶ Reduced innervation of glandular structures may be a unifying contributor to both dry eyes and dry mouth. This is supported by alterations in salivary innervation in patients with SS.⁴⁷ One study examined markers of neuronal activity in salivary gland biopsies of 10 individuals with SS (not specified if pSS or sSS) and 7 controls. Synaptophysin (a marker present where neural synapses innervate an acinar cell) was present in controls but absent in SS in areas where the glandular cell had atrophied. C-flanking peptide of neuropeptide (CPON), calcitonin gene-related peptide (GCRP), and substance P (all markers of neural innervation on small blood vessels) were similarly present throughout control but not SS biopsies.⁴⁸ Together these findings suggest that reduced lacrimal and salivary function in SS may be mediated by denervation and nerve dysfunction.

Figure 2. Two different sides of Sjögren’s syndrome.

Two different phenotypic presentations of Sjögren’s syndrome (SS) are represented. Patients with a neuropathic component (pictured left) to their symptoms can present with normal corneal nerve fiber densities, accompanied by hypersensitivity to external stimuli (wind icon) as well as pain (red alarm). Patients can also have a neurotrophic keratopathy presentation (pictured right) with decreased corneal nerve density and hyposensitivity (crossed out wind sign). In these patients, tear production (faded lacrimal gland, crossed out tear droplet) may be decreased due to impaired sensing of the environment and reduced distribution of nerve growth factors on the ocular surface. Patients with this phenotype may present with corneal staining and other signs of ocular surface disease. In both patients, corneal inflammation and recruitment of immune cells appear to play a role in the pathophysiology of disease (indicated by the white cells on the corneal bilaterally). Ocular findings in SS may be related to non-ocular findings. Patients with decreased innervation of the cornea and lacrimal gland may also have decreased innervation of salivary glands leading to oral dryness (pictured right). In patients with a neuropathic ocular phenotype, pain in the setting of migraines and peripheral neuropathy may be seen (pictured left).

On the other hand, individuals with neuropathic ocular pain (NOP) features often present with pain elsewhere, including widespread body pain and migraine.⁴⁹ While the latter association has not been studied in individuals with SS, studies outside the realm of SS have examined this link. One Turkish study examined 58 patients with migraine and 30 controls and evaluated corneal sensation with a Cochet-Bonnet esthesiometer. Patients in the migraine group had increased sensitivity in the nasal cornea when compared with patients in the control group (55.0 vs. 53.8 mm, p=0.02).⁵⁰ Another US study demonstrated that individuals with DE and migraine (n=31) had a different symptom profile compared to those with DE but no migraine (n=219). Individuals with migraine had higher neuropathic eye pain scores on the NPSI-E compared to individuals without migraine (39.9±23.3 vs. 21.9±20.2, p=0.0001), despite having similar ocular surface parameters.⁵¹ These findings suggest a relationship between ocular and systemic pain and may be applicable to individuals with SS.

Of note, these categories are not mutually exclusive and an overlap of phenotypes can be seen in an individual patient (e.g., neuropathic pain features in an individual with ATD and dry mouth).

Therapeutic Implications of Nerve Alterations in SS

Re-examining SS through a framework of structural and functional nerve abnormalities can help inform medical management and contribute to the development of new therapeutic strategies.

First, anti-inflammatory therapy can impact nerve status and thus addressing inflammation is an important consideration in SS. One established treatment for ocular inflammation is cyclosporine A (CsA), an immunosuppressant in the calcineurin inhibitor family.⁵² Suppressing inflammation with CsA can impact corneal nerves. One French study examined the effects of 6 months CsA 0.05% treatment in 30 individuals with SS (both pSS and sSS). After 6 months, individuals reported less severe symptoms on the OSDI (49.8 ± 18.9 vs. 60.1 ± 21.4, p<0.001) and increased sub-basal nerve density (16.5 ± 5.9 vs. 12.4 ± 4.5 mm/mm², p<0.0001), decreased tortuosity (graded 1-4) (1.9 ± 0.6 vs. 2.7 ± 0.6, p<0.001) and decreased dendritic cell density (93 ± 58 vs. 250 ± 108 number/mm², p<0.0001) were noted on IVCM.⁵³ These data suggest that long term treatment of inflammation had a positive impact on nerve status.

In individuals with decreased sensitivity, there is inappropriate sensing of the environment and, as a result, reduced tear secretion. Since tears play an important role in the distribution of growth factors at the ocular surface⁵⁴ decreased sensitivity may drive some phenotypes by this mechanism. As such, replacing growth factors, such as with autologous serum tears (AST) or nerve growth factor (NGF), are potential therapeutic avenues. One Italian study randomized 24 patients with SS to an AST (n=12) or artificial tears (n=12) (both 5 drops daily). After 1 year, individuals in the AST cohort had less nerve beadings (17.17 ± 1.64 vs. 21.00 ± 2.08 number/100 μm of nerve length, p<0.0001) and branchings (22.28 ± 1.22 vs. 32.57 ± 5.50 number/mm2, p<0.0001) compared to the artificial tear group.⁵⁵ While nerve status at baseline was not captured in this study, these findings suggest that AST use may impact corneal nerve morphology. NGF has also been found to improve nerve status in SS. In an Italian study, 18 patients with NK (6 with SS) were treated with cenergermin 6 times daily for 8 weeks. An increase in corneal sensitivity was noted at the 12, 24, 36, and 48 month follow up periods using the Cochet-Bonnet (mean change from baseline of 1.75 ± 0.81 cm, p<0.05; 95% CI: 1.35-2.15 cm).⁵⁶ These studies suggest that in SS patients with an NK-like phenotype, treatment with growth factors (autologous or recombinant) may be considered.

In individuals with neuropathic features, including increased sensitivity to wind, light, and other typically non-noxious stimuli, treatment can be targeted at treating peripheral and central sensitization, as appropriate. Systemic neuromodulators can be used in this regard including alpha 2 delta ligands, naltrexone, tricyclic antidepressants, and anticonvulsants.^57,58 One South Korean study assessed the efficacy of oral gabapentin in patients with suspected NOP associated with DE. The study included 24 individuals who reported persistent pain despite topical therapy. 13 individuals reported improved pain with adjunctive gabapentin (600 to 1200 mg/day). Notably, patients in the gabapentin response group had a higher incidence of rheumatological, neurological, and psychological comorbidities compared to the non-response group (53% vs. 9%, p=0.01).⁵⁹ Other therapies that have been studied in the treatment of NOP include transcutaneous trigeminal stimulation, periocular injections of bupivacaine/methylprednisolone, botulinum toxin, and blockade of sympathetic and parasympathetic ganglions.⁶⁰ These approaches can be considered in individuals with SS, as appropriate.

Conclusion

There is a growing body of evidence that peripheral and central nerve dysfunction can occur in SS and drive disease phenotypes. In the eye, some individuals present with evidence of neurotrophic keratitis (e.g., decreased corneal sensitivity, decreased tear production, epithelial irregularity out of proportion to symptoms). This ocular phenotype is often co-morbid with dry mouth. Other individuals present with neuropathic pain features, including burning pain and wind and light sensitivity, out of proportion to signs of tear dysfunction. These individuals often have co-morbid pain symptoms outside the eye, including migraine. Others can have a mix of these phenotypes (neurotrophic keratitis with neuropathic features of pain). Recognizing these presentations within SS is important as improving nerve status (both peripherally and centrally) may improve signs and symptoms of disease and offer additional pathways to alter disease course and reduce morbidity.