Pattern of peripheral neuropathy in systemic lupus erythematosus: clinical, electrophysiological, and laboratory properties and their association with disease activity

Aim To study clinical, electrophysiological, and laboratory properties of peripheral neuropathy (PN) in systemic lupus erythematosus (SLE) and their association with disease activity. Patients and methods A total of 30 patients who met the American College of Rheumatology case definition criteria for SLE-PN and 30 age-matched and sex-matched patients with SLE without PN were selected from the Main Alexandria University Hospital Physical Medicine, Rheumatology and Rehabilitation clinic. Demographic data, SLE-related clinical, laboratory data, Systemic Lupus Activity Measure (SLAM) index, and nerve conduction studies were done. This case–control study compared clinical and SLE-related features, laboratory, and SLAM index in patients with SLE with PN versus those without neuropathy. Results The results showed that the most common PN subtype was sensorimotor polyneuropathy which occurred in 18 (60%) patients; the most common PN pathology was axonal degeneration, which occurred 19 (63.3%) patients; and the most common associated nerve entrapment was carpal tunnel syndrome in 10 (33.3%) patients. In comparison between group I (SLE with PN) and group II (SLE without PN), there was no statistically significant difference between the two groups regarding demographic data, disease duration, and lupus clinical features, except malar rash and lupus nephritis, which showed significant increase in patients with SLE with PN compared with patients with SLE without PN (P=0.003 and P<0.001, respectively). There was no statistically significant difference among PN subtype groups regarding sex, age, and immunological markers. Regarding diseases activity, SLAM index showed a significant increase in patients with SLE with PN compared with patients with SLE without PN (P=0.006). Conclusion The pattern of neuropathy in SLE is mainly axonal. Moreover, the most common PN subtype is sensorimotor polyneuropathy. The study suggests significant association of PN in patients with SLE with nephritis, malar rash, and SLAM index.


Introduction
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with wide scope of clinical introductions. It affects both the central nervous system (CNS) and the peripheral nervous system (PNS). The American College of Rheumatology proposed case definitions and classification criteria for 19 CNS and PNS syndromes observed in SLE [1]. Peripheral neuropathy (PN) is a perceived manifestation of SLE [1][2][3][4][5]. However, unique sorts of neuropathy happen in SLE, including symmetrical polyneuropathy, mononeuropathy, and cranial neuropathy [1, 3,5,6]; in addition, other dysimmune neuropathies, including (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), as well as neuropathies owing to non-SLE causes, for example, nerve entanglement or other related clutters, are additionally found in patients with SLE [7,8]. In perspective on this heterogeneity, it is obvious that the revealed commonness of neuropathy in SLE has been variable [9,10]. However, because of contrasts in the criteria used to characterize neuropathy, regardless of whether clinical or electrophysiological, studies that have fundamentally utilized electrophysiological criteria for neuropathy have frequently revealed higher prevalence rates as they incorporate various asymptomatic patients with nerve conduction abnormalities [9,10]. The clinical presentation of PN relies upon the diameter of the affected nerve, the sort of demyelinating or axonal lesions, and their acute or chronic occurrence [11]. Routine nerve conduction studies just mirror the activity of the fast conducting myelinated A nerve fibers, which are physiologically irrelevant to pain. The overwhelming neuropathic manifestations are related to abnormalities of other smaller nerve fibers. Hence, quantitative sensory testing can evaluate small nerve fiber function [12], which should be subsequently applied to patients with SLE-related PNs.
The pathogenesis of SLE-related neuropathy is obscure, and the few pathological studies of the peripheral nerves in SLE have revealed axonal degeneration, inflammatory changes, and vasculitis [13]. Typical vasculitic neuropathy, because of medium-sized vessel vasculitis, is uncommon in SLE, and this may propose the likelihood of various pathogenetic components for the different types of SLE-related neuropathy [14]. A lot of mechanisms have been cited to explain the peripheral damage in lupus. Neurogenic inflammation is interceded by the release of different neuropeptides such as calcitonin gene-related protein, substance P, nitric oxide and chemokines resulting in vasodilatation, increasing vascular porousness and cell trafficking. The major inflammatory mediators released from immune cells act on sensory neurons, inducing peripheral sensitization and hyperalgesic phenomena. In addition, after damage, this natural inflammatory response could encourage the pathogenetic activity of antineural autoantibodies, in addition to ischemic vascular mechanism, by vasa nervorum vascularitis or by microthrombi linked to antiphospholipid antibodies. The other legitimate mechanisms are immunologic cause by a direct aggression by antibodies, entraining obliteration of the peripheral nerve component [15][16][17].
In the literature, research studies on the PNS manifestations are mostly represented by case reports or case series with few patients [18]. Furthermore, the PN has not been well prescribed in SLE in terms of onset, severity, clinical associations, and electrophysiological characteristics. Therefore, more studies are necessary to characterize PN in SLE with respect to the patient's clinical lupus properties, serologic markers, disease activity, and electrophysiological data. Eighteen (60%) patients had sensorimotor polyneuropathy (the most common subtype), whereas none of the patients had acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) or CIDP or plexopathy (Table 1 and Fig. 1).

Patients and methods
Distribution of the studied cases according to pathology of peripheral neuropathy in group I (n=30) Nineteen (63.3%) patients had axonal degeneration (the most common type), one (3.33%) patient had demyelination, eight (26.6%) patients had mixed pathology (demyelination and axonal degeneration), and two (6.7%) patients had pure small fiber neuropathy (SFN) ( Table 2 and Fig. 2).
Comparison among peripheral neuropathy subtypes regarding demographic data (sex and age) in group I There was no statistically significant difference among PN subtypes regarding sex and age (Table 4).

Comparison among peripheral neuropathy subtypes regarding immunological markers in group I
There was no statistically significant difference among PN subtype groups regarding ANA, APLs, C3, C4, anti-dsDNA, and MMP9 (Table 5).  There was no statistically significant difference between the two studied groups regarding sex, age, weight, height, and BMI (Table 6 and Figs 4 and 5).
Comparison between systemic lupus erythematosus with peripheral neuropathy (group I) and systemic lupus erythematosus without peripheral neuropathy (group II) regarding disease duration The disease duration in group I ranged from 3 to 240 months, with median of 36 months. In group I, it ranged from 4 to 168 months, with median of 36 months. There was no statistically significant difference between the two studied groups regarding disease duration (Table 7). Malar rash showed a significant increase in group I compared with group (Table 8 and Fig. 6).
In group I, 17 (56.7%) patients had nephritis, in comparison with four (13.3%) patients in group I. Nephritis showed a significant increase in group I compared with group (Table 8 and Fig. 6).  NC, nerve conduction; SFN, small fiber neuropathy.

Figure 2
Distribution of the studied cases according to pathology of PN in group I (n=30). PN, peripheral neuropathy. 130 with median of 41.5 mm/h. There was no statistically significant difference between the two studied groups according to ESR.
The CRP in group I ranged from 0.90 to 73 with median of 6 mg/l. In group I, it ranged from 2 to 122 with median of 7.5 mg/l. There was no statistically significant difference between the two studied groups regarding CRP (Table 10).
Comparison between systemic lupus erythematosus with peripheral neuropathy (group I) and systemic lupus erythematosus without peripheral neuropathy (group II) regarding immunological markers There was no statistically significant difference between the two studied groups regarding ANA, APLs, C3, C4, and anti-dsDNA (Table 11).

Discussion
The American College of Rheumatology proposed cases definitions and classification criteria for 19 CNS and PNS syndromes observed in SLE [1]. PN is a perceived manifestation of SLE [1][2][3][4][5]. The clinical presentation of PN relies upon the diameter of the affected nerve, the type of demyelinating or axonal damage, and their acute or chronic event [11]. The pathogenesis of SLE-related neuropathy is obscure, and the few pathological studies of the peripheral nerves in SLE have revealed axonal degeneration, inflammatory changes, and vasculitis [13], which may propose the likelihood of various pathogenetic components for the different types of SLE-related neuropathy [14].
The etiopathogenesis of PN relies upon its subtype. Mononeuropathy multiplex develops owing to vasculitic damage to vasa nervosum. Wallerian degeneration of nerve fibers is due to ischemic localized infarction caused by vasculitis, whereas sensory neuropathy is a disorder caused by sensory neurons involvement within the dorsal root ganglion. The degeneration is associated with an inflammatory T-cell reaction driven mainly by a cell-mediated immune response. In fact, nerve biopsy can be invasive and may lead to neurological complications and histological findings can be helpful only in difficult circumstances where nerve conduction studies are noncontributive [11]. If electrodiagnostic studies are normal, small-fiber neuropathy may be diagnosed by quantitative sensory testing [21].
Hardly few studies have found relationship of SLErelated neuropathy with other disease activity and laboratory markers, likely to be owing to small sample size as well as the incorporation of a heterogeneous group of neuropathies in SLE. However, associations have been reported with disease activity and CNS contribution. This case-control study was carried out to investigate electrophysiological patterns of peripheral nerves involvements in patients having SLE in relation to the disease activity.
The results showed that the most common PN subtype is sensorimotor polyneuropathy which occurred in 18 (60%) patients, and seven (23.3%) patients had mononeuritis multiplex. Two (6.7%) patients had cranial neuropathy. Only one (3.33%) patient had sensory polyneuropathy, two (6.66%) patients had mononeuropathy (single), one (3.33%) patient had length-dependent SFN, one (3.33%) patient had non-length-dependent SFN, and four (13.3%) patients had autonomic neuropathy. None of the patients had acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) or CIDP or plexopathy. The most common PN pathology was axonal degeneration, which occurred in 19/30 (63.3%)    [27,28] which found the most frequent PN subtype was sensorimotor polyneuropathy and the most common pattern was the axonal degeneration pathology.
Mccombe et al. [29] investigated the clinical features, nerve conduction studies, and pathological findings in the sural nerves are described in seven patients with PN. The PN was of a chronic sensorimotor type with overwhelmingly sensory manifestations and gradual onset. In two cases, the presentation was asymmetric. One patient had autonomic malfunction. The histopathological characteristics in the biopsied sural nerves were those of axonal degeneration and vasculitis.
A lot of mechanisms have been reported to clarify the peripheral damage in lupus. Neurogenic inflammation is interceded by the release of different neuropeptides such as calcitonin generelated protein, substance P, nitric oxide and chemokines resulting in vasodilatation, increasing vascular porousness and cell trafficking. The major inflammatory mediators released from immune cells act on sensory neurons inducing peripheral sensitization and hyperalgesic phenomena; moreover, after an injury, this natural inflammatory response could facilitate the pathogenetic activity of antineural autoantibodies, in addition to ischemic vascular mechanism by vasa nervorum vascularitis or by microthrombi linked to antiphospholipid antibodies. The other legitimate mechanisms are: immunologic effect by a direct antibodies aggression, entraining destruction of the peripheral nerve component [15][16][17].
In this study, only one patient showed evidence of subclinical neuropathy. In contradiction to this result, Goh et al. [26] stated that the subclinical PN is common in patients with SLE. Moreover, Fathalla and El-Badawy [30] investigated the association of subclinical autonomic and PN with SLE. Pure sensory, mixed sensory-motor abnormalities were detected in two patients. SSR Table 4 Comparison among peripheral neuropathy subtypes regarding demographic data (sex and age) in group I

Subtypes of PN [n (%)]
Test of significance P Sensory polyneuropathy was not elicited in 13 of 43 patients, whereas latency and amplitude abnormalities were detected in 11 of 43 and 9 of 43 patients, respectively. The sympathetic nervous system was affected in up to 40% of patients with lupus according to the study by Fathalla and El-Badawy [30].
This study did not show that frequency of subclinical PN in patients with SLE and the percentage of sympathetic nervous system affection was modest [four (13.3%) patients] in comparison with 40% in the study by Fathalla and El-Badawy [30]. The possible explanation is that the diagnosis of sympathetic neuropathy should be confirmed by the ACR nomenclature and case definitions for neuropsychiatric lupus syndromes after the screening by single diagnostic tool such as SSR.
Regarding common entrapment neuropathies, 10 (33.3%) patients had CTS, six (20%) patients had cubital tunnel syndrome, one (3.3%) patient had ulnar nerve compression at the wrist, one (3.3%) patient had tarsal tunnel syndrome, whereas 14 (46.66%) patients showed no evidence of entrapments. The only studied entrapment neuropathy was the carpal tunnel syndrome  Comparison between SLE with PN (group I) and SLE without PN (group II) regarding sex. PN, peripheral neuropathy; SLE, systemic lupus erythematosus.
described by Jasmin et al. [13] and Toledano et al. [22]. Jasmin et al. [13] reported a total of 17 (11.5%) patients (nine bilateral and eight unilateral) had NCS evidence of median nerve conduction slowing at the wrists indicative of CTS; in eight (5.4%) of whom, these were the only NCS abnormalities. The prevalence of carpal tunnel syndrome in the study conducted by Toledano et al. [22] was 4.2%, and it is like that found in the general population (3.8-4.9%), thus proposing that SLE is not, probably, a direct cause of this compression syndrome in most cases. The different prevalence among studies can be clarified by different CTS risk factors and socioeconomic state. Risk factors were being female, being middleaged, having a high BMI, smoking, and low socioeconomic status [31].
In this study, in comparison between group I (SLE with PN) and group II, there was no statistically significant difference between the two groups regarding demographic data, disease duration, and lupus clinical features except malar rash and lupus nephritis, which showed significant increase in group I compared with group II (P=0.003 and P<0.001, respectively).
In agreement with the current study, Florica et al. [3] reported no significant difference between SLE-related PN and non-SLE-related PN group regarding demographic and clinical information. However, patients with SLE-related PN had significantly shorter SLE disease duration and tended to be younger in contrast with those with non-SLE-related PN, whereas Jasmin et al. [13] stated that SLE-related polyneuropathy patients were significantly older (mean age 44.7 vs. 37.5 years), but had no other significant demographic or disease associations, in contrast with non-SLE-related neuropathy.
Oomatia et al. [25] compared between patients with SLE with PN and patients with SLE without PN, and in contrast to this study, those with PNs were more likely to have a history of infections (P<0.01) as well as osteoporotic fractures (P<0.01). There was no significant difference between the two studied groups regarding other clinical manifestations (malar rash and nephritis), and demographic data. In contrast, Saigal et al. [24] reported significant association of PN in patients with SLE with pyuria, pleurisy, and leucopenia, whereas Toledano et al. [22] stated that the involvement of PN occurs more frequently in patients who are diagnosed with SLE at older age and showed relation of hematological and renal manifestations in SLE with PN group.   In contradiction, Jasmin et al. [13] stated that most patients with SLE with PN did not have active disease (median SLEDAI=2) at the time of the study and no significant contributions of polyneuropathy were observed with current disease activity, number of relapses, or previous severe disease manifestations. However, this does not exclude the activity of lupus disease at the onset of neuropathy; its long-term persistence did not appear to be related to active or severe disease. This could mirror the nature of an axonal neuropathy, in which recovery from axonal denervation is usually deficient resulting in a chronic and persistent deficit. Consequently, contrasts in Comparison between SLE with PN (group I) and SLE without PN (group II) regarding diseases activity Systemic Lupus Activity Measure (SLAM) index. PN, peripheral neuropathy; SLE, systemic lupus erythematosus.   disease activity may account for differences in the frequency and spectrum of PNs.
In this study, acute-phase reactant (ESR and CRP) and immunological markers (ANA, antiphospholipid antibodies (APL), C3, C4, and anti-dsDNA) showed no statistically significant difference between SLE with PN and SLE without PN groups. These results were in agreement with Florica et al. [3], Jasmin et al. [13], and Oomatia et al. [25], which all showed no statistically significant difference between SLE with PN compared with SLE non-related PN or SLE without PN groups.
In contrast to the current results, Xianbin et al. [23] revealed that patients with SLE-PN had low serum C3 level (54.8 vs. 36.9%, P<0.05), whereas no significant difference between the two groups with respect to ANA, anti-dsDNA, and ESR. Saigal et al. [24] proposed significant association of PN in SLE patients with ESR level. These variations can be explained by the same theory of chronicity; it does not exclude disease being active at the onset of polyneuropathy; its persistence did not seem to be contributed to disease activity or severity. This could reflect the nature of an axonal neuropathy, in which recovery from axonal denervation is usually deficient resulting in a chronic disorder.

Conclusion
(1) PN is common in patients with SLE and sensorymotor polyneuropathy is the most frequent subtype. (2) The pathology of PN in SLE is mainly axonal.
(3) PN in patients with SLE is related to disease activity, lupus nephritis, and skin involvement.

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Conflicts of interest
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