Review

Peripheral nervous system involvement in systemic erythematosus: a review of the evidence

A. Bortoluzzi1, E. Silvagni1, F. Furini1, M. Piga2, M. Govoni1

1Department of Medical Sciences, Section ABSTRACT ripheral neuropathies (PN) recognises a of Rheumatology, University of Ferrara In the past years the peripheral nervous non-SLE aetiology (1). and Azienda Ospedaliero-Universitaria system (PNS) involvement in systemic The 1999 American College of Rheuma- Sant’Anna, Cona, Ferrara, Italy; lupus erythematosus (SLE) has received tology (ACR) provided the definitions 2Rheumatology Unit, University Clinic and AOU of Cagliari, Italy. little attention despite its potential sig- for 7 peripheral manifestations related nificant impact. The true prevalence of to SLE (2), but a revisiting of this clas- Alessandra Bortoluzzi, MD, PhD Ettore Silvagni, MD PNS in SLE reported in studies is vari- sification including small fibre neuropa- Federica Furini, MD able and strongly influenced by Ameri- thy has been advised by some Authors Matteo Piga, MD, PhD can College of Rheumatology (ACR) (1, 3). This review will focus on epide- Marcello Govoni, MD case definition that includes seven PNS miology, pathogenesis, diagnosis, clini- Please address correspondence to: manifestations (acute inflammatory de- cal features and treatment of peripheral Dr Alessandra Bortoluzzi, myelinating , neuropsychiatric SLE (NPSLE). Dipartmento di Scienze Mediche, autonomic disorder, mononeuropathy, Sezione di Reumatologia, myasthenia gravis, cranial neuropa- Epidemiology Azienda Ospedaliero-Universitaria thy, and ). Sant’Anna di Ferrara, The true prevalence of PNS involve- Via Aldo Moro 8, Other peripheral manifestations, such ment in SLE reported in studies is high- 44124 Cona, Italy. as chronic inflammatory demyelinating ly variable and strongly influenced by E-mail: [email protected] polyradiculoneuropathy and small fibre ACR nomenclature. The case definition Received on October 9, 2017; accepted neuropathy, not included in the ACR included acute inflammatory demyeli- in revised form on February 28, 2018. nomenclature, have not been well char- nating polyradiculoneuropathy (Guil- Clin Exp Rheumatol 2019; 37: 146-155. acterised in SLE. The aim of this review lain-Barrè syndrome, GBS), autonomic © Copyright Clinical and is to focus on epidemiology, pathogen- disorder, single/multiple mononeuropa- Experimental Rheumatology 2019. esis, diagnosis and clinical features thy, myasthenia gravis (MG), cranial of all possible different expressions of neuropathy, plexopathy and polyneu- Key words: peripheral nervous PNS involvement in SLE, with the final ropathy (2). system, neuropsychiatric lupus objective to profile the patient’s clinical The importance of the PNS involve- erythematosus, cranial neuropathy, characteristics. ment was clearly recognised once again myasthenia gravis, polyneuropathy, in the new 2012 Systemic Lupus Inter- small fibre neuropathy Introduction national Collaborating Clinics (SLICC) Systemic lupus erythematosus (SLE) classification criteria for SLE (4); here is an autoimmune-mediated disease, the neurologic criterion was substan- characterised by the production of au- tially implemented by including a larg- toantibodies and immune-complexes er number of neurologic manifestations deposition that can affect multiple or- of SLE related to a PNS involvement - gans and systems including both the like mononeuritis multiplex, peripheral central (CNS) and peripheral nervous or cranial neuropathy – not included system (PNS). in the original 1997 revised classifica- In past decades many studies have evalu- tion criteria for lupus (5). Most of the ated the CNS manifestations, while only studies that evaluated the NP involve- a limited number focused on the PNS ment in SLE, applying the 1999 ACR ones. To date, little is known about the nomenclature, are typically retrospec- actual prevalence and the demographic tive cohort and consider together the and specific immunological factors of peripheral and central involvement (4). peripheral neuro-lupus. In addition the The prevalence of PNS complications final attribution of PNS involvement to ranged between 2 and 10%, with a high- SLE is a relevant and challenging clini- er predominance of Competing interests: none declared. cal issue because up to one third of pe- (2–3%) and mononeuropathies (single

146 Clinical and Experimental Rheumatology 2019 PNS involvement in SLE / A. Bortoluzzi et al. or multiple: 0.5–1%), compared to rare Recent advances in pathogenesis tions of molecules released by nocic- or unusual events like GBS (0.1%), of PNS involvement in SLE eptors and distinct afferent stimulation MG (0.1%) and plexopathy (<0.1%) Despite significant advances in under- induced in periphery could create a (6–8). Unterman’s meta-analysis as- standing the pathogenesis, the causes chronic pain sensation (16). sessed the prevalence of NPSLE in of acute and chronic immune neuropa- the light of the publication of the 1999 thies remain largely unsolved. Reason- Autoantibodies ACR nomenclature analysing retro- ably no single pathogenetic mechanism The role of autoantibodies is a bridging spective and prospective studies. This is thought to be responsible for the va- condition between the concept of neu- work confirmed that CNS involvement riety of PNS pictures occurring in SLE. rogenic inflammation and the patho- was more frequent than the peripheral We report some conceivable emerging genesis of humoral-mediated axonal or one, accounting for the 93.1% of all key concepts. myelin damage. neurological manifestations. The rarest Nodes of Ranvier may be a vulnerable events were plexopathy, GBS, MG and Neurogenic inflammation target for due to the in- autonomic dysfunction (7). Neurogenic inflammation is mediated trinsic elevated number of potential an- More recent studies have focused on by the release of different neuropep- tigens and because of the crucial perme- the selective involvement of PNS. In tides such as calcitonin gene-related ability of blood- barrier in nodal the study of Oomatia (1), in addition protein, substance P, nitric oxide and and juxtaparanodal structures (Fig. 1). to complying with the ACR criteria for chemokines resulting in vasodilatation, A process of molecular mimicry may act NPSLE, patients had to meet the defini- increasing vascular permeability and as the starting motif to target different tions of provid- cell trafficking (Fig. 1) (11, 12). A key specific antigens within nerve structure. ed by the Task Force of the American communication between immune cells Carbohydrate sequences of the glyco- Academy of and the Ameri- and nociceptors is through cytokines. conjugate-related glycolipids of myelin can Academy of Physical Medicine and Upon activation of cytokine receptors, membrane are present in the lipopoly- Rehabilitation. The prevalence of PNS signal transduction pathways are ac- saccharide fraction of microorganism involvement was 6% (123/2097 of the tivated in sensory neurons leading to such as Campylobacter jejuni, Hae- patients), with 67% of the events (82 downstream phosphorylation of mem- mophilus influenzae and Mycoplasma of 123) attributable to SLE. Among the brane proteins including transient re- pneumoniae. Autoantibodies can explain peripheral neuropathies, the axonal pat- ceptor potential ion channels and volt- part of the pathogenesis of both axonal tern was the most frequent, observed in age-gated channels. In humans, an in- and demyelinating forms of GBS, where 46 cases (56.1%) divided into sensory creased number of proinflammatory cy- many of these glyconjugates act as tar- polyneuropathy (19 cases; 23.2%), sen- tokines (IL-1-beta, IL-6, TNF-alpha) is get antigens (17–19) resulting in a block sorimotor polyneuropathy (21 cases; reported in nerve biopsy from patients of neuronal voltage-gated sodium chan- 25.6%) and mononeuritis (6 cases; with painful neuropathies, especially nels (20). In PNSLE manifestations the 7.3%). In this study, close attention was in patients with vasculitic neuropathies positivity of anti-ganglioside antibodies paid to small fibre involvement, not in- (13). IL-1-beta and TNF-alpha are di- is frequent (15–24% of reactivity espe- cluded in the original ACR nomencla- rectly sensed by nociceptors which ex- cially to a monosialoganglioside) (21). ture, but resulting more frequent than press the cognate receptors and induce The role of routinely assessed autoanti- others and demonstrated by skin biopsy activation of map kinases leading to bodies is conflicting. In a case-control in 17.1% of patients (14 of 82). Toleda- increased membrane excitability. The study on asymptomatic cranial involve- no et al. (9) reported an overall preva- mediators released from sensory neu- ment in SLE, Gaber et al. (22) reported lence of PNS involvement of 13.5% in rons in periphery directly attract and an association with anti-ribosomal-P their SLE cohort, with 36.6% of pa- activate immune innate cells (dendrit- antibodies (odds ratio [OR] 5.4, 95% tients presenting with polyneuropathy ic, mast cells) and adaptative immune confidence interval [CI] 1.002–1.03, (mainly sensory-motor axonal polyneu- cells such as T lymphocites. Nerve p=0.002), anti-dsDNA (OR 1.01, ropathy) and 23.7% of mononeuropathy growth factor and prostaglandin E2 are 95%CI 1.2–24.8, p=0.032) and altered / mononeuritis multiplex; only manifes- major inflammatory mediators released electrophysiological testing (electrical tations included in ACR nomenclature from immune cells that act on sensory blink reflex, visually and brainstem au- were recorded in this study. Florica neurons inducing peripheral sensitisa- ditory evoked potentials). Conversely et al. have found a similar prevalence tion and hyperalgesic phenomena (14). other studies did not find an association of sensory (25%) and sensory-motor Moreover after an injury, this natural with antinuclear antibodies, anti double- (20%) axonal polyneuropathy (10). In inflammatory response could facilitate stranded DNA (anti-dsDNA), antiphos- this cohort, the prevalence of chronic the pathogenetic activity of anti-neural pholipid antibodies or low complement inflammatory demyelinating polyradic- autoantibodies (Fig. 1) (15). (1, 10). uloneuropathy (CIDP), another mani- Whilst the cascade of autoimmune re- festation not included in the ACR case sponse activation targeting PNS struc- Histopathology definition, was more frequent (5.3% of ture remains elusive, it is reasonable Histological studies demonstrated peri- the cases) than in other reports. to hypothesise that different combina- vascular mononuclear or T-cells infil-

Clinical and Experimental Rheumatology 2019 147 PNS involvement in SLE / A. Bortoluzzi et al.

Fig. 1. Pathogenesis of peripheral nervous system involvement in systemic lupus erythematosus. Different pathogenetic mechanisms could explain large and small fibre neuropathy. The figure illustrates some emerging key concepts. Neurogenic inflammation: (1) In humans, an increased number of proinflammatory cytokines (IL-1-Beta, IL-6, TNF-alpha) is reported in nerve biopsy from patients with painful neuropathies, especially in patients with vasculitic neuropathies. IL-1-Beta, IL-6, TNF-alpha are directly sensed by nociceptors which express the cognate receptors. Nociceptors can release different neuropeptides such as calcitonin gene-related protein and substance P resulting in vasodilatation and increasing vascular permeability. (2) The mediators released from sensory neurons in periphery directly attract and activate immune in- nate cells (dendritic, mast cells) and adaptative immune cells such as T lymphocytes. Autoantibodies: (3) Nodes of Ranvier may be, interestingly, a vulnerable target for autoimmunity due to the intrinsically elevated number of potential antigens and because of the crucial permeability of blood nerve barrier in nodal and juxtaparanodal structures. A process of molecular mimicry may act as the starting motif to target different specific antigens within nerve structure. Mechanisms implicated in small fibre neuropathy (4) Length-dependent small fibre neuropathy: immunoglobulin deposit on the surface of and the activation of dermal vascular endothelium lead to decreased intraepidermal nerve fibre density of unmyelinated fibres. (5) Non-length-dependent gan- glionopathy: the hypothesised pathogenetic mechanisms include the presence of anti DRG-antibodies, apoptosis of the DRG nucleus or axons and reduced apoptosis of anti-neuronal directed T-cell. DRG, dorsal root ganglion; IL-1β, interleukin 1-beta; IL-6, interleukin-6; TNF-α, tumour necrosis factor alpha. trates in polyneuropathies (23) and a Risk factors and attribution for whole PNS events judged not-SLE re- -associated pattern of ischae- PNS involvement in SLE lated. Mononeuritis multiplex was most mic and inflammatory damage in vas- In SLE, the correct attribution of NP likely to be SLE-related in agreement culitic neuropathy (24-26). events is of outstanding importance for with the new classification criteria for In SLE patients, sparse histopathologic the patient’s care and also to define both SLE that deemed this kind of manifes- data reported chronic axonal degenera- pathogenic mechanisms and therapeutic tation to be very specific. tion with reduction of myelinated and de- interventions (28-30). Oomatia report- Among clinical and demographic data, myelinated fibre density, demyelination, ed that from a total of 123 SLE patients comparing patients with and without inflammatory changes with mononuclear with PNS manifestations, 33.3% were PNS involvement, an older age at onset infiltration among nerve fibres, immune not attributable to SLE, due to other of the disease and a higher SLICC/ACR complexes deposition and vasculitis with non-SLE aetiologies like infectious or Damage Index (SDI) are traits that are thickening of the vessel wall, cellular in- metabolic (1). Florica et al. (10) report- associated with PNS involvement at- filtration and intimal changes (27). ed a similar result with 39.6% of the tributed to SLE (1, 10).

148 Clinical and Experimental Rheumatology 2019 PNS involvement in SLE / A. Bortoluzzi et al.

Polyneuropathy Table I. Classification of large fibre neuropathy. Large fibre neuropathy are divided by Classification of large fibre neuropathy electrodiagnostic studies into axonal or demyelinating neuropathies, and fuction- By damaged structure By functional involvement By pattern of trunk nerve involvement ally in sensory, motor or sensorimotor - axonal - sensory - polyneuropathy (1). The pattern of trunk nerve involve- - demyelinating - motor - multineuropathy (multiple mononeuropathy) ment defines the distinction in poli-, mul- - sensorimotor - mononeuropathy ti- and mononeuropathy (Table I). Polyneuropathy is the most frequent up, which suggested adopting a mainte- or more nerves could be concomitantly PNS manifestation in SLE, inducing nance therapy. affected (41). The involvement of the altered sensitivity, atrophic changes or medial longitudinal fascicle is also de- pain. Muscle strength is typically in- Cranial neuropathy scribed in SLE, resulting in internuclear volved later in the process, with weak- Optic neuropathy (II cranial nerve - ophthalmoplegia (42). VI CN is the most ness of toes extension, ankle dorsiflex- CN), the most frequent cranial neuropa- frequently affected among oculomotors ion (enhanced by walking on heels) and thy described in SLE (about 1% in SLE (40). A micro-thrombotic vasculopathy altered proprioception causing frequent cohorts), will not be discussed because related to antiphospholipid antibodies falls. The most common form in SLE it is part of CNS (as well as the olfac- has been advocated as a possible patho- is a symmetric distal axonal sensory or tory nerve). genetic mechanism; viral be- sensorimotor neuropathy. The axonal Most common cranial neuropathies are, fore developing clinical signs are some- forms typically follow a classic stock- in order of frequency, the eighth, the times reported. An overall good clinical ing-glove pattern of distribution with a oculomotor (third, fourth and sixth), outcome for CN neuropathies has been slow proximal spreading. the fifth and seventh nerve pairs (33). reported (40). Treatment protocols re- The diagnosis of polyneuropathy im- In the Florica cohort 12.5% (26 pts) quire glucocorticoids alone (at 1 mg/kg plies a combination of clinical symp- of the PNS-SLE were found to have a per day of prednisone equivalents) or toms, signs and electrodiagnostic find- concomitant cranial neuropathy, with a in combination with cyclophosphamide ings. Nerve conduction studies (NCS) rare involvement of III, V, VI and VII in refractory cases (34, 43) (Table IV). and needle are essen- CN (10), data confirmed by Xianbin et Relapses may occur and a maintenance tial to make a correct differential diag- al. (12.7% of PNS manifestations) (8). therapy is useful, using long-term corti- nosis and to monitor response to therapy. Hanly et al. reported a prevalence rang- costeroids and chronic immunosuppres- In axonal forms, treatment guidelines ing from 4.3 to 7.4% of all NP events sant regimens; anticoagulation can be suggest to use neurotrophic agents (tri- (38). Brey et al. described a 2.2% over- considered in antiphospholipid-positive cyclic antidepressants, serotonin-norep- all prevalence in their SLE population patients (33, 41) (Table IV). PEX is a inephrine reuptake inhibitors, as dulox- (39), with the predominance of trigemi- useful therapeutic approach in progres- etine and venlafaxine and anticonvulsi- nal involvement. sive palsy (44). A number of retrospec- vants such as gabapentin and pregabalin The differential diagnosis of cranial tive studies described several cases of (31, 32)) and glucocorticoids (33). Car- neuropathies includes , spontaneous recovery of oculomotor bamazepine is used in refractory cases. neuro-sarcoidosis, MG, and mid-brain involvement (45). The association of immunosuppressant or base-of-skull pathologic processes therapies (azathioprine, mycophenolate (2); diagnostic workup for CN involve- Mononeuropathy single/multiple mofetil, cyclophosphamide) should be ment in SLE involves electrodiag- Non-compression mononeuropathy is considered in severe forms (34) while nostic studies (electromyography and a vasculitic neuropathy characterised high dose intravenous immunoglobu- electroneurography). Blink reflex can by the damage in one or more (multi- lins (IVIG), plasma exchange (PEX), or be examined to investigate functional plex forms) nerves. Vasculitic insult in- rituximab are reserved to selected and integrity of V and VII CN; Hess chart volves vasa nervorum with subsequent refractory cases (35) (Table IV). The could help in distinguishing the correct Wallerian degeneration of nerve fibres only controlled clinical trial designed oculomotor involvement. secondary to ischaemic infarction due in SLE patients for severe neuropathy VIII is the most frequently affected CN to occlusion of blood vessels caused by showed that intravenous cyclophos- in SLE, resulting in both symptomatic leukocytoclastic vasculitis. Endoneuri- phamide treatment was more effective and asymptomatic sensorineural hear- al immune complex deposition in sural than pulses of steroids (36), but only 7 ing defects (22). Deafness or sudden nerve biopsy in SLE neuropathy patient cases of polyneuropathy were enrolled. sensorineural hearing loss, dtziness and would suggest their possible role in the Stojanovich confirmed the efficacy of tinnitus are the most common symp- demyelinating process and axonal dam- a low-dose regimen of cyclophospha- toms (40). age (27). A positive association with mide versus methylprednisolone in PNS Oculomotor involvement causes di- antiphospholipid antibody and cryoglo- manifestations (37), but more than 50% plopia or blurred vision (nausea and bulinaemia is also suggested (17, 46). of the patients, previously improved, vomiting could be present) with pupil Clinically mononeuropathy can mani- had a subsequent relapse during follow- diameter alterations in some cases; one fest as “” in case of radial

Clinical and Experimental Rheumatology 2019 149 PNS involvement in SLE / A. Bortoluzzi et al. involvement or “foot drop” in presence occasionally described in association tion and debris-laden macrophages in of sciatic or peroneal involvement, but with SLE (55–57). Diagnostic criteria endoneurium are enhanced (61). Elec- manifestations can also occur in other include supportive evidence by nerve trophysiological studies (including sen- nerves like tibial, ulnar and medial conduction block, slowing of conduc- sory and motor nerve conduction stud- (47). Electrophysiology usually shows tion velocity and prolongation of distal ies), spine magnetic resonance imaging a typical focal or multifocal pattern of latency. Nerve conduction abnormali- (MRI) and CSF analysis support the involvement. As suggested by EULAR ties may be subtle in early stages and diagnosis, while nerve biopsy is useful recommendations for the management may need repetition (2). Given the in selected cases (59). of NPLSE, specific therapy depends usual post-infectious nature of the dis- Randomised controlled trials demon- upon the nature of the underlying patho- ease, the first therapeutic approach for strated the effectiveness of glucocorti- genetic process (33). The reduction of the GBS involves the use of high dose coids, IVIG, and plasmapheresis in up inflammation around the epineurium is IVIG or PEX, in addition to respira- to two-thirds of CIDP (62, 63), but stud- the primary goal of treatment. Induc- tory and cardio-respiratory supporting ies are needed to characterise prelimi- tion therapy includes systemic gluco- measures. Otherwise, steroids and im- nary patterns of response to treatment. corticoids, IV cyclophosphamide (48); munosuppressants like cyclophospha- IVIG represent the first-line treatment; in refractory cases, rituximab, IVIG, mide could be an important treatment in IVIG-resistant diseases a response to PEX, azathioprine or mycophenolate option in lupus-related GBS (58). PEX was found in 66% of cases and to mofetil as a maintenance therapy have Chronic inflammatory demyelinating glucocorticoids in 58% of cases (64). been used (49) (Table IV). polyradiculoneuropathy (CIDP) is an Among 6 patients with CIDP second- immune-mediated non-length-depend- ary to SLE (65), Vina et al. found an Inflammatory demyelinating ent neuropathy (prevalence of 1–7 per improvement greater than 50% (in sub- poliardiculoneuropathy 100,000 people) characterised by pro- jective report of everyday function and Acute inflammatory demyelinating gressive symmetric or asymmetric de- objective neurological examination) in polyradiculoneuropathy or GBS is an myelinating polyneuropathy (although patients treated with IVIG within 1 year acute, inflammatory and demyelinat- axonal variants could be present) and from onset of symptoms. Poor IVIG- ing syndrome of spinal root, peripheral albumin-cytologic dissociation on cer- responders were patients with a later and occasionally cranial nerves (2). ebro-spinal fluid (CSF) examination. IVIG course and atypical clinical pat- In a retrospective study of 1,100 GBS It was often thought to be the chronic tern. It is reasonable that a more aggres- patients, SLE was diagnosed only in 7 counterpart of GBS (59). The ACR case sive treatment approach could result in cases (50). The prevalence of GBS in definition for NPSLE does not include improving the autoimmune processes SLE patients ranges between 0.6–1.7% this condition although SLE could be on the basis of CIDP. In refractory dis- of cases, mainly during the course of an autoimmune cause of CIDP, as well eases or to reduce the need for IVIG, the disease. The pathogenesis of GBS as infections ( or C, HIV), immunosuppressants in association to as a manifestation of active SLE is not inflammatory diseases (connective tis- steroids (59) and even rituximab can be clearly defined and both cell-mediated sue diseases, inflammatory bowel dis- effective (66) (Table IV). No evidence- and humoral processes are implicated. eases, thyrotoxicosis) and other het- based guidelines are available for main- The co-occurrence with infections, fre- erogeneous conditions (lymphomas, tenance therapy that would be advisable quently observed in immunosuppressed mellitus, transplants, inherited for the majority of patients. patients, could represent another rel- neuropathies, nephrotic syndrome). evant pathogenetic factor. Autoantibod- Compared to GBS, CIDP rarely in- Small fibre neuropathy ies reacting with specific neural tissues, volves bulbar tract or autonomic system Small fibre neuropathy is frequently such as myelin components, may be and presents maximal symptoms in usu- associated with painful burning sen- produced as part of the broad spectrum ally more than eight weeks, while GBS sations; however, its association with of SLE- associated autoantibodies; re- reaches nadir within four weeks from SLE is not always defined, and this con- cently dysfunctional autophagy, a pro- the onset. Autoantibodies to Schwann dition was not included in 1999 ACR cess linked with SLE pathogenesis and cells and myelin sheath proteins are part case definitions for NPSLE. type I – Interferon production (51–53), of the pathogenetic mechanism in CIDP Causes of small fibre neuropathy are is under investigation in animal models (17); autoantigens are recognised by a multiple and heterogeneous (Table II) mimicking GBS (54). GBS is charac- phenomenon of molecular mimicry, as and no further clinical characteristics terised by rapidly progressive mono- well as in GBS (26) and neurofascin, distinguish SLE patients. Half of the phasic course (<1 month), usually with- a protein of the nodes of Ranvier, has cases reflect an idiopathic cause (67) out relapsing, determinating a progres- been identified as a possible antigenic and sometimes these symptoms could sive ascending limb weakness usually target for pathogenetic autoantibod- be confused with fibromyalgia and starting in the inferior distal extremi- ies (60). Among pathological findings chronic pain syndrome. ties. Miller-Fisher syndrome is a vari- in CIDP, segmental demyelination and Clinical assessment contemplates care- ant of GBS characterised by the triad of re-myelination, formation of “onion- ful neurological examination, aimed ophthalmoplegia, ataxia, and areflexia, bulbs” due to Schwann cells prolifera- at excluding clinical signs of large fi-

150 Clinical and Experimental Rheumatology 2019 PNS involvement in SLE / A. Bortoluzzi et al.

Table II. Causes of small fibre neuropathy (adapted from Themistocleouset al. (67)).

Primary Secondary Conditions related / matters of debate

idiopathic small fibre neuropathy impaired glucose tolerance, diabetes mellitus complex regional pain syndrome

burning mouth syndrome infections (HIV, , influenza) subtypes of fibromyalgia

genetic forms (Fabry’s disease, Tangier’s, drugs (antiretrovirals, Metronidazole, chronic pain syndrome NAv1.7 mutations, NAv1.8 mutations, Nitrofurantoin, Linezolid, Bortezomib, familial amyloid polyneuropathy) Flecainide, statins, alcohol, vitamin B6 toxicity, TNF-alpha inhibitors) autoimmune diseases (coeliac disease, painful channelopathies (inherited sarcoidosis, , SLE, Sjögren’s erythromelalgia; paroxysmal extreme pain syndrome, vasculitis, inflammatory bowel disease) disorder; familial episodic pain syndrome) chronic kidney disease restless leg syndrome vitamin B12 deficiency neurodegenerative conditions dyslipidaemia, metabolic syndrome hypothyroidism paraneoplastic syndromes monoclonal gammopathy/amyloidosis

Table III. A purpose of diagnostic criteria for small fibre neuropathy in diabetes mellitus (69).

Possible Probable Definite

presence of length-dependent symptoms presence of length-dependent symptoms, presence of length-dependent symptoms, and/or clinical signs of small fibre damage clinical signs of small fibre damage, clinical signs of small fibre damage, normal and normal sural NCS sural NCS, and altered IENF density at the ankle and/or abnormal quantitative sensory testing thermal thresholds at the foot

NCS: nerve conduction study; IENF: intraepidermal nerve fibre. bre involvement or autonomic nerv- PN when electrodiagnostic studies are degeneration in the area of maximal ous system dysfunction and to confirm normal (33). More recently, corneal vulnerability to different causes. In the positive signs as allodynia, hyperal- confocal microscopy (CCM) has been second group neuropathic pain occured gesia, hyperpathia or the presence of purposed as a diagnostic non-invasive with a patchy, asymmetric or proximal coexisting autonomic impairment with tool for early nerve damage in diabetic pattern. In skin biopsy, the proximal leg atrophy, dryness or oedema of the sur- patients (72). was unorthodoxically more affected rounding area of the skin. Standard di- Recent studies have suggested small than the distal leg, suggesting a dif- agnostic methods include Quantitative fibre neuropathies occur in SLE pa- ferent nervous target, which involves Sensory Testing (QST) and skin biopsy tients more frequently than other PNS DRG (75, 76). (Table III) (68, 69). manifestations described in ACR case Pathogenetic mechanisms of this selec- QST in a non-invasive method that ex- definitions (1), but available data are tive damage to A-delta and C-fibres are plores the function of unmyelinated and scarce. still largely unexplained; a specific im- thinly myelynated afferent nerves as- Goransson et al. (73) described a prev- munoglobulin deposit (peripherin-IgG sessing responses to pressure, pinprick, alence of 13% of SLE patients with (77) and antisulfatide antibodies (78)) vibration, heat; it requires the active biopsy-proven small fibre neuropathy. on the surface of nerves or an activa- collaboration of the subject and can- Tseng et al. found a reduction in IEN- tion of dermal vascular endothelium are not differentiate between central and FD in 82% of SLE patients, compared counted, resulting in vulnerability or peripheral causes of sensory loss (70). to healthy controls (74). Oomatia et al. apoptosis of nerves (79). Elevated pro- Skin biopsy assesses morphological al- characterised 5.9% of SLE patients with inflammatory cytokine-mediated dam- terations, investigating intraepidermal PN in their John Hopkins SLE cohort age and microglial-activation have also nerve fibre density (IENFD), showing and small fibre neuropathies occurred been advocated (80, 81) (Fig. 1). reduction in number of fibres crossing in 17.1% of cases, 6.1% length-depend- In non-length-dependent ganglionopa- the dermal-epidermal junction, but also ent and 11% non-length-dependent thy anti DRG-antibodies, apoptosis of alterations in structure of fibres and ax- (1). In the first group neuropathic pain the DRG nucleus or axons or reduced onal swelling. So far the quantification developed in the distal feet, with a apoptosis of anti-neuronal directed T- of IENFD is the efficient technique to “stocking-glove” distribution. Skin bi- cells have been described (82), (Fig. prove diagnosis, showing a decreased opsy showed decreased intraepidermal 1). Birnbaum evaluated MRI morphol- IENFD (71) and it is indicated in di- nerve fibre density of unmyelinated ogy of DRG in small fibre neuropathy, agnostic work-up of SLE patients with fibres suggesting a distal-most axonal Sjögren’s syndrome and underlined

Clinical and Experimental Rheumatology 2019 151 PNS involvement in SLE / A. Bortoluzzi et al.

Table IV. Summary of treatment options available for peripheral nervous system involvement in systemic lupus erythematosus.

PNS manifestation First-line treatment approach Treatment of refractory cases

polyneuropathy neurotrophic agents (tricyclic carbamazepine antidepressants, SNRI (duloxetine, venlafaxine), high dose IVIG, PEX, Rituximab (33,35) anticonvulsivants (gabapentin, pregabalin)) (31,32) glucocorticoids (1 mg/kg/day of prednisone equivalent) (33) severe forms: immunosuppressants (azathioprine, mycophenolate mofetil, cyclophosphamide) (33,34,36,37)

cranial neuropathy glucocorticoids (1 mg/kg/day of prednisone equivalent) cyclophosphamide (34,43) with long-term dosage reduction (33) immunosuppressants as maintenance treatment (33) spontaneous recovery possible for oculomotor anticoagulation in presence of aPL-ab (33,41) involvement (45) PEX (44)

mononeuropathy single/multiple systemic glucocorticoids (1-2 mg/kg/day of prednisone Rituximab, IVIG, PEX (49,92) equivalent or pulses of methylprednisolone 500/1000 mg mycophenolate mofetil (49) for 3-5 days with long-term dosage reduction) (33,48,49) azathioprine (49) IV cyclophosphamide (33,48,49)

acute inflammatory demyelinating high dose IVIG (58,92) glucocorticoids (1 mg/kg/day of prednisone polyradiculoneuropathy (GBS) PEX (58) equivalent or pulses of methylprednisolone cardio-respiratory supporting measures 1000 mg for 3 days) and immunosuppressants – cyclophosphamide (58)

chronic inflammatory demyelinating IVIG (62,64,65,71,92) immunosuppressants in association with polyradiculoneuropathy (CIDP) PEX (59,63) glucocorticoids (59) glucorticoids (1 mg/kg/day of prednisone Rituximab (66) equivalent) (59,62,64,65)

small fibre neuropathy neurotrophic agents (tricyclic antidepressants, immunosuppressants (80) SNRI (duloxetine, venlafaxine), anticonvulsivants IVIG (67,84) (gabapentin, pregabalin)) (80) psychological support (67) topical anaesthetics (67) analgesics

autonomic nervous system dysfunction specific symptomatic therapy (88) IVIG, PEX (88) immunosuppressants (89)

myasthenia gravis symptomatic treatments (anticholinesterase Rituximab, eculizumab, cyclophosphamide, agents, cardio-respiratory supporting measures). IVIG, PEX (91,92) glucocorticoids (1-1.5 mg/kg/day of prednisone equivalent or pulses of 500-2000 mg of methylprednisolone for 3-5 days or 10-20 mg/day of prednisone equivalent followed by dosage increase of 5 mg/day per week until 1 mg/kg/day) plus azathioprine (91). other immunosuppressants (cyclosporine A, methotrexate, micophenolate mofetil, tacrolimus) (91).

plexopathy glucocorticoids? (94)

PNS: peripheral nervous system; SNRI: serotonin-norepinephrine reuptake inhibitors; IVIG: intravenous immunoglobulins; PEX: plasma exchange; aPL-ab: antiphospholipid antibodies; IV: intravenous; GBS: Guillain-Barrè syndrome; CIDP: chronic inflammatory demyelinating polyradiculoneuropathy. pathological alterations of ganglions, pathic small fibre neuropathy (75, 83, SLE patients (85, 86), maybe because describing an increase in their size, 84). Prognosis is characterised by slow symptoms of autonomic dysfunction T2-signal and gadolinium-enhance- progression of the disease with a chron- are non-specific and vary remarkably; ment (83). ic pain condition. moreover, tests to detect autonomic Medication includes antidepressants, dysfunction are not routinely employed anticonvulsants, topical anaesthetics Rare syndromes in clinical practice. Criteria for diag- and analgesics. Poor data are available Autonomic nervous system nosis of ANS are provided in glossary for steroidal or immunomodulatory dysfunction definition in British Isles Lupus As- therapeutical options in autoimmune There are still controversies concern- sessment Group (BILAG) index and diseases and are limited to case reports. ing the precise prevalence of autonomic by 1999 ACR classification (2, 87). Recently, a randomised controlled trial nervous system (ANS) dysfunction, The general management of ANS dys- with IVIG has been designed in idio- variously reported in 6 to 93% of all function depends on the clinical sever-

152 Clinical and Experimental Rheumatology 2019 PNS involvement in SLE / A. Bortoluzzi et al. ity. Autonomic neuropathies usually Conclusions large cohort from a single centre. Autoimmun require specific symptomatic therapy. In this review, we have examined the Rev 2017; 16: 750-5. 10. FLORICA B, AGHDASSI E, SU J, GLADMAN If an autoimmune cause of the auto- peripheral involvement in SLE, from DD, UROWITZ MB, FORTIN PR: Peripheral nomic neuropathy is found or strongly epidemiological data to pathogenetic neuropathy in patients with systemic lupus suspected, immunomodulatory therapy new evidence and the patient’s clini- erythematosus. Semin Arthritis Rheum 2011; may be considered. IVIG, plasmapher- cal profile and treatment. Although to a 41: 203-11. 11. BRAIN SD, WILLIAMS TJ: Interactions be- esis (88) and oral immunosuppressant lesser extent than CNS, PNS involve- tween the tachykinins and calcitonin gene- medications have been used success- ment is a well recognised but also un- related peptide lead to the modulation of fully (89). derestimated manifestation of NPSLE. oedema formation and blood flow in rat skin. Br J Pharmacol 1989; 97: 77-82. Damage accrual and higher age are 12. HUGHES SR, WILLIAMS TJ, BRAIN SD: Evi- Myasthenia gravis potential risk factors associated to PNS dence that endogenous nitric oxide modu- The coexistence of MG is rare in SLE involvement. Peripheral polyneuropa- lates oedema formation induced by sub- but is not coincidental and the preva- thy is the most common manifestation stance P. Eur J Pharmacol 1990; 191: 481-4. 13. LINDENLAUB T, SOMMER C: Cytokines in lence of MG in SLE is estimated at throughout the studies, followed by sural nerve biopsies from inflammatory and 1.3%, which is higher than the 0.02% cranial nerve neuropathy (7). GBS and non-inflammatory neuropathies.Acta Neuro- prevalence of MG in general population plexopathy are extremely rare in SLE pathol (Berl). 2003; 105: 593-602. (43). In most patients MG appeared first suggesting that they may reflect the 14. SKAPER SD: Nerve growth factor: a neuroim- mune crosstalk mediator for all seasons. Im- and atypical presentations are reported manifestation of a distinct and coinci- munology 2017; 151: 1-15. (90). MG expected both symptomatic dental neurologic syndrome rather than 15. KOHR D, TSCHERNATSCH M, SCHMITZ K et treatment and immunotherapy. 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