Review Peripheral nervous system involvement in systemic lupus 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 polyradiculoneuropathy, neuropsychiatric SLE (NPSLE). Dipartmento di Scienze Mediche, autonomic disorder, mononeuropathy, Sezione di Reumatologia, myasthenia gravis, cranial neuropa- Epidemiology Azienda Ospedaliero-Universitaria thy, plexopathy and polyneuropathy). 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 polyneuropathies 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 autoimmunity 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-nerve 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 peripheral neuropathy 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 Neurology 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