Sjögren Syndrome-Associated Small Fiber Neuropathy

We conducted the current study to analyze the clinical, immunologic, and neurophysiologic features of primary Sjögren syndrome (pSS)-associated sensory small fiber neuropathies (SFNs). Forty consecutive pSS patients with SFN were included. SFN was defined by the presence of suggestive sensory painful symptoms with normal nerve conduction studies and abnormal neurophysiologic tests for small nerve fibers or a low intraepidermal nerve fiber density at skin biopsy. Included patients were compared to 100 pSS patients without peripheral neuropathy. SFN patients were mainly female (92.5%). Age at pSS diagnosis was 55.3 T 13.1 years, and at SFN diagnosis, 58.9 T 11.8 years, with a median time to SFN diagnosis after symptom onset of 3.4 years. Clinical symptoms included burning pains (90%), numbness (87.5%), tingling (82.5%), pins and needles (72.5%), electric discharges (70%), and allodynia (55%). Dysautonomia included vasomotor symptoms (66%) and hyperhidrosis (47%). Abnormal neurophysiologic tests included laser evoked potentials (97.5%), thermal quantitative sensory testing (67.5%), and sympathetic skin reflex (40%). A skin biopsy revealed low intraepidermal nerve fiber density in 76% of the 17 tested patients. Compared to the 100 pSS patients without peripheral neuropathy, the 40 pSS-SFN patients were older at pSS diagnosis (55.3 T 13.1 vs. 49.5 T 14.9 yr; p = 0.03), and more often had xerostomia (97.5% vs. 81%; p = 0.01) and arthralgia (82.5% vs. 65.0%; p = 0.04). Immunologically, they were characterized by a lower prevalence of serum B-cell activation markers, that is, antinuclear antibodies (65% vs. 85%; p = 0.01), anti-SSA (42.5% vs. 71%; p = 0.002), and anti-SSB (17.5% vs. 39%; p = 0.017); rheumatoid factor (32.5% vs. 66%; p = 0.0005); and hypergammaglobulinemia (35% vs. 62%; p = 0.005). In conclusion, we report the main features of SFN in patients with pSS, the first such study to our knowledge. Our results show that patients with pSS-associated SFN are characterized by an older age at pSS diagnosis and a distinctive immunologic profile hallmarked by a lower frequency of serum B-cell activation markers. (Medicine 2013;92: e10Ye18) Abbreviations: ANA = antinuclear antibodies, CI = confidence interval, DN4 = ‘‘Douleur Neuropathique 4’’ questionnaire, ENMG = electroneuromyographic examination, IENFD = intraepidermal nerve fiber density, LEP = laser evoked potential, MRI = magnetic resonance imaging, NCS = nerve conduction studies, OR = odds ratio, pSS = primary Sjögren syndrome, QST = quantitative sensory testing, SFN = small fiber neuropathy, SSR = sympathetic skin reflex. INTRODUCTION P rimary Sjögren Syndrome (pSS) is a systemic autoimmune disease characterized by glandular involvement and systemic extraglandular organ involvement, including skin, lung, kidney, peripheral, and central nervous system. Peripheral neurologic involvement is reported in nearly 20% of patients (range, 5%Y60%). The diagnosis is usually based on clinical neurologic symptoms and signs, and confirmed by electroneuromyographic examination (ENMG). However, conventional ENMG assesses only large nerve fibers (diameter Q5Y7 Km) and remains normal in patients with neuropathy selectively affecting the small nerve fibers (diameter G5Y7 Km), which condition is typically revealed by the occurrence of subjective sensory symptoms, mostly painful, including burning, numbness, prickling, paresthesia and dysesthesia, or signs of dysautonomia. The diagnosis of a pure small fiber neuropathy (SFN) requires specific histologic or neurophysiologic examinations. The histologic investigation is based on the evaluation of the intraepidermal nerve fiber density (IENFD) by skin biopsy after immunostaining with antineuropeptide (peptide gene product 9.5) antibodies. Neurophysiologic investigations include the recording of evoked potentials to nociceptive (laser) stimulation (LEP), quantitative sensory testing (QST) to thermal stimuli, and autonomic nervous system testing, such as sympathetic skin reflex (SSR) recording. Due to the limited availability of these procedures, SFN has scarcely been evaluated among pSS patients, and only a few series have been published to date. We previously reported 11 cases of pSSassociated SFN from a series of 120 pSS patients, which represented 30% of the 30 pSS-associated peripheral neuropathies, and 56% of the pSS-associated nonataxic sensory peripheral neuropathies. On the other hand, pSS might represent 9%Y30% of causes of pure SFN. Given the limited number of reported cases, and the lack of characterization of the main features of pSS-associated SFN, we designed a study to investigate systematically our pSS patients presenting with symptoms suggestive of SFN and having a normal ENMG. We report herein the clinical, laboratory, neurophysiologic, and histologic features of a consecutive series of 40 pSS patients whom we have characterized as having pure SFN, in comparison with a control group of 100 pSS patients e10 www.md-journal.com Medicine & Volume 92, Number 5, September 2013 From the Service de Médecine Interne 2, AP-HP, Hôpital Lariboisière, Université Paris Diderot-Paris 7, Paris (D. Sène, PJG); Service de Médecine Interne 2, AP-HP, Hôpital Pitié-Salpêtrière, Paris, Université, Pierre et Marie Curie-Paris 6, Paris (PC, JH, D. Saadoun, ZA); Centre de Référence des Maladies Neuromusculaire Garches-Necker-Mondor-Hendaye, AP-HP, Hôpital Henri Mondor; INSERM U955, Equipe 10, Université Paris EstCréteil, Créteil (FJA); and Service de Neurologie (AC) and Service de Physiologie-Explorations Fonctionnelles (JPL), APHP, Hôpital Henri Mondor, Créteil, Université Paris Est-Créteil, Créteil; France. Financial support and conflicts of interest: The authors have no funding or conflicts of interest to disclose. Reprints: Dr Damien Sène, MD, PhD, Service de Médecine Interne 2, Hôpital Lariboisière, 2 Rue Ambroise Paré 75010 Paris, France (e-mail: damien.sene)lrb.aphp.fr). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000005 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. who did not present neurologic symptoms suggestive of SFN at the time of their last clinical evaluation. PATIENTS AND METHODS Starting inMarch 2009, we set up the SFINESS study (Small Fiber Neuropathy in Sjögren Syndrome), based on a systematic clinical and neurophysiologic investigation of patients with suggestive neurologic symptoms of SFN and a normal ENMG. Until March 2012, we prospectively included 40 patients characterized as having pSS-associated SFN. For the control group, we collected 100 pSS patients whowere followed in the Pitié-Salpêtrière (Paris, France) and Lariboisière (Paris, France) tertiary university internal medicine departments, and who did not present any suggestive clinical symptom of SFN or peripheral neuropathy. All patients fulfilled the American-European Consensus Group (AECG) criteria for pSS. The study was approved by the Ile-deFrance VI (Pitié-Salpêtrière University Hospital, Paris, France) ethical committee, and each subject gave written informed consent before SFN investigation. Clinical Neurologic Investigation of Patients With pSS-Associated SFN As aforementioned, the presence of subjective sensations, mostly painful, such as burning, painful cold, electric discharge, tingling, pins and needles, numbness, or itching, was considered suggestive of SFN and recorded. Clinical examination searched for allodynia to mechanical stimuli and for objective deficit affecting any sensory modality (pain, warm, cold, touch, vibration, and proprioception), the motor system (weakness and atrophy), or the tendon reflexes (especially ankle jerks). All patients completed a questionnaire for dysautonomic signs and the ‘‘Douleur Neuropathique 4’’ (DN4) questionnaire for the presence of neuropathic pain. Electroneuromyography (ENMG) Conventional motor and sensory nerve conduction studies (NCS) were performed in the median, ulnar, peroneal, tibial, and sural nerve territories of all patients with sensory symptoms. In addition, electromyographic activity was studied in various muscles using a standard concentric needle. Small Fiber Neurophysiologic Investigation Neurophysiologic investigation of small fibers was performed by 1 of the authors (JPL) in all patients with suggestive symptoms of SFN and a normal ENMG. The tests included the measurements of LEP (amplitude and latency) and QST (warm and cold detection thresholds) using normal values established in our laboratory, as previously described. The neurophysiologic evaluation of the autonomic system involvement was performed in all patients using the SSR (amplitude and latency) previously described. In case of abnormal results, brain and spine magnetic resonance imaging (MRI) was performed to exclude a central cause of such abnormal results. Evaluation of IENFD by Skin Biopsy The evaluation of IENFD by skin biopsy was not routinely available at the beginning of the study. Thus, only 17 patients were evaluated for IENFD by 1 of the authors (FJA). The skin biopsy was performed using a 3-mm punch at the distal leg (10 cm above lateral malleolus) and the proximal lateral thigh (15 cm below anterior superior iliac spine). The IENFD evaluation was performed on 50-Km frozen sections after visualization of axons by immunofluorescence technique with polyclonal antibodies to protein gene product 9.5, as described. The lower limit of normal values was set at 7.6/mm at the distal leg, and 12.8/mm at the thigh, as proposed by Devigili et al. Small Fiber Neuropathy Definition SFN was diagnosed when patients had clinical signs and symptoms of small fiber impairment, with distribution consistent with peripheral neuropathy (lengthor non-lengthdependent neuropathy) without any ENMG abnormalities but alteration in small fiber neurophysiologic investigation and/or reduced IENFD in skin biopsy. Exclusion Criteria Particular attention was paid to exclude patients with neuropathic pain due to alternative possible causes other than SFN. Thus, patients were excluded in the presence of 1) any clinical sign of large sensory fiber impairment (light touch and/or vibratory and/or proprioceptive sensory loss and/or absent deep tendon reflexes); 2) any clinical sign of motor fiber impairment (muscle waste and/or weakness); 3) any abnormality on sensory or motor NCS; 4) any clinical or ENMG feature of painful radiculopathy; 5) any typical presentation of fibromyalgia syndrome, based on the classical tender points, although SFN can be observed in patients with fibromyalgia syndrome; 6) any risk factor for SFN (diabetes mellitus, glucose intolerance, systemic amyloidosis, systemic vasculitis, human immunodeficiency virus (HIV) infection, alcoholism, paraneoplastic syndrome, celiac disease, B9 and B12 vitamin deficiency, and sarcoidosis). Immunochemistry Antinuclear antibodies (ANA) were detected using indirect immunofluorescence on HEp-2000 cells (Immuno Concepts, San Diego, CA), with a positive result defined as Q1:80. Antiextractable nuclear antigen antibodies (anti-ENA), including anti-SSA (anti-Ro 52/60) and anti-SSB (anti-La), were detected using a multiplexed microparticle-based Luminex immunoassay (AtheNAMulti-Lyte, Ingen, Antony, France). Serum cryoglobulin detection and immunochemical typing were performed with a validated immunoblotting method. Rheumatoid factor was determined by ELISA (BMD, France), and results 920 IU/mL were considered positive. Dosage of serum immunoglobulins (IgG, IgA, IgM) was performed by nephelometry (BNII, DadeBehring). The following laboratory parameters were used as serum markers of chronic B-cell activation: ANA, anti-SSA (Ro), anti-SSB (La), rheumatoid factors, and gammaglobulin levels. Statistical Analysis Categorical variables were compared using the Fisher exact test, and continuous variables using the Mann-Whitney test. On the basis of the results of univariate analyses, variables were included in multivariate analyses using a stepwise multiple logistic regression analysis to assess independent associations. The level of significance (p value) was set at 0.05 (2-tailed). All analyses were performed using MedCalc software version 12.3.0.0 (Mariakerke, Belgium).