European Review for Medical and Pharmacological Sciences 2020; 24: 8151-8159 Improvement of pure sensory mononeuritis multiplex and IgG1 deficiency with sitagliptin plus Vitamin D3 M. MAIA PINHEIRO1,2, F. MOURA MAIA PINHEIRO3, L.L. PIRES AMARAL RESENDE4, S. NOGUEIRA DINIZ2, A. FABBRI5, M. INFANTE5,6,7 1UNIVAG University Center, Várzea Grande, Mato Grosso, Brazil 2Postgraduation Program in Biotechnology and Health Innovation, Professional Master Degree in Pharmacy, Anhanguera University of São Paulo, Brazil 3Hospital de Base – FAMERP, São José do Rio Preto, Brazil 4Oncovida – Oncology and Immunology Clinic, Cuiabá, Brazil 5Endocrine Unit, CTO Hospital, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy 6Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome, Italy 7UniCamillus, Saint Camillus International University of Health Sciences, Rome, Italy Abstract. – INTRODUCTION: Mononeuritis CONCLUSIONS: To the best of our knowledge, multiplex (MM) is an unusual form of peripher- this is the first case showing a remarkable clin- al neuropathy involving at least two noncontig- ical improvement of MM and selective IgG1 de- uous peripheral nerve trunks. The pure sensory ficiency achieved through a combination thera- form of MM occurs rarely. Immunoglobulin (Ig)G py with sitagliptin and vitamin D3. subclass deficiency is a clinically and genetical- ly heterogeneous disorder. Up to 50% of adults Key Words: with selective subnormal IgG1 levels or selec- Mononeuritis multiplex, Mononeuropathy multi- tive IgG1 deficiency have a concomitant auto- plex, Selective IgG1 deficiency, DPP-4 inhibitors, Sita- immune disorder. Herein, we report the case of gliptin, Vitamin D, Vitamin D3, Cholecalciferol, Hypo- a patient with MM and selective IgG1 deficiency vitaminosis D. who showed remarkable clinical improvement after 2-year combination therapy with the DPP- 4 inhibitor sitagliptin plus vitamin D3. CASE REPORT: A 49-year-old man devel- oped numbness in right hand and forearm. Af- Introduction ter 6 months, the patient developed left fore- foot numbness. Approximately 8 years later, the patient started to develop numbness also Mononeuritis multiplex (MM), also known as in the right forefoot, along with symptoms of mononeuropathy multiplex, is an unusual form of evening fatigue and occasional orthostatic hy- peripheral neuropathy, which consists of a pain- potension. The patient also reported recurrent ful, asymmetrical, asynchronous sensory and candidiasis in glans and intergluteal areas since motor neuropathy afflicting at least two non con- adolescence. Electromyoneurography of lower tiguous peripheral nerve trunks1. The disease can and upper limbs revealed the presence of mul- affect multiple peripheral nerves in random areas tiple mononeuropathies. Protein electrophore- sis showed hypogammaglobulinemia and low of the body. Although MM is necessarily a sen- 2 serum IgG1 levels. Sural nerve biopsy showed sory neuropathy , the pure sensory form of MM the presence of perineuritis. The patient was occurs rarely. diagnosed with MM due to perineuritis probably The electrophysiological diagnosis of MM secondary to IgG1 deficiency. We, then, pro- requires a side-to-side asymmetry (greater than posed combination therapy with sitagliptin and 50%) in the amplitudes of motor and somatosen- vitamin D3 in the attempt to achieve immuno- modulation. At the last follow-up visit (2 years), sory evoked potentials of two or more peripheral the patient showed persistent clinical improve- nerves. The nerve conduction velocity must be at ment, increase in IgG1 levels and normalization least 75% lower than the normal values or no more of protein electrophoresis. than 25% above the upper limit of the normal Corresponding Author: Marcelo Maia Pinheiro, MD; e-mail: [email protected] 8151 M. Maia Pinheiro, F. Moura Maia Pinheiro, L.L. Pires Amaral Resende, et al range3-6. MM is typically associated with various in vivo and in clinical settings27-29. Our group has underlying systemic disorders, including vascu- recently published a review article on the possible litis (either systemic or isolated to the nerves), synergistic immunomodulatory effects exerted by diabetes mellitus, amyloidosis, inflammatory a combination therapy based on DPP-4 inhibitors rheumatic diseases (e.g., rheumatoid arthritis, plus vitamin D3, which may have a remarkable systemic lupus erythematosus), infectious diseas- therapeutic potential in autoimmune diabetes30. es, malignancies, paraneoplastic syndromes7-10. DPP-4, also known as CD26, is a serine exopep- In some instances, perineuritis can present with tidase expressed as a cell surface antigen (DPP-4/ clinical patterns of MM11,12. In cutaneous nerve CD26) on several immune cells including T and and sural nerve biopsies, the perineuritis appears B-lymphocytes, macrophages, and natural killer as a marked thickening of the perineurium sur- cells and appears to have an important role in the rounded by a mononuclear cell infiltrate and asso- activation and differentiation of these cells31. ciated with axonal degeneration and/or prominent Herein, we report the case of a patient with axon loss, which is particularly evident at the lev- MM and selective IgG1 deficiency who expe- el of large and small myelinated fibers13. rienced remarkable clinical improvement after Other causes of neuropathy must be exclud- 2-year combination therapy with the DPP-4 in- ed to establish the diagnosis of MM, such as in- hibitor sitagliptin plus vitamin D3. fection caused by acid-fast bacilli or interstitial immunoglobulin (Ig), complement, albumin or amyloid deposition14,15. Bourque et al16 observed Case Report the presence of focal immunoglobulin G (IgG) and IgM deposits in the perineurium of the sural A 49-year-old man developed numbness in right nerve from a patient with sensorimotor perineuri- hand and forearm in May 2008. The numbness tis, thus suggesting an autoimmune origin of the was more pronounced in thumb, second finger, and disease. third finger. After 6 months, he also developed left Antibody deficiency disorders may be idio- forefoot numbness, which was more pronounced in pathic or may occur due to several causes, such as the toes. The patient did not report pain or muscle T-lymphocyte inability to signal B-lymphocytes weakness. Physical examination and laboratory or genetic defects in B-cell development resulting tests excluded the presence of diabetes, viral infec- in immature B cells that are unable to prolifer- tions or autoimmune and rheumatic diseases. The ate into mature Ig-producing B cells17. Deficiency patient had previously undergone electromyogra- of one of the IgG subclasses is a clinically and phy, but the results were not available in this time. genetically heterogeneous disorder characterized The symptoms remained stable until July 2016, by frequent or severe bacterial infections of the when the man started to develop numbness even upper and lower respiratory tract18-21. Up to 50% in the right forefoot. During the same period, the of adults with selective subnormal IgG1 levels patient also experienced evening fatigue and occa- or selective IgG1 deficiency may have concomi- sional orthostatic hypotension. He also complained tant autoimmune diseases22,23. IgG1 deficiency is of sporadic electric-shock-like pain episodes in usually associated with hypogammaglobulinemia the same areas affected by numbness, which last- because IgG1 antibodies constitue about 70% of ed only a few seconds. Moreover, he reported that the total serum IgG pool. Therefore, most of the numbness, fatigue, and symptoms of orthostat- patients with IgG1 deficiency will be classified as ic hypotension worsened substantially when he patients affected by common variable immuno- consumed alcoholic beverages. Additionally, he deficiency (CVID) if IgA levels or IgM levels (or reported recurrent candidiasis in glans and inter- both) are also reduced. IgG1 deficiency is consid- gluteal areas since adolescence. However, he did erably more frequent in adults than children24. not report recurrent respiratory infections, erectile Dipeptidyl peptidase 4 (DPP-4) inhibitors dysfunction or fecal incontinence. There was no (which are used as oral hypoglycemic agents for family history of autoimmune diseases. His parents the treatment of type 2 diabetes) and vitamin D3 are first cousins and both are affected by hyperten- (cholecalciferol), have both been shown to exert sion. His father was diagnosed with type 2 diabe- anti-inflammatory and immunomodulatory ef- tes mellitus 40 years ago and has been affected by fects in vitro25,26 , as well as in different autoim- diabetic peripheral and autonomic neuropathy for mune diseases like type 1 diabetes mellitus, auto- the past 20 years. The patient has one brother, one immune encephalomyelitis and multiple sclerosis sister, and two children, who are healthy. 8152 Improvement of pure sensory mononeuritis multiplex and IgG1 deficiency Physical examination revealed: body weight 96 osis D; reference range: 30-100 ng/mL). Electro- kg, height 181 cm (body mass index 29.3 kg/m2), lyte levels and markers of renal, liver and thyroid blood pressure 110/70 mmHg, heart rate 96 bpm. function were within the normal range. Serological Orthostatic hypotension was not observed during tests for HIV, HBV, HCV, syphilis and HTLV-I/II the physical examination. Neurological examina- were negative. The erythrocyte sedimentation rate tion revealed