AB0484 PROTEINASE 3–ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)–POSITIVE AND ANCA–NEGATIVE OR MYELOPEROXIDASE–ANCA–POSITIVE PATIENTS WITH GRANULOMATOSIS WITH POLYANGIITIS: DISTINCT PATIENT SUBSETS

Background:Most patients with clinical diagnoses of Granulomatosis with polyangiitis (GPA) are proteinase 3 (PR3)-ANCA positive, but a significant minority are myeloperoxidase (MPO)-ANCA positive or are negative for ANCA [1]. Several clinical and genome-wide association studies have suggested that classification based on ANCA type, i.e., PR3-ANCA positivity as opposed to MPO-ANCA positivity, may be more relevant clinically than the traditional classification based on specific diagnosis [2].Objectives:To analyze demographic feature, disease manifestations and laboratory findings of patients with PR3-ANCA positive GPA in comparison with patients ANCA-negative or MPO- ANCA positive GPA.Methods:This is a retrospective analysis of 37 patients with GPA from a single center in Ukraine observed from 2010 till the end of 2019. The clinical and demographic data, initial Birmingham vasculitis activity score (BVAS/WG), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were compared between patients with PR3-ANCA positive GPA and ANCA-negative or MPO-ANCA positive GPA.Results:Of the 37 patients analyzed, 24 (64.9%) had PR3-ANCA–positive GPA, 6 (16.2%) had MPO-ANCA–positive GPA and 7 (18.9%) had ANCA-negative GPA. ANCA–negative GPA patients were younger at diagnosis compared to PR3-ANCA–positive and MPO-ANCA-positive patients (36 versus 47 and 49 years; p = 0.04). The gender ratio was similar in patients with PR3-ANCA–positive GPA and patients with MPO-ANCA–positive GPA or ANCA-negative GPA (33% vs 38% male, p= 0.61). The ocular manifestations - conjunctivitis/episcleritis (15% vs 50%) and ear involvement - otitis, mastoiditis (0% vs 33%) occurred more often in patients with PR3-ANCA–positive GPA (p<0.05), whereas sensory peripheral neuropathy (54 % vs 21%) and Raynaud’s syndrome (31 % vs 0%) were more frequent in compared group (p<0.05). ANCA-negative patients with GPA had lower, but no significant, initial BVAS/WG score than PR3-ANCA–positive or MPO-ANCA-positive patients with GPA (17.9 versus 23.5 and 24.8; p=0.20). There were no significant differences between groups in ESR or CRP levels and in the frequency of involvement of other organs and systems.Conclusion:We demonstrate clinical differences between PR3-ANCA–positive patients with GPA and MPO-ANCA–positive or ANCA-negative patients with GPA. The eye and ear involvement are common for patients with PR3-ANCA–positive GPA. The MPO-ANCA–positive GPA or ANCA-negative GPA is characterized by higher frequency of sensory peripheral neuropathy and Raynaud’s syndrome.References:[1]Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367:214–23.[2]Finkielman JD, Lee AS, Hummel AM, Viss MA, Jacob GL, Homburger HA, et al. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med. 2007;120:643.e9–14.Disclosure of Interests: :None declared

Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

The Influence of Diabetic Foot Exercise in Sensory Peripheral Neuropathy with Monofilament Test on Diabetes Mellitus Clients

Background: Peripheral neuropathy is a long-term complication that attacks the nerves and loses the sensation of protection which affects about 50% of people with diabetes mellitus (DM). Diabetic foot exercises can help blood circulation, especially in the legs or lower limbs. This researched aimed to analyze the effect of diabetic foot exercise on sensory peripheral neuropathy in DM clients.Method: The study design used quasi-experimental pre-post test with control group. Samples were 28 respondents using purposive sampling and divided into two groups of 14 respondents each. The independent variable is diabetic foot training, and the dependent variable is peripheral sensory neuropathy. Interventions are carried out 3 times a week for 4 weeks. The research instrument was Weinstein Monofilament 10 g Semmes and a diabetic foot training checklist. Data analysis using the Wilcoxon-signed rank test and Mann Whitney test with α≤0.05.Result: The Wilcoxon-signed rank test in the treatment group showed differences in sensory peripheral neuropathy after treatment (p=0,000) and no difference in the control group (p=0.564). The Mann Whitney test results showed differences in sensory peripheral neuropathy between the treatment group and the control group after treatment p=0.039.Conclusion: Diabetic foot exercises can be used as an alternative measure to improve sensory peripheral neuropathy.

Charcot neuroarthropathy of the knee due to idiopathic sensory peripheral neuropathy

Background Charcot neuroarthropathy is a systemic disease that generates pathological changes in the musculoskeletal system, causing instability, dislocations, and deformities. Charcot neuroarthropathy of the knee, due to either diabetes mellitus or syringomyelia, is anecdotally reported with the epidemic of the diseases. However, idiopathic sensory peripheral neuropathy can inflict osteoarticular structures directly, inducing a dysfunctional Charcot neuroarthropathy. An early diagnosis and effective relief of the symptomatic deformity is essential for the treatment. Case presentation We report the case of a patient with idiopathic sensory peripheral neuropathy who presented with a swelling right knee, as well as distorted and painless gait disorder, diagnosed as Charcot neuroarthropathy of the knee. Partial weight bearing with a hinged knee brace was used to correct the abnormal alignment and gait posture, and bisphosphonates were prescribed to decrease pathological bone resorption. Although the alignment and Knee Society Score got a gradual deterioration, the combination of orthosis and pharmacy could alleviate the symptom to a certain extent. Conclusion The diagnosis of Charcot neuroarthropathy of the knee is rare that requiring early diagnosis. The presence of features, including painlessness, numbness, and deformed arthropathy following chronic-onset algesthesia loss should be taken carefully.

Distal Sensory Peripheral Neuropathy in Human Immunodeficiency Virus Type 1–Positive Individuals Before and After Antiretroviral Therapy Initiation in Diverse Resource-Limited Settings

Background Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)–naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. Methods PLWH with a CD4+ count &lt;300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once. Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. Results Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P &lt; .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P &lt; .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. Conclusions Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.