Evaluation of peripheral neuropathy in lower limbs of patients with rheumatoid arthritis and its relation to fall risk

Fabio de Araújo Pereira Mariana de Almeida Lourenço Marcos Renato de Assis About the authors

Abstract

Background:

Rheumatoid Arthritis (RA) is a chronic disabling systemic disease characterized by joint inflammation, and extra-articular manifestations, including peripheral neuropathy, a condition that can be associated with changes in muscle strength, proprioception and postural balance contributing for the risk of falls. The objective of this study is to analyze the incidence of peripheral neuropathy in patients with RA and its association with the occurrence of falls.

Methods:

Patients were assessed by an electroneuromyography (ENMG) exam and by a questionnaire on accidental falls occurrence in the previous 12 months. They were also assessed on balance by the Short Physical Performance Battery (SPPB), functionality by the Health Assessment Questionnaire (HAQ), disease activity by the Disease Activity Score (DAS-28), neuropathic pain by the Questionnaire for the Diagnosis of Neuropathic Pain (DN4), and cutaneous sensitivity of the feet by the monofilament testing of Semmes–Weinstein. Monthly calls on falls were made in the subsequent six months. Data analysis was performed using the Shapiro–Wilk test for normality and Spearman, Chi-square, and T-student correlation tests, with a significant P level ≤0.05.

Results:

A sample of 33 patients were evaluated. The incidence of peripheral neuropathy was 48.5%, of which 68.7% were axonal and 31.3% myelinic. The sensorimotor type was present in 64.7%, motor in 17.6%, and sensorial in 11.7% of the cases. Neuropathy was associated to balance (P = 0.026), neuropathic pain (P =0.016), deep tendon reflexes absence (P =0,049), altered skin sensitivity of the feet (P =0.029) and fear of falling (P =0.001). No association was found between peripheral neuropathy and age, gender, disease activity, or functionality. No significant association was found between peripheral neuropathy and occurrence of falls, in a 12-month retrospective and 6-month prospective evaluation.

Conclusion:

Peripheral neuropathy has a high incidence in patients with RA, and is related to neuropathic pain, altered postural balance, but not to the occurrence of falls.

Keywords:
Rheumatoid arthritis; Peripheral nervous system diseases; Accidental falls; Postural balance

Background

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disabling disease in which synovial inflammation leads to a deforming symmetrical polyarthritis. Its prevalence in adults ranges from 0.4 to 1.3% of the general population [11 van der Woude D, van der Helm-van Mil AHM. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2018;32(2):174–87. https://doi.org/10.1016/j.berh.2018.10.005.
https://doi.org/10.1016/j.berh.2018.10.0...
33 Smolen JS, Aletaha D, Mcinnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–38. https://doi.org/10.1016/S0140-6736(16)30173-8.
https://doi.org/10.1016/S0140-6736(16)30...
].

Since the 1990s studies have shown a high risk of falls in patients with RA compared to the general population, varying between 10 and 54% in these patients [44 Brenton-Rule A, Dalbeth N, Bassett S, Menz HB, Rome K. The incidence and risk factors for falls in adults with rheumatoid arthritis: a systematic review. Semin Arthritis Rheum. 2015;44(4):389–98.66 de Lourenço MA, Roma I, de Assis MR. Falls and their association with physical tests, functional capacity, clinical and demographic factors in patients with rheumatoid arthritis. Rev Bras Reumatol. 2017;57(3):217–23.]. In the elderly population well-defined predictors to the occurrence of falls have been classified in biological, behavioral, environmental, and socioeconomic factors [77 Falsarella GR, Gasparotto LPR, Coimbra AMV. Quedas: conceitos, frequências e aplicações à assistência ao idoso: Revisão da literatura. Rev Bras Geriatr e Gerontol. 2014;17(4):897–910. https://doi.org/10.1590/1809-9823.2014.13064.
https://doi.org/10.1590/1809-9823.2014.1...
]. In RA, studies have associated some conditions, such as previous history of falling in the last year, polypharmacy, use of antidepressants, psychotropic drugs, number of comorbidities, number of painful and swollen joints, pain intensity and static balance alteration. However the evidence is limited based in only one study with conflicting results to other studies [44 Brenton-Rule A, Dalbeth N, Bassett S, Menz HB, Rome K. The incidence and risk factors for falls in adults with rheumatoid arthritis: a systematic review. Semin Arthritis Rheum. 2015;44(4):389–98.].

Peripheral neuropathy often shortened to neuropathy, is a general term describing damage to the neuronal cells and fibers with variable causes, including compression, toxic, genetic, metabolic, and connective tissue diseases [88 England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363(9427):2151–61., 99 Martyn CN, Hughes RA. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry. 1997;62(4):310–8. https://doi.org/10.1136/jnnp.62.4.310.
https://doi.org/10.1136/jnnp.62.4.310...
]. Neuropathy has been identified as an important risk factor for falls in the elderly population [1010 Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk factor for falls. J Gerontol Ser A Biol Sci Med Sci. 1995;50(4):211–5.]. In RA, Hart et al. [1111 Hart FD, Golding JR, Mackienzie DH. Neuropathy in rheumatoid disease. Ann Rheum Dis. 1957;16(4):471–80.] began investigating the relationship between peripheral neuropathy and RA, but only in 1965, Good et al. [1212 Good AE, Cristopher RP, Koepke GH, Bender LF. Peripheral neuropathy associated with rheumatoid arthritis. Ann Intern Med. 1965;63(1):87–99.], performed the first study using Electroneuromyography (ENMG) to access neuropathy in RA, showing a high incidence of neuropathy that is often subclinical. Later studies have confirmed neuropathy is frequent in RA patients and sometimes could require an ENMG exam to differentiate symptoms related to joint inflammation or neuropathy [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4.1616 Kaeley N, Ahmad S, Pathania M, Kakkar R. Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis. J Fam Med Prim care. 2019;8(1):22–6.].

A correlation between neuropathy in lower limbs and altered balance is well documented as an important risk factor for falls in the general population, but no study has investigated this correlation in RA patients [77 Falsarella GR, Gasparotto LPR, Coimbra AMV. Quedas: conceitos, frequências e aplicações à assistência ao idoso: Revisão da literatura. Rev Bras Geriatr e Gerontol. 2014;17(4):897–910. https://doi.org/10.1590/1809-9823.2014.13064.
https://doi.org/10.1590/1809-9823.2014.1...
, 1717 Winter D. Human balance and posture control during standing and walking. Gait Posture. 1995;03(4):193–214.1919 Rome K, Dixon J, Gray M, Woodley R. Evaluation of static and dynamic postural stability in established rheumatoid arthritis: exploratory study. Clin Biomech. 2009;24(6):524–6. https://doi.org/10.1016/j.clinbiomech.2009.03.005.
https://doi.org/10.1016/j.clinbiomech.20...
].

The objective of this study is to evaluate the relationship between neuropathy in lower limbs, balance, and the occurrence of falls in RA patients.

Methods

This is a cross-sectional study with Rheumatoid Arthritis outpatients from Marilia Medical School. A 6-months follow-up on falls were also performed.

Participants were selected by convenience from patients diagnosed with RA in the rheumatology outpatient clinic, by invitation during consultation or by telephone call.

Patients with rheumatoid arthritis according to the classification criteria for RA 2010 ACR/EULAR and 18 years of age or older were included, and those with cognitive impairment, lower limb amputation, uncontrolled hypothyroidism, amyloidosis, alcoholism, and renal failure on dialysis treatment were excluded.

The sample size was estimated to test the association between peripheral neuropathy and falls in patients with RA assuming a large effect size (0.50) according to the study by Richardson et al. [1010 Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk factor for falls. J Gerontol Ser A Biol Sci Med Sci. 1995;50(4):211–5.], with a study power of 80%, a type I margin of error of 5%, and one degree of freedom, resulting in the minimum sample size of 32 individuals. The sample size calculation was performed in the software G*Power, version 3.1.9.2 (Franz Faul, Universität Kiel, Germany).

Data collection was performed in the outpatient clinic from December 2019 until January 2021. After signing the Informed Consent Form, patients were submitted to questionnaires, physical examination, and clinical tests.

The patients were submitted to a neurological physical examination with assessment of deep tendon reflexes, vibratory sensitivity, and assessment of the cutaneous sensitivity of the feet with Semmes–Weinstein monofilament, and then the ENMG examination was performed.

Blood samples were collected in the same day and were analyzed at the blood center to perform the erythrocyte sedimentation rate and C-reactive protein tests.

In order to minimize information bias, the assessment of disease activity (DAS-28) was performed in all patients by the same rheumatologist, and all other tests and questionnaires and examination were performed by the same neurologist.

To minimize the recall bias, a 6 months prospective evaluation was performed with monthly phone contact questioning about falls. The calls were made by trained physicians.

Assessment instruments

Disease activity was assessed by the Disease Activity Score (DAS-28), Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI); functionality was assessed by the Health Assessment Questionnaire (HAQ) [2020 Stanford University School of Medicine. The health assessment questionnaire. Clin Exp Rheumatol. 2005; 2000:1–38., 2121 Ferraz M. Tradução para o português e validação do questionário para avaliar a capacidade funcional “Stanford health assessment questionnaire” [Tese - Doutorado]. 1990. http://repositorio.unifesp.br/handle/11600/13967.
http://repositorio.unifesp.br/handle/116...
]; neuropathic pain by the Questionnaire for Diagnosis of Neuropathic Pain (DN4) [2222 Santos JG, Brito JO, de Andrade DC, Kaziyama VM, Ferreira KA, Souza I, et al. Translation to Portuguese and validation of the douleur neuropathique 4 Questionnaire. J Pain. 2010;11(5):484–90.]; and balance by the Short Physical Performance Battery—SPPB [2323 Nakano MM, Diogo MJDe, Filho WJ. Versão brasileira da short physical performance battery-SPPB: adaptação cultural e estudo de confiabilidade. Intergovernmental Panel on Climate Change, editor. Vol. 67, Universidade Estadual de Campinas Faculdade de Educação. [Campinas]; 2007.].

Clinical neurological examination

Patellar and Achilles deep tendon reflexes was performed bilaterally with Babinski's hammer, and vibratory sensitivity was examined on the lateral knee prominences and malleolus bilaterally with a 128 Hz tuning fork, according to standard neurological semiology.

Skin sensitivity was examined with Semmes–Weinstein monofilament [2424 Souza A, Augusto C, Nery DS, Helena L, Camargo S, José A. Avaliação da neuropatia periférica : correlação entre a sen- sibilidade cutânea dos pés, achados clínicos e eletroneuro- miográficos Evaluation of diabetic neuropathy : correlation between cuta- neous sensibility in the feet, clinical and eletroneuromyo. Acta Fisiátrica. 2005;12(2):87–93.] on specific territories as shown in Fig. 1.

Fig. 1
Visual representation of the cutaneous points for sensitivity assessment. From Souza et al. [2323 Nakano MM, Diogo MJDe, Filho WJ. Versão brasileira da short physical performance battery-SPPB: adaptação cultural e estudo de confiabilidade. Intergovernmental Panel on Climate Change, editor. Vol. 67, Universidade Estadual de Campinas Faculdade de Educação. [Campinas]; 2007.]

Neurophysiological evaluation by electroneuromyography test was performed with a NIHON-KOHDEN MEB-9400 K (Tokyo, Japan) device in the lower limbs. Sural nerve sensory conduction, and fibular and tibial nerves motor conduction were analyzed by the Quantitative EMG software QP-946BK (Tokyo, Japan). Skin temperature was maintained between 31 and 34 °C. Sensory conduction was studied antidromically on the sural nerve bilaterally.

Motor conduction in the tibial nerve was studied through orthodromic stimulation in the ankle and popliteal fossa, and uptake in the abductor hallucis brevis muscle, including F-waves. Orthodromic motor conduction was studied on the fibular nerve with stimulation at the ankle and below the head of the fibula, and uptake in the extensor digitorum brevis muscle, including F-wave. All amplitudes were determined on a base-to-peak value basis. Peak latency and onset latency were measured for the sensory nerve action potential (SNAP) and compound motor action potential (CMAP), respectively. The conduction velocity of each nerve was measured. Myography was performed with a concentric needle, assessing insertion activity, resting activity, and response to spontaneous contraction in the medial gastrocnemius, tibialis anterior, rectus femoris, and extensor digitorum brevis muscles bilaterally. Neuropathy was determined according to the parameters defined by Preston [2525 Preston D, Shapiro B. Electromyography and neuromuscular disorders. Electromyography and neuromuscular disorders. 2013. p. 1–7. https://doi.org/10.1016/B978-1-4557-2672-1.00041-6%5Cnpapers2://publication/doi/10.1016/B978-1-4557-2672-1.00041-6.
https://doi.org/10.1016/B978-1-4557-2672...
].

The fall occurrence was assessed by a semi-structured questionnaire, previously approved, and used by this group to study RA patients. The number and the characterization of the falls in the previous 12 months were recorded. Monthly phone calls were made in the following six months to prospectively assess the occurrence of falls.

Statistical analysis

The comparison between two independent groups was performed by the Student's t-test for unpaired samples based on the homogeneity of variances observed in Levene's test.

The association between qualitative variables was analyzed by the Chi-square association test. The Odds ratio for falling was calculated and analyzed using the 95% confidence interval (95%CI). The normality distribution was analyzed by the Shapiro–Wilk test.

The correlation between number of falls, fear of falling and SPPB with the study variables was performed by Spearman's test. The quantitative variables that showed significant correlation were represented in the scatter plot and analyzed by the linear R2, which represents the explanation factor, indicating the percentage of variation of the dependent variable (y-axis) explained by the variation of the independent variable (x-axis).

SPSS software version 19.0 for Windows was used, with a significance level of 5%.

Results

The complete evaluation was performed in 33 RA patients and the selection of participants is shown in Fig. 2.

Fig. 2
Flowchart of sample selection

The excluded patients were, 7 for dementia, 12 for alcoholism, 3 for dialysis, and 2 for amputation of lower limbs. There was a high number of refusals to the ENMG exam due to the possibility of unpleasant symptoms related to electric shocks and needle insertion. There where tree dropouts, two caused by refusals and one compromised by a high degree of obesity compromising exam quality. ENMG after having performed the other tests. The sample characteristics are described in Table 1.

Table 1
Rheumatoid arthritis patients sample characteristic

Among the patients, 23 were using immunobiological disease course modifying drugs (DCMD) and only 4 were using corticosteroids at the time of the evaluation. The use of benzodiazepines was reported only by 4 patients and antidepressants by 9.

Peripheral neuropathy was found in 48.5% of the patients and the characteristics of the changes in ENMG are described in Table 2.

Table 2
Electroneuromyography examination

Deep reflexes were absent in 42.4% of the cases, and 81.8% and 40.7% among them reported pain in the lower limbs, classified as neuropathic pain.

Reduced sensitivity was found in the area corresponding to the sural nerve in 72.7% of the patients, fibular in 69.6%, and posterior tibial nerve in 72.7%. The associations of peripheral neuropathy to the main variables are shown in Table 3.

Table 3
Main outcomes associated to peripheral neuropathy

Motor neuropathy, pure or combined with sensory neuropathy, was associated with longer times in the 5-repetition chair stand test (P = 0.049).

Peripheral neuropathy was not associated to diabetes (P = 0.133), disease duration (P = 0.697), disease activity (P = 0.879), functionality (P = 0.460), and to the number of falls at 12 months pre assessment (P = 0.350) and 6 months post assessment (P = 0.674).

The main individual data collected are shown in Table 4.

Table 4
Individual data collected

In the 12 months prior to the evaluation, 17 patients fell, totaling 62 episodes, only 6 patients reported more than 3 falls and 15 of them did not fall in the period. Falls occurred predominantly during the day (86.8%), at the patient's home (55.7%) being 73.5% inside the house and the others in the backyard, by tripping (59%) or slipping (21%). Most patients (85.4%) reported no injuries or minor injuries and only 6 falls led to hospital care, 4 of them for fracture.

The number of falls was significantly related to gender (P = 0.015), being higher in females, body mass index (r = 0.360, P = 0.040), use of antihypertensives (P = 0.007), and fear of falling (P = 0.030).

Fear of falling was higher in patients with neuropathic pain (P = 0.030) and with the associated symptoms of pinprick (P = 0.035) and painful cold sensation (P = 0.027).

Antidepressant was the unique drug significantly related to fear of falling (P = 0.014).

The SPPB showed a mean of 7.8 with a standard deviation of 2.21 and was worse among patients with diabetes mellitus (P = 0.001), neuropathic pain (P = 0.018), altered sural nerve sensitivity (P = 0.034), and those who used more than 4 medications (P = 0.045).

No relationship was found between balance (SPPB) and the number of falls in the previous 12 months.

In the six months following the evaluation 11 patients fell, totaling 30 episodes, and only 4 patients reported more than 3 falls. The falls occurred predominantly during the day (93.3%), in the patient's home (66.7%), being 76.7% inside the house and the others in the backyard, by tripping (43.3%) or slipping (30%). The majority (90%) reported no injury or minor injuries, 3 falls led to hospital care, and only one to fracture.

There was an association between falls in the previous 12 months and in the subsequent 6 months (P = 0.003); 55.6% of the patients who have fallen in the previous 12 months fell again in the subsequent 6 months.

The number of falls was significantly associated to BMI (R = 0.376, P = 0.031), but not to gender (P = 0.393), fear of falling (P = 0.117), antihypertensive (P = 0,168) and antidepressant use (P = 0.103), disease activity (P = 0.513), functionality, (P = 0,165) balance-(P = 0.145), and neuropathic pain (P = 0.871).

Patients with worse balance presented with higher disease activity with DAS-28CRP (R = − 0.408, P = 0.018) and worse functionality (R = − 0.673, P = 0.000), as shown in Figs. 3 and 4.

Fig. 3
Correlation between balance and disease activity
Fig. 4
Correlation between balance and functionality

Discussion

The prevalence of peripheral neuropathy was 48.5%, in agreement with the literature, which presents results between 17 and 72.2% depending on the methodology and the local of assessment if in upper, lower limbs or both [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4.1616 Kaeley N, Ahmad S, Pathania M, Kakkar R. Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis. J Fam Med Prim care. 2019;8(1):22–6., 2626 Biswas M, Chatterjee A, Ghosh SK, Dasgupta S, Ghosh K, Ganguly PK. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann Indian Acad Neurol. 2011;14(3):194–7.].

The findings regarding the type of neural involvement are similar to the studies by Lanzillo et al. [2727 Lanzillo B, Pappone N, Crisci C, Di Girolamo C, Massini R, Caruso G. Subclinical peripheral nerve involvement in patients with rheumatoid arthritis. Arthritis Rheum. 1998;41(7):1196–202.], Nadkar et al. [2828 Nadkar MY, Agarwal R, Samant RS, Chhugani SJ, Idgunji SS, Iyer S, et al. Neuropathy in rheumatoid arthritis. J Assoc Physicians India. 2001;49:217–20.], Bayrak et al. [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4.] and Sim et al. [22 Sim MK, Kim D-Y, Yoon J, Park DH, Kim Y-G. Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms. Ann Rehabil Med. 2014;38(2):249–55.] in which there is a predominance of the sensorimotor pattern; however, they differ from Biswas et al. [2626 Biswas M, Chatterjee A, Ghosh SK, Dasgupta S, Ghosh K, Ganguly PK. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann Indian Acad Neurol. 2011;14(3):194–7.] and Agarwal et al. [2929 Agarwal V, Singh R, Wiclaf CS, Tahlan A, Ahuja CK, et al. A clinical, electro-physiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27(7):841–4.], who found a slight predominance of the sensory pattern in relation to the sensorimotor.

Regarding the type of neuronal lesion, the findings of the present study are like those in the literature in which there is a clear predominance of axonal type lesions, although it is difficult to compare due to differences in the methods of ENMG assessment [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4., 1414 Umay EK, Gurcay E, Karsli PB, Cakci A. Sensory disturbance and polyneuropathy in rheumatoid arthritis patients with foot deformity. Rev Bras Reumatol. 2016;56(3):191–7. https://doi.org/10.1016/j.rbre.2015.08.010.
https://doi.org/10.1016/j.rbre.2015.08.0...
, 2626 Biswas M, Chatterjee A, Ghosh SK, Dasgupta S, Ghosh K, Ganguly PK. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann Indian Acad Neurol. 2011;14(3):194–7., 2727 Lanzillo B, Pappone N, Crisci C, Di Girolamo C, Massini R, Caruso G. Subclinical peripheral nerve involvement in patients with rheumatoid arthritis. Arthritis Rheum. 1998;41(7):1196–202., 2929 Agarwal V, Singh R, Wiclaf CS, Tahlan A, Ahuja CK, et al. A clinical, electro-physiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27(7):841–4.].

There was no association between age, gender and peripheral neuropathy as well as in several previous reports [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4., 1515 Aktekin LA, Gözlükaya H, Bodur H, Borman P, Köz Ö. Peripheral neuropathy in rheumatoid arthritis patients: an electroneurophysiological study. Turk J Rheumatol. 2009;24(2):62–6., 2828 Nadkar MY, Agarwal R, Samant RS, Chhugani SJ, Idgunji SS, Iyer S, et al. Neuropathy in rheumatoid arthritis. J Assoc Physicians India. 2001;49:217–20.], only the study by Sim et al. [22 Sim MK, Kim D-Y, Yoon J, Park DH, Kim Y-G. Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms. Ann Rehabil Med. 2014;38(2):249–55.] found an association between age and peripheral neuropathy.

Most of the sample was women above 50 years old, which was also found in most studies due to two to three times higher prevalence of RA in females and common age of presentation starting from the fourth decade of life [3030 Jamison M, Neuberger GB, Miller PA. Correlates of falls and fear of falling among adults with rheumatoid arthritis. Arthritis Care Res. 2003;49(5):673–80.]. Although advanced, the age range was below the age in which alterations of the peripheral nerves are known to be detected, which is from 80 years on [3131 Bouche P, Cattelin F, Saint-Jean O, Léger JM, Queslati S, Guez D, et al. Clinical and electrophysiological study of the peripheral nervous system in the elderly. J Neurol. 1993;240(5):263–8.].

No previous study had investigated the association between neuropathy in patients with RA and the occurrence of falls. However, we did not find in our study a significant correlation between peripheral neuropathy and falls.

There was no significant association between neuropathy and disease activity indices which was also reported by Biswas et al. [2626 Biswas M, Chatterjee A, Ghosh SK, Dasgupta S, Ghosh K, Ganguly PK. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann Indian Acad Neurol. 2011;14(3):194–7.], Agarwal et al. [2929 Agarwal V, Singh R, Wiclaf CS, Tahlan A, Ahuja CK, et al. A clinical, electro-physiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27(7):841–4.] and Li et al. [3232 Li Y, Jiang L, Zhang Z, Li H, Jiang L, Wang L, et al. Clinical characteristics of rheumatoid arthritis patients with peripheral neuropathy and potential related risk factors. Clin Rheumatol. 2019;38(8):2099–107.], different however from the results of Bayrak et al. [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4.] and Umay et al. [1414 Umay EK, Gurcay E, Karsli PB, Cakci A. Sensory disturbance and polyneuropathy in rheumatoid arthritis patients with foot deformity. Rev Bras Reumatol. 2016;56(3):191–7. https://doi.org/10.1016/j.rbre.2015.08.010.
https://doi.org/10.1016/j.rbre.2015.08.0...
], revealing that this is still a risk factor to be studied regarding neuropathy in patients with RA.

In the present study no association was found between peripheral neuropathy and functionality as well as in the studies by Agarwal et al. [2929 Agarwal V, Singh R, Wiclaf CS, Tahlan A, Ahuja CK, et al. A clinical, electro-physiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27(7):841–4.], Sim et al. [22 Sim MK, Kim D-Y, Yoon J, Park DH, Kim Y-G. Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms. Ann Rehabil Med. 2014;38(2):249–55.] and Umay et al. [1414 Umay EK, Gurcay E, Karsli PB, Cakci A. Sensory disturbance and polyneuropathy in rheumatoid arthritis patients with foot deformity. Rev Bras Reumatol. 2016;56(3):191–7. https://doi.org/10.1016/j.rbre.2015.08.010.
https://doi.org/10.1016/j.rbre.2015.08.0...
], only the study by Bayrak et al. [1313 Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4.] found significant relationship between neuropathy and HAQ scores.

There was a significant association between peripheral neuropathy and balance disorders, which corroborates our hypothesis that neuropathy may contribute to the risk of falls, although it is not possible to establish a causal relationship in this type of study. The association between altered sural nerve sensation and balance disorder (P = 0.034) could also corroborate this hypothesis.

As expected, it was also observed association of neuropathic pain with peripheral neuropathy (P = 0.016) and neuropathy was found in 72.2% of patients with neuropathic pain as well as in the study of Filatova and Erdes [3333 Filatova ES, Lila AM, Parfenov VA. Neuropathic pain in rheumatoid arthritis. Sovrem Revmatol. 2020;12(5):60–5.] who found it in 96%.

Reduced cutaneous sensitivity in the fibular nerve was significantly associated to peripheral neuropathy as with Souza et al. [2424 Souza A, Augusto C, Nery DS, Helena L, Camargo S, José A. Avaliação da neuropatia periférica : correlação entre a sen- sibilidade cutânea dos pés, achados clínicos e eletroneuro- miográficos Evaluation of diabetic neuropathy : correlation between cuta- neous sensibility in the feet, clinical and eletroneuromyo. Acta Fisiátrica. 2005;12(2):87–93.] who demonstrated in patients with diabetes a good correlation between the severity of neuropathy assessed by monofilament examination and the ENMG exam. These findings help to support the hypothesis that the noninvasive monofilament test may be useful in the evaluation of peripheral neuropathy in patients with RA.

The absence of deep reflexes showed significant relation with peripheral neuropathy as well as in the studies of Good et al. [1212 Good AE, Cristopher RP, Koepke GH, Bender LF. Peripheral neuropathy associated with rheumatoid arthritis. Ann Intern Med. 1965;63(1):87–99.] and Agarwal et al. [2929 Agarwal V, Singh R, Wiclaf CS, Tahlan A, Ahuja CK, et al. A clinical, electro-physiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27(7):841–4.], which was not confirmed by Yanshan et al. [3232 Li Y, Jiang L, Zhang Z, Li H, Jiang L, Wang L, et al. Clinical characteristics of rheumatoid arthritis patients with peripheral neuropathy and potential related risk factors. Clin Rheumatol. 2019;38(8):2099–107.].

No other study was found on the relationship between peripheral neuropathy and fear of falling. In the present study, fear of falling was significantly associated with peripheral neuropathy (P = 0.001), suggesting that reduced muscle strength and altered sensitivity may increase walking instability and fear of falling.

Age in this study, showed a surprisingly negative correlation with the number of falls in the previous 12 months (r = − 0.375, P = 0.032) different from that found in the general population in which age is an important risk factor [77 Falsarella GR, Gasparotto LPR, Coimbra AMV. Quedas: conceitos, frequências e aplicações à assistência ao idoso: Revisão da literatura. Rev Bras Geriatr e Gerontol. 2014;17(4):897–910. https://doi.org/10.1590/1809-9823.2014.13064.
https://doi.org/10.1590/1809-9823.2014.1...
, 3434 Khow KSF, Visvanathan R. Falls in the aging population. Clin Geriatr Med. 2017;33(3):357–68. https://doi.org/10.1016/j.cger.2017.03.002.
https://doi.org/10.1016/j.cger.2017.03.0...
]. Studies in RA found no relationship between age and falls [44 Brenton-Rule A, Dalbeth N, Bassett S, Menz HB, Rome K. The incidence and risk factors for falls in adults with rheumatoid arthritis: a systematic review. Semin Arthritis Rheum. 2015;44(4):389–98., 3333 Filatova ES, Lila AM, Parfenov VA. Neuropathic pain in rheumatoid arthritis. Sovrem Revmatol. 2020;12(5):60–5., 3535 Smulders E, Schreven C, Weerdesteyn V, Van Den Hoogen FHJ, Laan R, Van Lankveld W. Fall incidence and fall risk factors in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1795–6.]. We found a small negative association between age and falls, but the lower mobility of the older patients could be associated to a lower occurrence of falls. In the 6 months following the assessment, there was no association between the number of falls and age (R = − 0.340, P = 0.053).

The incidence of falls in the present study was 51.5% in retrospective analysis and 33.3% in 6-month prospective analysis agreeing with the literature that presents incidence from 10 to 54%, including two recent studies published 2019 and 2020 that found incidence of 52.2% and 51% respectively [3636 Zonzini Gaino J, Barros Bértolo M, Silva Nunes C, de Morais BC, Sachetto Z, Davitt M, et al. Disease-related outcomes influence prevalence of falls in people with rheumatoid arthritis. Ann Phys Rehabil Med. 2019;62(2):84–91., 3737 Mikos M, Kucharska E, Lulek AM, Klosinski M, Batko B. Evaluation of risk factors for falls in patients with rheumatoid arthritis. Med Sci Monit. 2020;26:1–9.].

Most of the falls, in both retrospective (55.7%) and prospective (66.7%) analysis occurred at home similarly to the study of Stanmore et al. (68.5%), Lourenço, Roma, and Assis [1818 Kleiner AFR, Schlittler DXDC, Sanchez-Arias MDR. O papel dos sistemas visual, vestibular, somatosensorial e auditivo para o controle postural the role of visual, vestibular, somatosensory and auditory systems for the postural control. Rev Neurociências. 2011;19(2):349–57.], and Lourenço, Carli, and Assis [2020 Stanford University School of Medicine. The health assessment questionnaire. Clin Exp Rheumatol. 2005; 2000:1–38.]. It is likely that similarly to the elderly [77 Falsarella GR, Gasparotto LPR, Coimbra AMV. Quedas: conceitos, frequências e aplicações à assistência ao idoso: Revisão da literatura. Rev Bras Geriatr e Gerontol. 2014;17(4):897–910. https://doi.org/10.1590/1809-9823.2014.13064.
https://doi.org/10.1590/1809-9823.2014.1...
, 3838 Gazibara T, Kurtagic I, Kisic-Tepavcevic D, Nurkovic S, Kovacevic N, Gazibara T, et al. Falls, risk factors and fear of falling among persons older than 65 years of age. Psychogeriatrics. 2017;17(4):215–23.], a combination of functional impairment and fear of falling reduces the patient's mobility to other environments, increasing the time staying at home where the environment is more familiar and safer.

Fear of falling was associated to the retrospective assessment of falls, as seen by Stanmore et al. [3939 Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Fall incidence and outcomes of falls in a prospective study of adults with rheumatoid arthritis. Arthritis Care Res. 2013;65(5):737–44.] and Gaino et al. [3636 Zonzini Gaino J, Barros Bértolo M, Silva Nunes C, de Morais BC, Sachetto Z, Davitt M, et al. Disease-related outcomes influence prevalence of falls in people with rheumatoid arthritis. Ann Phys Rehabil Med. 2019;62(2):84–91.], but not in the prospective one as most of the studies [66 de Lourenço MA, Roma I, de Assis MR. Falls and their association with physical tests, functional capacity, clinical and demographic factors in patients with rheumatoid arthritis. Rev Bras Reumatol. 2017;57(3):217–23., 3535 Smulders E, Schreven C, Weerdesteyn V, Van Den Hoogen FHJ, Laan R, Van Lankveld W. Fall incidence and fall risk factors in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1795–6., 4040 Marques WV, Cruz VA, Rego J, da Silva NA. The influence of physical function on the risk of falls among adults with rheumatoid arthritis. Rev Bras Reumatol. 2014;54(5):404–8. https://doi.org/10.1016/j.rbre.2014.03.019.
https://doi.org/10.1016/j.rbre.2014.03.0...
, 4141 Çakit BD, Nacir B, Erdem HR, Karagöz A, Saraçoǧlu M. Romatoid artritli hastalarda düšme korkusu, düšme riski ve disabilite. Turk J Rheumatol. 2011;26(3):217–25.]. Few patients presented repeated falls in the retrospective and prospective assessments and that could be related to the post-fall syndrome in which a reduction of overall mobility and daily activities is observed after the first fall [4242 Meyer M, Constancias F, Vogel T, Kaltenbach G, Schmitt E. Gait disorder among elderly people, psychomotor disadaptation syndrome: post-fall syndrome, risk factors and follow-up—a cohort study of 70 patients. Gerontology. 2021;67(1):17–24.].

In the present sample there was a significant positive association between BMI and the occurrence of falls, both in the retrospective and prospective evaluation, although most of the studies have not found association [3636 Zonzini Gaino J, Barros Bértolo M, Silva Nunes C, de Morais BC, Sachetto Z, Davitt M, et al. Disease-related outcomes influence prevalence of falls in people with rheumatoid arthritis. Ann Phys Rehabil Med. 2019;62(2):84–91., 4141 Çakit BD, Nacir B, Erdem HR, Karagöz A, Saraçoǧlu M. Romatoid artritli hastalarda düšme korkusu, düšme riski ve disabilite. Turk J Rheumatol. 2011;26(3):217–25., 4343 Hayashibara M, Hagino H, Katagiri H, Okano T, Okada J, Teshima R. Incidence and risk factors of falling in ambulatory patients with rheumatoid arthritis: a prospective 1-year study. Osteoporos Int. 2010;21(11):1825–33.], the largest cohort in the study by Furuya [4444 Furuya T, Yamagiwa K, Ikai T, Inoue E, Taniguchi A, Momohara S, et al. Associated factors for falls and fear of falling in Japanese patients with rheumatoid arthritis. Clin Rheumatol. 2009;28(11):1325–30.], confirmed our finding.

Most falls did not lead to serious consequences. In the 12 months prior to the assessment 17.6% of the group who fell had fractures, and 9.1% in the prospective evaluation, which agrees with the findings of most studies that have found a range between 5 and 18,3% [66 de Lourenço MA, Roma I, de Assis MR. Falls and their association with physical tests, functional capacity, clinical and demographic factors in patients with rheumatoid arthritis. Rev Bras Reumatol. 2017;57(3):217–23., 4343 Hayashibara M, Hagino H, Katagiri H, Okano T, Okada J, Teshima R. Incidence and risk factors of falling in ambulatory patients with rheumatoid arthritis: a prospective 1-year study. Osteoporos Int. 2010;21(11):1825–33.4747 Bugdayci D, Paker N, Rezvani A, Kesiktas N, Yilmaz O, Sahin M, et al. Frequency and predictors for falls in the ambulatory patients with rheumatoid arthritis: a longitudinal prospective study. Rheumatol Int. 2013;33(10):2523–7.].

Most patients reported some type of lower limb pain, being 40.7% classified as neuropathic pain, but no association was found between the risk of falls or any type of pain, in retrospective and prospective evaluation, as in other studies [3737 Mikos M, Kucharska E, Lulek AM, Klosinski M, Batko B. Evaluation of risk factors for falls in patients with rheumatoid arthritis. Med Sci Monit. 2020;26:1–9., 4444 Furuya T, Yamagiwa K, Ikai T, Inoue E, Taniguchi A, Momohara S, et al. Associated factors for falls and fear of falling in Japanese patients with rheumatoid arthritis. Clin Rheumatol. 2009;28(11):1325–30., 4545 Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Risk factors for falls in adults with rheumatoid arthritis: a prospective study. Arthritis Care Res. 2013;65(8):1251–8.]. Pain intensity measured by the visual analogue scale showed a positive relationship with falls in some studies [3535 Smulders E, Schreven C, Weerdesteyn V, Van Den Hoogen FHJ, Laan R, Van Lankveld W. Fall incidence and fall risk factors in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1795–6., 4545 Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Risk factors for falls in adults with rheumatoid arthritis: a prospective study. Arthritis Care Res. 2013;65(8):1251–8.] but this data was not evaluated in our study.

We found an association between worse balance and neuropathic pain (R = 0.450, P = 0.018), but we did not find other similar study in patients with RA.

In the present study, patients with worse balance also had worse functionality. Assessment of balance and functionality in patients with RA was found only in the study by Aydog et al. [4848 Aydoǧ E, Bal A, Aydoǧ ST, Çakci A. Evaluation of dynamic postural balance using the Biodex Stability System in rheumatoid arthritis patients. Clin Rheumatol. 2006;25(4):462–7.] who assessed dynamic balance using the Biodex Stability System platform but found no differences in HAQ between patients who completed and those who failed to complete the test. Balance was also related to measures of disease activity DAS-28ESR, DAS-28CRP and CDAI as well as in a previous study performed in our outpatient clinic and in the study by Bohler et al. [66 de Lourenço MA, Roma I, de Assis MR. Falls and their association with physical tests, functional capacity, clinical and demographic factors in patients with rheumatoid arthritis. Rev Bras Reumatol. 2017;57(3):217–23., 4949 Böhler C, Radner H, Ernst M, Binder A, Stamm T, Aletaha D, et al. Rheumatoid arthritis and falls: the influence of disease activity. Rheumatol (UK). 2012;51(11):2051–7.].

Association between balance and disease activity was not confirmed in The study by Dimachkie et al. [5050 Dimachkie MMBR. Indicators of walking speed in rheumatoid arthritis: relative influence of articular, psychosocial, and body composition characteristics. Bone. 2011;23(1):1–7.] that used 4-m walk test and the study by Aydog et al. [4848 Aydoǧ E, Bal A, Aydoǧ ST, Çakci A. Evaluation of dynamic postural balance using the Biodex Stability System in rheumatoid arthritis patients. Clin Rheumatol. 2006;25(4):462–7.] that used dynamic platform balance test.

We found a medication use median of 6, higher than severe polypharmacy criterion proposed by Kusano [5151 Kusano LTE. Prevalência da Polifarmácia em Idosos com Demência. 2009;1–111.], however, there was no relationship between the number of medications in use and the risk of falls in both retrospective and prospective evaluation, differing from the studies of Stanmore et al. [4545 Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Risk factors for falls in adults with rheumatoid arthritis: a prospective study. Arthritis Care Res. 2013;65(8):1251–8.] and Armstrong et al. [5252 Armstrong C, Swarbrick CM, Pye SR, O’Neill TW. Occurrence and risk factors for falls in rheumatoid arthritis. Ann Rheum Dis. 2005;64(11):1602–4.].

Regarding use of antihypertensive drugs and the risk of falling the odds ratio observed were 7 in the present study, 9 in the study by Hayashibara et al. [4343 Hayashibara M, Hagino H, Katagiri H, Okano T, Okada J, Teshima R. Incidence and risk factors of falling in ambulatory patients with rheumatoid arthritis: a prospective 1-year study. Osteoporos Int. 2010;21(11):1825–33.] and 2.82 in the study by Mikos et al. [3737 Mikos M, Kucharska E, Lulek AM, Klosinski M, Batko B. Evaluation of risk factors for falls in patients with rheumatoid arthritis. Med Sci Monit. 2020;26:1–9.]. The mechanism to the risk increment risk in patients with RA is not known, but in elderly orthostatic hypotension has been suggested [5353 Juraschek SP, Simpson LM, Davis BR, Beach JL, Ishak A, Mukamal KJ. Effects of antihypertensive class on falls, syncope, and orthostatic hypotension in older adults. Hypertension. 2019;74(4):1033–40. https://doi.org/10.1161/HYPERTENSIONAHA.119.13445.
https://doi.org/10.1161/HYPERTENSIONAHA....
]. There was no elevation in the risk of falls in the prospective assessment.

The use of benzodiazepines and antidepressants that are often associated with the risk of falls in the elderly and in RA [77 Falsarella GR, Gasparotto LPR, Coimbra AMV. Quedas: conceitos, frequências e aplicações à assistência ao idoso: Revisão da literatura. Rev Bras Geriatr e Gerontol. 2014;17(4):897–910. https://doi.org/10.1590/1809-9823.2014.13064.
https://doi.org/10.1590/1809-9823.2014.1...
, 5252 Armstrong C, Swarbrick CM, Pye SR, O’Neill TW. Occurrence and risk factors for falls in rheumatoid arthritis. Ann Rheum Dis. 2005;64(11):1602–4.] was not related to the number of falls in the present study, which may have been due to the small number of patients using these medications.

The duration of the disease had no correlation with the number of falls, as in several other studies [3030 Jamison M, Neuberger GB, Miller PA. Correlates of falls and fear of falling among adults with rheumatoid arthritis. Arthritis Care Res. 2003;49(5):673–80., 3535 Smulders E, Schreven C, Weerdesteyn V, Van Den Hoogen FHJ, Laan R, Van Lankveld W. Fall incidence and fall risk factors in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1795–6., 4141 Çakit BD, Nacir B, Erdem HR, Karagöz A, Saraçoǧlu M. Romatoid artritli hastalarda düšme korkusu, düšme riski ve disabilite. Turk J Rheumatol. 2011;26(3):217–25.].

Disease activity measures showed a sample with a predominance of disease in activity, with no correlation between this indexes and the number of falls evaluated retrospectively or prospectively, which agrees with several studies [3030 Jamison M, Neuberger GB, Miller PA. Correlates of falls and fear of falling among adults with rheumatoid arthritis. Arthritis Care Res. 2003;49(5):673–80., 4343 Hayashibara M, Hagino H, Katagiri H, Okano T, Okada J, Teshima R. Incidence and risk factors of falling in ambulatory patients with rheumatoid arthritis: a prospective 1-year study. Osteoporos Int. 2010;21(11):1825–33., 4444 Furuya T, Yamagiwa K, Ikai T, Inoue E, Taniguchi A, Momohara S, et al. Associated factors for falls and fear of falling in Japanese patients with rheumatoid arthritis. Clin Rheumatol. 2009;28(11):1325–30.], but was not confirmed in other studies [3636 Zonzini Gaino J, Barros Bértolo M, Silva Nunes C, de Morais BC, Sachetto Z, Davitt M, et al. Disease-related outcomes influence prevalence of falls in people with rheumatoid arthritis. Ann Phys Rehabil Med. 2019;62(2):84–91., 4545 Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Risk factors for falls in adults with rheumatoid arthritis: a prospective study. Arthritis Care Res. 2013;65(8):1251–8., 4949 Böhler C, Radner H, Ernst M, Binder A, Stamm T, Aletaha D, et al. Rheumatoid arthritis and falls: the influence of disease activity. Rheumatol (UK). 2012;51(11):2051–7.]. This shows that disease activity is still a risk factor to be studied in relation to falls in RA.

The functionality assessment showed a sample with mild disability and was not related to the number of falls in retrospective and prospective evaluation, as in several previous studies [3535 Smulders E, Schreven C, Weerdesteyn V, Van Den Hoogen FHJ, Laan R, Van Lankveld W. Fall incidence and fall risk factors in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1795–6., 4141 Çakit BD, Nacir B, Erdem HR, Karagöz A, Saraçoǧlu M. Romatoid artritli hastalarda düšme korkusu, düšme riski ve disabilite. Turk J Rheumatol. 2011;26(3):217–25., 4343 Hayashibara M, Hagino H, Katagiri H, Okano T, Okada J, Teshima R. Incidence and risk factors of falling in ambulatory patients with rheumatoid arthritis: a prospective 1-year study. Osteoporos Int. 2010;21(11):1825–33., 5252 Armstrong C, Swarbrick CM, Pye SR, O’Neill TW. Occurrence and risk factors for falls in rheumatoid arthritis. Ann Rheum Dis. 2005;64(11):1602–4.]. Some recent studies found association, including Oh et al. [5454 Oh K, Furuya T, Inoue E, Tanaka E, Ikari K, Taniguchi A, et al. A simple screening test to assess risk of falls in Japanese patients with rheumatoid arthritis: results from the IORRA cohort study. Mod Rheumatol. 2021;31(2):506–9. https://doi.org/10.1080/14397595.2020.1746016.
https://doi.org/10.1080/14397595.2020.17...
] that evaluated a large cohort with 3469 patients [3737 Mikos M, Kucharska E, Lulek AM, Klosinski M, Batko B. Evaluation of risk factors for falls in patients with rheumatoid arthritis. Med Sci Monit. 2020;26:1–9.].

We found no relationship between falls and altered balance in both retrospective and prospective evaluation, which is a controversial finding among studies even though the tests used to assess balance vary among them. The study by Lourenço, Roma, and Assis [66 de Lourenço MA, Roma I, de Assis MR. Falls and their association with physical tests, functional capacity, clinical and demographic factors in patients with rheumatoid arthritis. Rev Bras Reumatol. 2017;57(3):217–23.] showed moderate to strong correlation between SPPB and other balance tests such as the Berg Balance Scale and the Timed Up and Go Test. Kawabata et al. [5555 Kawabata K, Matsumoto T, Kasai T, Chang SH, Hirose J, Tanaka S. Association between fall history and performance-based physical function and postural sway in patients with rheumatoid arthritis. Mod Rheumatol. 2021;31(2):373–9. https://doi.org/10.1080/14397595.2020.1731134.
https://doi.org/10.1080/14397595.2020.17...
] in a study evaluating balance in patients with RA found no differences in SPPB between fallers and non-fallers, however there was a difference when only the 5-repetition chair stand test was used, suggesting that the scores in performance and/or balance could compensate the lower values of muscle strength. These findings are in line with our results, which showed longer times in the 5-repetition chair stand test in patients with any type of motor neuropathy, suggesting that motor impairment could be more important in increasing the risk of falls in patients with RA. Other finding that corroborates this hypothesis is that the major cause of falls in our sample was tripping, which can be explained by the motor impairment caused by the neuropathy leading to diminished foot dorsiflexion and hip flexion, impairments that are commonly associated to an increase in the trip related fall risk [5656 Mills PM, Barrett RS, Morrison S. Toe clearance variability during walking in young and elderly men. Gait Posture. 2008;28(1):101–7.].

One limitation of our study is the small size of the sample, caused by the recruitment difficulties imposed by the COVID-19 pandemics, so we believe a study with bigger sample could help to find associations we did not find. Prospective studies with a control group could also help to stablish causal relation between neuropathy and the other outcomes, and studies comparing a group with intervention in muscle strength of lower limbs, with a control group, could also corroborate our finding that the motor impairment caused by the neuropathy could increase the risk of falls.

Another limitation of our study was not excluding patients diagnosed with diabetes, which is known to be the main condition associated with peripheral neuropathy [2424 Souza A, Augusto C, Nery DS, Helena L, Camargo S, José A. Avaliação da neuropatia periférica : correlação entre a sen- sibilidade cutânea dos pés, achados clínicos e eletroneuro- miográficos Evaluation of diabetic neuropathy : correlation between cuta- neous sensibility in the feet, clinical and eletroneuromyo. Acta Fisiátrica. 2005;12(2):87–93.]. This choice was made to maintain a larger sample size with better external validity, since diabetes is commonly found among patients with RA with incidence ranging between 9.2% and 20.7%, as demonstrated by a recent systematic review [5757 Tian Z, McLaughlin J, Verma A, Chinoy H, Heald AH. The relationship between rheumatoid arthritis and diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Endocrinol Metab. 2021;2021:125–31.]. It must be considered that the peripheral nerve involvement caused by RA or diabetes are similar, since Good et al. [1212 Good AE, Cristopher RP, Koepke GH, Bender LF. Peripheral neuropathy associated with rheumatoid arthritis. Ann Intern Med. 1965;63(1):87–99.] observed no differences in the electrophysiological study in RA in patients with and without diabetes.

The relevance of this study is evaluating, for the first time, the relationship between peripheralneuropathy, balance and falls in patients with RA. However, no association was found and the occurrence of falls in this group of patients still needs a better determination of risk factors and predictors.

Conclusions

Peripheral neuropathy showed a high incidence in patients with RA and was associated with neuropathic pain, fear of falling, absence of tendon reflexes, alteration in the cutaneous sensitivity of the feet, and balance alteration.

Peripheral neuropathy was not associated with age, gender, disease activity, functionality, and with the occurrence of falls assessed retrospectively and prospectively.

The change in balance was associated with neuropathic pain and change in skin sensitivity of the feet, but not with the number of falls.

The occurrence of falls was associated with fear of falling, body mass index, and the use of antihypertensive drugs in retrospective evaluation and with body mass index in prospective evaluation. The occurrence of falls, in retrospective and prospective evaluation, was not associated with the duration of RA, disease activity, functionality, neuropathic pain, high number of medications, use of benzodiazepines and antidepressants.

Other studies, preferably with a larger sample, which evaluate peripheral neuropathy as a risk factor for falls in patients with RA are necessary to advance towards the knowledge of predictors and thus help prevent falls and its consequences.

  • Funding
    The authors declare no external source of funding.
  • Availability of data and materials
    The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
  • Declarations
    Ethics approval and consent to participate
    The study was approved by the Ethics Committee on Research Involving Human Beings of the Marilia Medical School (FAMEMA), on 01/01/2019 under protocol number 3676026. All individuals received verbal and written explanations and participated in the study after signing the Informed Consent Form, one copy of which was given to the participant.
  • Consent for publication
    Not applicable.
  • Publisher's Note
    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abbreviations

  • RA:  Rheumatoid arthritis;
  • ENMG:  Electroneuromyography;
  • BMI:  Body Mass Index;
  • DAS-28:  Disease Activity Score-28;
  • ESR:  Erythrocyte sedimentation rate;
  • CRP:  C-reactive protein;
  • HAQ:  Health Assessment Score;
  • DN4:  Neuropathic pain questionnaire;
  • SPPB:  Short physical performance battery;
  • SD:  Standard deviation;
  • Min:  Minimum;
  • Max:  Maximum;
  • Kg:  Kilogram.

Acknowledgements

Eduardo Federighi Baisi Chagas has worked on the statistical data analysis. Isabela Silva Souza, Isabela Badan Fernandes, Eduardo Silveira Marques Branco, Beatriz Cassarotti, Lucas de Oliveira Pinto Bertoldi, and Alana Strucker Barbosa performed the phone calls.

References

  • 1
    van der Woude D, van der Helm-van Mil AHM. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2018;32(2):174–87. https://doi.org/10.1016/j.berh.2018.10.005
    » https://doi.org/10.1016/j.berh.2018.10.005
  • 2
    Sim MK, Kim D-Y, Yoon J, Park DH, Kim Y-G. Assessment of peripheral neuropathy in patients with rheumatoid arthritis who complain of neurologic symptoms. Ann Rehabil Med. 2014;38(2):249–55.
  • 3
    Smolen JS, Aletaha D, Mcinnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–38. https://doi.org/10.1016/S0140-6736(16)30173-8
    » https://doi.org/10.1016/S0140-6736(16)30173-8
  • 4
    Brenton-Rule A, Dalbeth N, Bassett S, Menz HB, Rome K. The incidence and risk factors for falls in adults with rheumatoid arthritis: a systematic review. Semin Arthritis Rheum. 2015;44(4):389–98.
  • 5
    de Lourenço MA, Carli FVBO, de Assis MR. Characterization of falls in adults with established rheumatoid arthritis and associated factors. Adv Rheumatol (Lond, Engl). 2018;58(1):16.
  • 6
    de Lourenço MA, Roma I, de Assis MR. Falls and their association with physical tests, functional capacity, clinical and demographic factors in patients with rheumatoid arthritis. Rev Bras Reumatol. 2017;57(3):217–23.
  • 7
    Falsarella GR, Gasparotto LPR, Coimbra AMV. Quedas: conceitos, frequências e aplicações à assistência ao idoso: Revisão da literatura. Rev Bras Geriatr e Gerontol. 2014;17(4):897–910. https://doi.org/10.1590/1809-9823.2014.13064
    » https://doi.org/10.1590/1809-9823.2014.13064
  • 8
    England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363(9427):2151–61.
  • 9
    Martyn CN, Hughes RA. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry. 1997;62(4):310–8. https://doi.org/10.1136/jnnp.62.4.310
    » https://doi.org/10.1136/jnnp.62.4.310
  • 10
    Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk factor for falls. J Gerontol Ser A Biol Sci Med Sci. 1995;50(4):211–5.
  • 11
    Hart FD, Golding JR, Mackienzie DH. Neuropathy in rheumatoid disease. Ann Rheum Dis. 1957;16(4):471–80.
  • 12
    Good AE, Cristopher RP, Koepke GH, Bender LF. Peripheral neuropathy associated with rheumatoid arthritis. Ann Intern Med. 1965;63(1):87–99.
  • 13
    Bayrak AO, Demir I, Onar MK, Durmus D, Durmaz Y, Canturk F. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010;32(7):711–4.
  • 14
    Umay EK, Gurcay E, Karsli PB, Cakci A. Sensory disturbance and polyneuropathy in rheumatoid arthritis patients with foot deformity. Rev Bras Reumatol. 2016;56(3):191–7. https://doi.org/10.1016/j.rbre.2015.08.010
    » https://doi.org/10.1016/j.rbre.2015.08.010
  • 15
    Aktekin LA, Gözlükaya H, Bodur H, Borman P, Köz Ö. Peripheral neuropathy in rheumatoid arthritis patients: an electroneurophysiological study. Turk J Rheumatol. 2009;24(2):62–6.
  • 16
    Kaeley N, Ahmad S, Pathania M, Kakkar R. Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis. J Fam Med Prim care. 2019;8(1):22–6.
  • 17
    Winter D. Human balance and posture control during standing and walking. Gait Posture. 1995;03(4):193–214.
  • 18
    Kleiner AFR, Schlittler DXDC, Sanchez-Arias MDR. O papel dos sistemas visual, vestibular, somatosensorial e auditivo para o controle postural the role of visual, vestibular, somatosensory and auditory systems for the postural control. Rev Neurociências. 2011;19(2):349–57.
  • 19
    Rome K, Dixon J, Gray M, Woodley R. Evaluation of static and dynamic postural stability in established rheumatoid arthritis: exploratory study. Clin Biomech. 2009;24(6):524–6. https://doi.org/10.1016/j.clinbiomech.2009.03.005
    » https://doi.org/10.1016/j.clinbiomech.2009.03.005
  • 20
    Stanford University School of Medicine. The health assessment questionnaire. Clin Exp Rheumatol. 2005; 2000:1–38.
  • 21
    Ferraz M. Tradução para o português e validação do questionário para avaliar a capacidade funcional “Stanford health assessment questionnaire” [Tese - Doutorado]. 1990. http://repositorio.unifesp.br/handle/11600/13967
    » http://repositorio.unifesp.br/handle/11600/13967
  • 22
    Santos JG, Brito JO, de Andrade DC, Kaziyama VM, Ferreira KA, Souza I, et al. Translation to Portuguese and validation of the douleur neuropathique 4 Questionnaire. J Pain. 2010;11(5):484–90.
  • 23
    Nakano MM, Diogo MJDe, Filho WJ. Versão brasileira da short physical performance battery-SPPB: adaptação cultural e estudo de confiabilidade. Intergovernmental Panel on Climate Change, editor. Vol. 67, Universidade Estadual de Campinas Faculdade de Educação. [Campinas]; 2007.
  • 24
    Souza A, Augusto C, Nery DS, Helena L, Camargo S, José A. Avaliação da neuropatia periférica : correlação entre a sen- sibilidade cutânea dos pés, achados clínicos e eletroneuro- miográficos Evaluation of diabetic neuropathy : correlation between cuta- neous sensibility in the feet, clinical and eletroneuromyo. Acta Fisiátrica. 2005;12(2):87–93.
  • 25
    Preston D, Shapiro B. Electromyography and neuromuscular disorders. Electromyography and neuromuscular disorders. 2013. p. 1–7. https://doi.org/10.1016/B978-1-4557-2672-1.00041-6%5Cnpapers2://publication/doi/10.1016/B978-1-4557-2672-1.00041-6
    » https://doi.org/10.1016/B978-1-4557-2672-1.00041-6%5Cnpapers2://publication/doi/10.1016/B978-1-4557-2672-1.00041-6
  • 26
    Biswas M, Chatterjee A, Ghosh SK, Dasgupta S, Ghosh K, Ganguly PK. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann Indian Acad Neurol. 2011;14(3):194–7.
  • 27
    Lanzillo B, Pappone N, Crisci C, Di Girolamo C, Massini R, Caruso G. Subclinical peripheral nerve involvement in patients with rheumatoid arthritis. Arthritis Rheum. 1998;41(7):1196–202.
  • 28
    Nadkar MY, Agarwal R, Samant RS, Chhugani SJ, Idgunji SS, Iyer S, et al. Neuropathy in rheumatoid arthritis. J Assoc Physicians India. 2001;49:217–20.
  • 29
    Agarwal V, Singh R, Wiclaf CS, Tahlan A, Ahuja CK, et al. A clinical, electro-physiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27(7):841–4.
  • 30
    Jamison M, Neuberger GB, Miller PA. Correlates of falls and fear of falling among adults with rheumatoid arthritis. Arthritis Care Res. 2003;49(5):673–80.
  • 31
    Bouche P, Cattelin F, Saint-Jean O, Léger JM, Queslati S, Guez D, et al. Clinical and electrophysiological study of the peripheral nervous system in the elderly. J Neurol. 1993;240(5):263–8.
  • 32
    Li Y, Jiang L, Zhang Z, Li H, Jiang L, Wang L, et al. Clinical characteristics of rheumatoid arthritis patients with peripheral neuropathy and potential related risk factors. Clin Rheumatol. 2019;38(8):2099–107.
  • 33
    Filatova ES, Lila AM, Parfenov VA. Neuropathic pain in rheumatoid arthritis. Sovrem Revmatol. 2020;12(5):60–5.
  • 34
    Khow KSF, Visvanathan R. Falls in the aging population. Clin Geriatr Med. 2017;33(3):357–68. https://doi.org/10.1016/j.cger.2017.03.002
    » https://doi.org/10.1016/j.cger.2017.03.002
  • 35
    Smulders E, Schreven C, Weerdesteyn V, Van Den Hoogen FHJ, Laan R, Van Lankveld W. Fall incidence and fall risk factors in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1795–6.
  • 36
    Zonzini Gaino J, Barros Bértolo M, Silva Nunes C, de Morais BC, Sachetto Z, Davitt M, et al. Disease-related outcomes influence prevalence of falls in people with rheumatoid arthritis. Ann Phys Rehabil Med. 2019;62(2):84–91.
  • 37
    Mikos M, Kucharska E, Lulek AM, Klosinski M, Batko B. Evaluation of risk factors for falls in patients with rheumatoid arthritis. Med Sci Monit. 2020;26:1–9.
  • 38
    Gazibara T, Kurtagic I, Kisic-Tepavcevic D, Nurkovic S, Kovacevic N, Gazibara T, et al. Falls, risk factors and fear of falling among persons older than 65 years of age. Psychogeriatrics. 2017;17(4):215–23.
  • 39
    Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Fall incidence and outcomes of falls in a prospective study of adults with rheumatoid arthritis. Arthritis Care Res. 2013;65(5):737–44.
  • 40
    Marques WV, Cruz VA, Rego J, da Silva NA. The influence of physical function on the risk of falls among adults with rheumatoid arthritis. Rev Bras Reumatol. 2014;54(5):404–8. https://doi.org/10.1016/j.rbre.2014.03.019
    » https://doi.org/10.1016/j.rbre.2014.03.019
  • 41
    Çakit BD, Nacir B, Erdem HR, Karagöz A, Saraçoǧlu M. Romatoid artritli hastalarda düšme korkusu, düšme riski ve disabilite. Turk J Rheumatol. 2011;26(3):217–25.
  • 42
    Meyer M, Constancias F, Vogel T, Kaltenbach G, Schmitt E. Gait disorder among elderly people, psychomotor disadaptation syndrome: post-fall syndrome, risk factors and follow-up—a cohort study of 70 patients. Gerontology. 2021;67(1):17–24.
  • 43
    Hayashibara M, Hagino H, Katagiri H, Okano T, Okada J, Teshima R. Incidence and risk factors of falling in ambulatory patients with rheumatoid arthritis: a prospective 1-year study. Osteoporos Int. 2010;21(11):1825–33.
  • 44
    Furuya T, Yamagiwa K, Ikai T, Inoue E, Taniguchi A, Momohara S, et al. Associated factors for falls and fear of falling in Japanese patients with rheumatoid arthritis. Clin Rheumatol. 2009;28(11):1325–30.
  • 45
    Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, et al. Risk factors for falls in adults with rheumatoid arthritis: a prospective study. Arthritis Care Res. 2013;65(8):1251–8.
  • 46
    Graham K, Birt L, MacGregor A, Watts L, Poland F. “It's my own fault”: accounts and consequences of falling when living with rheumatoid arthritis. Musculoskelet Care. 2019;17(4):346–53.
  • 47
    Bugdayci D, Paker N, Rezvani A, Kesiktas N, Yilmaz O, Sahin M, et al. Frequency and predictors for falls in the ambulatory patients with rheumatoid arthritis: a longitudinal prospective study. Rheumatol Int. 2013;33(10):2523–7.
  • 48
    Aydoǧ E, Bal A, Aydoǧ ST, Çakci A. Evaluation of dynamic postural balance using the Biodex Stability System in rheumatoid arthritis patients. Clin Rheumatol. 2006;25(4):462–7.
  • 49
    Böhler C, Radner H, Ernst M, Binder A, Stamm T, Aletaha D, et al. Rheumatoid arthritis and falls: the influence of disease activity. Rheumatol (UK). 2012;51(11):2051–7.
  • 50
    Dimachkie MMBR. Indicators of walking speed in rheumatoid arthritis: relative influence of articular, psychosocial, and body composition characteristics. Bone. 2011;23(1):1–7.
  • 51
    Kusano LTE. Prevalência da Polifarmácia em Idosos com Demência. 2009;1–111.
  • 52
    Armstrong C, Swarbrick CM, Pye SR, O’Neill TW. Occurrence and risk factors for falls in rheumatoid arthritis. Ann Rheum Dis. 2005;64(11):1602–4.
  • 53
    Juraschek SP, Simpson LM, Davis BR, Beach JL, Ishak A, Mukamal KJ. Effects of antihypertensive class on falls, syncope, and orthostatic hypotension in older adults. Hypertension. 2019;74(4):1033–40. https://doi.org/10.1161/HYPERTENSIONAHA.119.13445
    » https://doi.org/10.1161/HYPERTENSIONAHA.119.13445
  • 54
    Oh K, Furuya T, Inoue E, Tanaka E, Ikari K, Taniguchi A, et al. A simple screening test to assess risk of falls in Japanese patients with rheumatoid arthritis: results from the IORRA cohort study. Mod Rheumatol. 2021;31(2):506–9. https://doi.org/10.1080/14397595.2020.1746016
    » https://doi.org/10.1080/14397595.2020.1746016
  • 55
    Kawabata K, Matsumoto T, Kasai T, Chang SH, Hirose J, Tanaka S. Association between fall history and performance-based physical function and postural sway in patients with rheumatoid arthritis. Mod Rheumatol. 2021;31(2):373–9. https://doi.org/10.1080/14397595.2020.1731134
    » https://doi.org/10.1080/14397595.2020.1731134
  • 56
    Mills PM, Barrett RS, Morrison S. Toe clearance variability during walking in young and elderly men. Gait Posture. 2008;28(1):101–7.
  • 57
    Tian Z, McLaughlin J, Verma A, Chinoy H, Heald AH. The relationship between rheumatoid arthritis and diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Endocrinol Metab. 2021;2021:125–31.

Publication Dates

  • Publication in this collection
    04 Apr 2022
  • Date of issue
    2022

History

  • Received
    18 Oct 2021
  • Accepted
    17 Feb 2022
  • Published
    22 Mar 2022
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