Zahedan J Res Med Sci
Zahedan J Res Med Sci

article information

Zahedan Journal of Research in Medical Sciences: Vol.24, issue 1; e108918
published online: December 8, 2021
article type: Research Article
received: August 27, 2020
revised: December 2, 2020
accepted: December 9, 2020
DOI: https://doi.org/10.5812/zjrms.108918
Crossmark

Impact of Gender and Age-at-onset on Clinical and Medical Features of Rheumatoid Arthritis in Western Algerian Population

authors:

avatar Siheme Ouali ORCID 1 , avatar Khalida Zemri ORCID 1 , avatar Khedoudja Kanoun 1 , avatar Harir Noria ORCID 1 , * , avatar Feriel Sellam ORCID 2 , avatar Zahira Benaissa 1 , avatar Sid Tadj Hebri 3 , avatar Ouassini Bensaber 4 , avatar Douniazad Elmehadji 1 , avatar Zouaoui Nadji 3

Laboratory of Molecular Microbiology, Proteomics and Health, Department of Biology, DjillaliLiabes University of Sidibel Abbes, (EX ITMA), Algeria, North Africa
National Research Center of Biotechnology (CRBt), Algeria, North Africa
Department of Internal Medicine, CHU SidiBel Abbes, Algeria, North Africa
Department of Functional Rehabilitation, CHU SidiBel Abbes, Algeria, North Africa

how to cite: Ouali S, Zemri K, Kanoun K, Noria H, Sellam F, et al. Impact of Gender and Age-at-onset on Clinical and Medical Features of Rheumatoid Arthritis in Western Algerian Population. Zahedan J Res Med Sci. 2022;24(1):e108918. https://doi.org/10.5812/zjrms.108918.

Abstract

Background:

This study aimed to demonstrate the gender and age-at-onset differences in rheumatoid arthritis (RA) in the western Algerian population and their impacts on patients' clinical features and medical management.

Methods:

A retrospective cross-sectional study was carried out at the Internal Medicine and Functional Rehabilitation Departments (University Hospital of Sidi-bel-Abbes region) based on medical records of over 306 RA patients diagnosed between 2016 and 2019 according to ACR 1987 criteria. Late-onset RA (LORA) was defined as disease onset at 51 years of age or older. All data were processed and analyzed via SPSS 22.0.

Results:

We enrolled 306 rheumatoid arthritis patients (85% women) with a mean age-at-onset of 52.47 ± 12.14. Algerian RA women were more at risk of developing type 2 diabetes (P = 0.035), hypertension (P = 0.003), and thyroid disorders (P = 0.05). We did not find any significant relationship between clinical features, laboratory data, and gender. The LORA group comprised 60.5% of our study population with a higher number of comorbidities such as hypertension (P < 0.001), osteoporosis (P = 0.007), and scleroderma (P = 0.014). Nonetheless, we found evidence of an association between positive anti-CCP, RF rate, and age-at-onset (P = 0.001 and P < 0.001, respectively).

Conclusions:

Algerian RA women with LORA presented a higher prevalence of comorbidities, while Young-onset RA (YORA) was associated with a high rate of RF.

1. Background

Rheumatoid arthritis (RA) is a common systemic autoimmune disease characterized by chronic inflammation and irreversible destruction of joints and bones (1). The disease has a prevalence of 0.5% and 1% in European and North American populations, respectively, and 0.1% in North Africa (2). It is four times more prevalent in women than men due to sex hormones and genetic predisposition (3). Several studies found that comorbidities differ between genders (3, 4). Moreover, the published data concluded different clinical aspects, including age, biological assessment, radiological damage, and comorbidities between genders (5).

Age at RA onset could be considered a criterion of poor prognosis frequently found in the literature, which explains the importance of studies and research about the effect of age-at-onset on RA development (6). As accepted, late-onset RA (LORA) usually begins after 50 to 65 years, while young-onset RA (YORA) develops between 30 to 45 years. Besides, YORA is characterized by a high rate of remission, a lower frequency of radiographic progression and functional score, a higher rate of anti-CCP and RF than LORA (7).

2. Objectives

This study aimed to investigate the gender and age at RA onset differences in the western Algerian population and their effects on clinical features and medical management of Algerian RA patients.

3. Methods

3.1. Population

This cross-sectional study was done at the level of Internal Medicine in partnership with the Functional Rehabilitation Departments of the University Hospital of Sidi-bel-Abbes region from 2016 to 2019 on the records of over 306 RA patients diagnosed according to ACR 1987 criteria. We recorded the demographic characteristics, such as sex and age, and clinical features, including disease duration, Disease Activity Score 28 (DAS28, running from 0 to 10), radiologic progression, laboratory assessment, and medication. We aimed to make a comparative study of gender and age-at-onset in RA. Besides, LORA was defined as a disease onset at 51 years of age or older.

3.2. Statistical Analysis

Our results were presented as frequencies and percentages for categorical variables using Pearson chi-square test (χ2) and means and standard deviations for continuous variables using the independent sample t test. Values are expressed as numbers (percentages) or mean ± standard deviation. Anti-CCP and rheumatoid factor (RF) ratios were compared according to age-at-onset using the correlation test. All data were processed and analyzed via SPSS 22.0 (Statistical Package for the Social Sciences, IBM Corporation; Chicago, IL, August 2013). The level of significance was set at < 5%.

4. Results

4.1. Patient Characteristics

We enrolled 306 RA patients (85% women) with a mean age of 52.47±12.14.

4.2. Gender Difference

The sample included 260 women and 46 men of comparable age-at-onset of RA (52.58 ± 2.23 and 53.65 ± 11.68 years, respectively; P = 0.58), disease duration (4.15 ± 3.93 and 4.56 ± 4.06, respectively; P = 0.52), and DAS28 (4.52 ± 1.22 and 4.63 ± 1.23, respectively; P = 0.6). Hand joints were the most reported sites of joint disorder in both genders (57.5% and 10.8%, respectively; P = 0.59). Besides, 21.2% of women had erosive RA (P = 0.87). We did not find any significant relationship between laboratory data (CRP, ESR, anti-CCP, and RF), treatment, and gender. Women presented anemia more frequently than men (21.9% vs. 1%; P = 0.004) (Table 1).

Table 1.

Clinical, Radiologic, and Laboratory Data in Rheumatoid Arthritis Patients Based on Gender

WomenMenP Value
Age-at-onset52.588 ± 2.235953.652 ± 11.68710.585
Disease duration4.158 ± 3.93414.565 ± 4.06420.52
Region0.851
Rural70 (22.9)13 (4.2)
Urban190 (62.1)33 (10.8)
Radiologic joint damage
Hands176 (57.5)33 (10.8)0.59
Wrists161 (52.6)30 (9.8)0.67
Knees146 (47.6)24 (7.8)0.61
Elbows95 (31)21 (6.9)0.24
Shoulders93 (30.4)15 (4.9)0.68
Feet77 (25.2)17 (5.6)0.32
Ankle35 (11.4)10 (3.3)0.14
Erosion65 (21.2)12 (3.9)0.87
DAS284.5286 ± 1.22904.632 ± 1.23900.6
ESR 43.446 ± 24.764143.478 ± 24.97980.25
CRP19.2303 ± 30.806213.9391 ± 12.45310.99
Anti-CCP positivity 208 (68)38 (12.4)0.68
RF positivity 209 (68.3)40 (13.1)0.29
Anemia67 (21.9)3 (1)0.004
DMARDs
Methotrexate 215 (70.3)34 (11.1)0.16
Leflunomide40 (13.1)8 (2.6)0.73

Table 2 illustrates the comorbidity profile against gender in RA. As observed, most of the men were smokers (P < 0.001). Also, 13.7% and 36.6% of patients (women) suffered from type 2 diabetes and hypertension, respectively, with a significant correlation (P = 0.035 and P = 0.003, respectively). Moreover, 5.6% of patients had lung disorders, including 4.9% of men (P < 0.001). A significant correlation was found between thyroid disorders and female gender (P = 0.05).

Table 2.

Comorbidity Profile Against Gender in Rheumatoid Arthritis Patients

WomenMenP Value
Smoking0 (0)31 (10.1)< 0.001
Type 2 diabetes42 (13.7)2 (0.7)0.035
Hypertension112 (36.6)9 (2.9)0.003
Solid neoplasia3 (1)0 (0)0.46
Osteoporosis22 (7.2)1 (0.3)0.136
Thyroid disorders20 (6.5)0 (0)0.05
Stomach ulcers7 (2.3)0 (0)0.26
Pulmonary disease2 (0.7)15 (4.9)< 0.001
Scleroderma 9 (2.9)0 (0)0.20

4.3. Age Difference

More than half of our patients (60.5%) were in the LORA group (51% women and 9.5% men; P = 0.69). The mean disease duration was 3.82 ± 3.23 in YORA against 4.47 ± 4.34 years in LORA (P = 0.16). A significant relationship was found between LORA and knee damage (P = 0.008) but not with erosion, DAS28, and ESR. Most of the patients (44.8%) in the LORA group presented positive anti-CCP and RF (P = 0.001 and P < 0.001, respectively) (Table 3). Concerning comorbidities, we noticed a dominance of hypertension, osteoporosis, and scleroderma in the LORA group (P < 0.001, P = 0.007, and P = 0.014, respectively) (Table 4).

Table 3.

Clinical, Radiologic and Laboratory Data in Rheumatoid Arthritis Patients Based on Age-at-onset

YORA (≤ 50 Years)LORA (≥ 51 Years)P Value
Age-at-onset40.529 ± 7.91960.741 ± 6.408—
Disease duration3.826 ± 3.23184.476 ± 4.34530.16
Area0.756
Rural34 (11.1)49 (16)
Urban87 (28.4)136 (44.4)
Joint damage
Hands84 (27.5)125 (40.8)0.73
Wrists80 (26.1)111 (36.3)0.28
Knees56 (18.3)114 (37.3)0.008
Elbows47 (15.4)69 (22.5)0.78
Shoulders45 (14.7)63 (20.6)0.57
Feet32 (10.5)62 (20.3)0.19
Ankle15 (9.4)30 (9.8)0.35
Erosion37 (12.1)40 (13.1)0.078
DAS284,5534 ± 1,28014,5380 ± 1,19790.91
ESR 42,5619 ± 25,101744,0324 ± 24,57720.61
CRP18,5157 ± 38,023718,3819 ± 20,89970.96
Anti-CCP positivity 109 (35.6)137 (44.8)0.001
RF positivity 112 (36.6)137 (44.8)<0.001
Anemia26 (8.5)44 (14.4)0.64
DMARDs
Methotrexate 103 (33.7)146 (47.7)0.17
Leflunomide20 (6.5)28 (9.2)0.74
Table 4.

Comorbidity Profile of Rheumatoid Arthritis Patients Against Age-at-onset

YORA (≤ 50 Years)LORA (≥ 51 Years)P Value
Smoking13 (4.2)18 (5.9)0.774
Type 2 diabetes12 (3.9)32 (10.5)0.072
Hypertension27 (8.8)94 (30.7)< 0.001
Solid neoplasia1 (0.3)2 (0.7)0.825
Osteoporosis3 (1)20 (6.5)0.007
Thyroid disorders8 (2.6)12 (3.9)0.96
Stomach ulcers2 (0.7)5 (1.6)0.548
Pulmonary disease6 (2)11 (3.6)0.712
Scleroderma 0 (0)9 (2.9)0.014

Figures 1 and 2 and Table 5 show the correlation between serological rates (anti-CCP and RF titer) and age-at-onset.

Linear correlation of Anti-CCP rates and age-at-onset of rheumatoid arthritis
Linear correlation of Anti-CCP rates and age-at-onset of rheumatoid arthritis
Figure 1.

Linear correlation of Anti-CCP rates and age-at-onset of rheumatoid arthritis

Linear correlation between RF titer and age-at-onset of rheumatoid arthritis
Linear correlation between RF titer and age-at-onset of rheumatoid arthritis
Figure 2.

Linear correlation between RF titer and age-at-onset of rheumatoid arthritis

Table 5.

Correlation Between Age-at-onset and Serological Parameters

VariablesAge-at-onset (y)
r (Correlation Coefficient)p
Anti-CCP-0.770.18
RF-0.1550.006

5. Discussion

To the best of our knowledge, the current study is the first that examines the profile of rheumatoid arthritis against gender and age-at-onset in the western Algerian population. This study aimed to evaluate the impacts of gender and age on clinical characteristics, medical management, and comorbidities of rheumatoid arthritis patients.

5.1. Gender Difference

The clinical features of RA patients vary according to sex (8). Our study demonstrated that Algerian RA women suffered from comorbidities more than men. Cross-sectional studies in Latin-American countries reported a clear female predominance (3). Ouali et al. (9) reported that most patients were women, which concords with our results and could be explained by the impact of sex hormones on the immune system (10). In the present study, we found no significant relationship between clinical variables (mean age, disease duration, and DAS28) and gender of RA patients, as confirmed by several studies (4, 11, 12). It also agrees with Barragán-Martínez et al. (3), Ahlmén et al. (13), and Coffey et al. (14) studies.

Anti-CCP and RF can be predictors of rheumatoid arthritis activity (15). Our results add to several authors' findings (4, 9, 14, 16, 17), highlighting that anti-CCP or RF titer did not differ between female and male RA patients. Similar to our prior results, erosions were not associated with gender groups (13, 14).

Anemia is a common comorbidity associated with RA (18). Agrawal et al. (19) illustrated that RA women suffered from anemia more than RA men. Our cohort found a significant correlation between anemia and female sex (P = 0.004). Besides, most RA men were smokers (P < 0.001). Our results and those of Uhlig et al. (20), Manfredsdottir et al. (21), and Ruiz-Esquide et Sanmartí (22) emphasize the relationship between smoking and RA risk in men.

Dougados et al. (23) confirmed the strong association of some comorbidities with rheumatoid arthritis. According to several data, there is a high impact of sex on RA comorbidities (24). We reported a significant gender difference according to some comorbidities. Sex hormones have a significant impact on the development of type 2 diabetes mellitus (25, 26). Accordingly, previous studies reported a significant correlation between female sex and type 2 diabetes in RA patients (4, 11), and our results confirm this association (P = 0.0035).

Medication, inflammations, and oxidative stress were the most risk factors of hypertension prevalence in RA patients (27, 28). Aurrecoechea et al. (4, 11) did not find any correlation between gender and hypertension. Other studies disagreed with this investigation (3, 29), similar to our survey (P = 0.003). On the other hand, many studies confirmed the association between RA and autoimmune thyroid disease (AITD) (30). It was reported that women are affected more than men by AITD (31), with an incidence of 4.4% (× 1,000,000) in the USA (32). Barragán-Martínez (3) affirmed that RA women are most affected by AITD, with a significant association (P = 0.005).

Our results illustrated a significant association of pulmonary disease with the men group (P < 0.001). Aurrecoechea et al. (4, 11) attempted to explain this association. Nevertheless, other investigators demonstrated pulmonary disease prevalence among males due to a genetic predisposition (33, 34).

5.2. Age Difference

We aimed to evaluate the impact of age-at-onset on RA patients' clinical and medical features. The RA incidence is relatively high in elderly-onset RA (35) due to the immunosenescence phenomenon associated with age (36). Clinical and medical management of RA differs between elderly and young subjects with RA (37), including serology, medication, and comorbidities (38-41). Our results are consistent with previous findings, but we did not observe any significant differences in disease duration (7, 42), articular erosion, and DAS28 (40, 41, 43) based on age-at-onset.

Anti-CCP was more often positive in the young-onset RA (YORA) than in the late-onset RA (LORA) groups (44), with a higher frequency of the PTPN22 T-variant (45). Our study found evidence of an association between serology status (anti-CCP and RF) and age-at-onset (P = 0.001, P < 0.001). Similarly, the results of other investigations confirmed a significant association between the anti-CCP titer and age-at-onset in RA patients (7, 9, 46). Tan et al., Chen et al., and Sparks et al. (40, 41, 47) illustrated a significant relationship between positive RF and age. However, García de Veas Silva et al. and González-Febles et al. (48, 49) did not observe any significant relationship between seropositive RA and age.

It was noted that comorbidities were more common in older subjects with a higher prevalence (50). The LORA group presented a significant association with hypertension and osteoporosis (P < 0.001) (40, 51), which is similar to the current investigation. Furthermore, the median age at diagnosis was 50 - 58 years in scleroderma (52, 53). Our study confirmed the significant relationship between LORA and scleroderma (P = 0.014).

Since this is a retrospective study, we were unable to conclude the impact of gender and age-at-onset on disease severity, RA outcome, and DMARDs choice.

5.3. Conclusions

Clinical, medical, and biological features of RA patients did not differ between genders. However, the comorbidity profile was different between women and men. Anti-CCP and RF were higher in the YORA group. Nevertheless, patients with LORA presented some comorbidities, with a significant impact. Further studies are required to prove the effects of gender and age-at-onset on specific outcomes in RA.

Acknowledgements

References

  • 1.

    Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2006;65(7):845-51. [PubMed ID: 16606649]. [PubMed Central ID: PMC1798205]. https://doi.org/10.1136/ard.2006.051391.

  • 2.

    Minichiello E, Semerano L, Boissier M. [Incidence, prevalence and severity of rheumatoid arthritis in the 21st century]. Revue du Rhumatisme Monographies. 2017;84(4):303-10. French. https://doi.org/10.1016/j.monrhu.2017.07.002.

  • 3.

    Barragan-Martinez C, Amaya-Amaya J, Pineda-Tamayo R, Mantilla RD, Castellanos-de la Hoz J, Bernal-Macias S, et al. Gender differences in Latin-American patients with rheumatoid arthritis. Gend Med. 2012;9(6):490-510 e5. [PubMed ID: 23217568]. https://doi.org/10.1016/j.genm.2012.10.005.

  • 4.

    Aurrecoechea E, Llorca Diaz J, Diez Lizuain ML, McGwin GJ, Calvo-Alen J. Gender-associated comorbidities in rheumatoid arthritis and their impact on outcome: data from GENIRA. Rheumatol Int. 2017;37(4):479-85. [PubMed ID: 27987002]. https://doi.org/10.1007/s00296-016-3628-7.

  • 5.

    llorcadiaz J AE, McGwin G Jr DM. Impact of Gender in the Quality of Life of Patients with Rheumatoid Arthritis. J Arthritis. 2015;4(3). https://doi.org/10.4172/2167-7921.1000160.

  • 6.

    Arnold MB, Bykerk VP, Boire G, Haraoui BP, Hitchon C, Thorne C, et al. Are there differences between young- and older-onset early inflammatory arthritis and do these impact outcomes? An analysis from the CATCH cohort. Rheumatology (Oxford). 2014;53(6):1075-86. [PubMed ID: 24501240]. https://doi.org/10.1093/rheumatology/ket449.

  • 7.

    Krams T, Ruyssen-Witrand A, Nigon D, Degboe Y, Tobon G, Fautrel B, et al. Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort. Joint Bone Spine. 2016;83(5):511-5. [PubMed ID: 26992954]. https://doi.org/10.1016/j.jbspin.2015.09.010.

  • 8.

    Da Silva JAP, Hall GM. The effects of gender and sex hormones on outcome in rheumatoid arthritis. Baillière's Clin Rheumatol. 1992;6(1):193-219. https://doi.org/10.1016/s0950-3579(05)80344-9.

  • 9.

    Ouali S, Zemri K, Sellam F, Harir N, Beniassa Z, Hebri ST, et al. Is there an association between Anti-Citrullinated Peptide Antibodies and the Severity of Rheumatoid Arthritis Parameters in Algerian Patients? J Drug Deliv Ther. 2020;10(4):17-24. https://doi.org/10.22270/jddt.v10i4.4201.

  • 10.

    Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus. 2004;13(9):635-8. [PubMed ID: 15485092]. https://doi.org/10.1191/0961203304lu1094oa.

  • 11.

    Aurrecoechea E, Diezlizuain ML, Mcgwin Jr G, Calvo-alen J. Impact of gender in the quality of life of patients with rheumatoid arthritis. J Arthritis. 2015;4(3):1-7.

  • 12.

    Katz PP, Yazdany J, Trupin L, Schmajuk G, Margaretten M, Barton J, et al. Sex differences in assessment of obesity in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65(1):62-70. [PubMed ID: 22833513]. [PubMed Central ID: PMC3501549]. https://doi.org/10.1002/acr.21810.

  • 13.

    Ahlmen M, Svensson B, Albertsson K, Forslind K, Hafstrom I, Barfot Study Group. Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage. Ann Rheum Dis. 2010;69(1):230-3. [PubMed ID: 19158113]. https://doi.org/10.1136/ard.2008.102244.

  • 14.

    Coffey CM, Davis J3, Crowson CS. The impact of gender on time to rheumatoid arthritis classification: a retrospective analysis of a population-based cohort. Rheumatol Int. 2019;39(12):2025-30. [PubMed ID: 31338568]. [PubMed Central ID: PMC6879821]. https://doi.org/10.1007/s00296-019-04360-2.

  • 15.

    Syversen SW, Gaarder PI, Goll GL, Odegard S, Haavardsholm EA, Mowinckel P, et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study. Ann Rheum Dis. 2008;67(2):212-7. [PubMed ID: 17526555]. https://doi.org/10.1136/ard.2006.068247.

  • 16.

    Cheng TT, Yu SF, Su FM, Chen YC, Su BY, Chiu WC, et al. Anti-CCP-positive patients with RA have a higher 10-year probability of fracture evaluated by FRAX(R): a registry study of RA with osteoporosis/fracture. Arthritis Res Ther. 2018;20(1):16. [PubMed ID: 29382355]. [PubMed Central ID: PMC5791167]. https://doi.org/10.1186/s13075-018-1515-1.

  • 17.

    Forslind K, Ahlmen M, Eberhardt K, Hafstrom I, Svensson B, Barfot Study Group. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004;63(9):1090-5. [PubMed ID: 15308518]. [PubMed Central ID: PMC1755129]. https://doi.org/10.1136/ard.2003.014233.

  • 18.

    Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature. Am J Med. 2004;116 Suppl 7A:50S-7S. [PubMed ID: 15050886]. https://doi.org/10.1016/j.amjmed.2003.12.012.

  • 19.

    Agrawal S, Misra R, Aggarwal A. Anemia in rheumatoid arthritis: high prevalence of iron-deficiency anemia in Indian patients. Rheumatol Int. 2006;26(12):1091-5. [PubMed ID: 16673131]. https://doi.org/10.1007/s00296-006-0133-4.

  • 20.

    Uhlig T, Hagen KB, Kvien TK. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol. 1999;26(1):47-54. [PubMed ID: 9918239].

  • 21.

    Manfredsdottir VF, Vikingsdottir T, Jonsson T, Geirsson AJ, Kjartansson O, Heimisdottir M, et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford). 2006;45(6):734-40. [PubMed ID: 16403829]. https://doi.org/10.1093/rheumatology/kei240.

  • 22.

    Ruiz-Esquide V, Sanmartí R. Tobacco and Other Environmental Risk Factors in Rheumatoid Arthritis. Reumatología Clínica (English Edition). 2012;8(6):342-50. https://doi.org/10.1016/j.reumae.2012.06.007.

  • 23.

    Dougados M. Comorbidities in rheumatoid arthritis. Curr Opin Rheumatol. 2016;28(3):282-8. [PubMed ID: 27027814]. https://doi.org/10.1097/BOR.0000000000000267.

  • 24.

    Favalli EG, Biggioggero M, Crotti C, Becciolini A, Raimondo MG, Meroni PL. Sex and Management of Rheumatoid Arthritis. Clin Rev Allergy Immunol. 2019;56(3):333-45. [PubMed ID: 29372537]. https://doi.org/10.1007/s12016-018-8672-5.

  • 25.

    Kautzky-Willer A, Harreiter J, Pacini G. Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus. Endocr Rev. 2016;37(3):278-316. [PubMed ID: 27159875]. [PubMed Central ID: PMC4890267]. https://doi.org/10.1210/er.2015-1137.

  • 26.

    Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361(12):1152-63. [PubMed ID: 19657112]. [PubMed Central ID: PMC2774225]. https://doi.org/10.1056/NEJMoa0804381.

  • 27.

    Panoulas VF, Metsios GS, Pace AV, John H, Treharne GJ, Banks MJ, et al. Hypertension in rheumatoid arthritis. Rheumatology (Oxford). 2008;47(9):1286-98. [PubMed ID: 18467370]. https://doi.org/10.1093/rheumatology/ken159.

  • 28.

    Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, Metsios GS, Nightingale P, Kita MD, et al. Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008;47(1):72-5. [PubMed ID: 18077493]. https://doi.org/10.1093/rheumatology/kem311.

  • 29.

    Reckelhoff JF, Zhang H, Srivastava K. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system. Hypertension. 2000;35(1 Pt 2):480-3. [PubMed ID: 10642345]. https://doi.org/10.1161/01.hyp.35.1.480.

  • 30.

    Lazurova I, Jochmanova I, Benhatchi K, Sotak S. Autoimmune thyroid disease and rheumatoid arthritis: relationship and the role of genetics. Immunol Res. 2014;60(2-3):193-200. [PubMed ID: 25427993]. https://doi.org/10.1007/s12026-014-8598-9.

  • 31.

    Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2(9):777-80. [PubMed ID: 11526384]. https://doi.org/10.1038/ni0901-777.

  • 32.

    Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med. 1994;96(5):457-62. https://doi.org/10.1016/0002-9343(94)90173-2.

  • 33.

    Nicolini A, Barbagelata E, Tagliabue E, Colombo D, Monacelli F, Braido F. Gender differences in chronic obstructive pulmonary diseases: a narrative review. Panminerva Med. 2018;60(4):192-9. [PubMed ID: 29856178]. https://doi.org/10.23736/S0031-0808.18.03463-8.

  • 34.

    Tam A, Churg A, Wright JL, Zhou S, Kirby M, Coxson HO, et al. Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2016;193(8):825-34. [PubMed ID: 26599602]. https://doi.org/10.1164/rccm.201503-0487OC.

  • 35.

    Rasch EK, Hirsch R, Paulose-Ram R, Hochberg MC. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States: effect of different methods of case classification. Arthritis Rheum. 2003;48(4):917-26. [PubMed ID: 12687533]. https://doi.org/10.1002/art.10897.

  • 36.

    Lindstrom TM, Robinson WH. Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc. 2010;58(8):1565-75. [PubMed ID: 20942872]. [PubMed Central ID: PMC3055796]. https://doi.org/10.1111/j.1532-5415.2010.02965.x.

  • 37.

    Serhal L, Lwin MN, Holroyd C, Edwards CJ. Rheumatoid arthritis in the elderly: Characteristics and treatment considerations. Autoimmun Rev. 2020;19(6):102528. [PubMed ID: 32234572]. https://doi.org/10.1016/j.autrev.2020.102528.

  • 38.

    Soubrier M, Mathieu S, Payet S, Dubost J, Ristori J. La polyarthrite rhumatoïde du sujet âgé. Revue du Rhumatisme. 2010;77(4):326-32. https://doi.org/10.1016/j.rhum.2009.11.024.

  • 39.

    Tiosano S, Yavne Y, Gendelman O, Watad A, Comaneshter D, Shoenfeld Y, et al. Stroke among Rheumatoid Arthritis Patients: Does Age Matter? A Real-Life Study. Neuroepidemiology. 2017;49(3-4):99-105. [PubMed ID: 29136635]. https://doi.org/10.1159/000481992.

  • 40.

    Tan TC, Gao X, Thong BY, Leong KP, Lian TY, Law WG, et al. Comparison of elderly- and young-onset rheumatoid arthritis in an Asian cohort. Int J Rheum Dis. 2017;20(6):737-45. [PubMed ID: 27135312]. https://doi.org/10.1111/1756-185X.12861.

  • 41.

    Chen DY, Hsieh TY, Chen YM, Hsieh CW, Lan JL, Lin FJ. Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid arthritis: a comparison with younger-onset disease. Gerontology. 2009;55(3):250-8. [PubMed ID: 18849599]. https://doi.org/10.1159/000164393.

  • 42.

    Oguro N, Yajima N, Miwa Y. Age and quality of life in patients with rheumatoid arthritis treated with biologic agents. Mod Rheumatol. 2020;30(1):44-9. [PubMed ID: 30605041]. https://doi.org/10.1080/14397595.2018.1551274.

  • 43.

    Romao VC, Humby F, Kelly S, Di Cicco M, Mahto A, Lazarou I, et al. Treatment-resistant synovitis and radiographic progression are increased in elderly-onset rheumatoid arthritis patients: findings from a prospective observational longitudinal early arthritis cohort study. Semin Arthritis Rheum. 2020;50(4):735-43. [PubMed ID: 32531503]. https://doi.org/10.1016/j.semarthrit.2020.03.018.

  • 44.

    Berglin E, Johansson T, Sundin U, Jidell E, Wadell G, Hallmans G, et al. Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgA-RF at disease onset. Ann Rheum Dis. 2006;65(4):453-8. [PubMed ID: 16176994]. [PubMed Central ID: PMC1798112]. https://doi.org/10.1136/ard.2005.041376.

  • 45.

    Kokkonen H, Johansson M, Innala L, Jidell E, Rantapaa-Dahlqvist S. The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden. Arthritis Res Ther. 2007;9(3):R56. [PubMed ID: 17553139]. [PubMed Central ID: PMC2206338]. https://doi.org/10.1186/ar2214.

  • 46.

    Barra L, Bykerk V, Pope JE, Haraoui BP, Hitchon CA, Thorne JC, et al. Anticitrullinated protein antibodies and rheumatoid factor fluctuate in early inflammatory arthritis and do not predict clinical outcomes. J Rheumatol. 2013;40(8):1259-67. [PubMed ID: 23378461]. https://doi.org/10.3899/jrheum.120736.

  • 47.

    Sparks JA, O'Reilly EJ, Barbhaiya M, Tedeschi SK, Malspeis S, Lu B, et al. Association of fish intake and smoking with risk of rheumatoid arthritis and age of onset: a prospective cohort study. BMC Musculoskelet Disord. 2019;20(1):2. [PubMed ID: 30611246]. [PubMed Central ID: PMC6320647]. https://doi.org/10.1186/s12891-018-2381-3.

  • 48.

    García de Veas Silva JL, González Rodríguez C, Hernández Cruz B. Association of the shared epitope, smoking and the interaction between the two with the presence of autoantibodies (anti-CCP and RF) in patients with rheumatoid arthritis in a hospital in Seville, Spain. Reumatología Clínica (English Edition). 2019;15(5):289-95. https://doi.org/10.1016/j.reumae.2017.08.010.

  • 49.

    Gonzalez-Febles J, Rodriguez-Lozano B, Sanchez-Piedra C, Garnier-Rodriguez J, Bustabad S, Hernandez-Gonzalez M, et al. Association between periodontitis and anti-citrullinated protein antibodies in rheumatoid arthritis patients: a cross-sectional study. Arthritis Res Ther. 2020;22(1):27. [PubMed ID: 32054521]. [PubMed Central ID: PMC7020577]. https://doi.org/10.1186/s13075-020-2121-6.

  • 50.

    Tutuncu Z, Reed G, Kremer J, Kavanaugh A. Do patients with older-onset rheumatoid arthritis receive less aggressive treatment? Ann Rheum Dis. 2006;65(9):1226-9. [PubMed ID: 16414968]. [PubMed Central ID: PMC1798297]. https://doi.org/10.1136/ard.2005.051144.

  • 51.

    Innala L, Berglin E, Moller B, Ljung L, Smedby T, Sodergren A, et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2014;16(2):R94. [PubMed ID: 24731866]. [PubMed Central ID: PMC4060263]. https://doi.org/10.1186/ar4540.

  • 52.

    Kyndt X, Launay D, Hebbar M, Hatron PY, Fournier C, Michon-Pasturel U, et al. Influence de l'âge sur les caractéristiques cliniques et biologiques de la sclérodermie systémique. La Revue de Médecine Interne. 1999;20(12):1088-92. https://doi.org/10.1016/s0248-8663(00)87522-0.

  • 53.

    Gaultier JB, Hot A, Cathebras P, Grange C, Ninet J, Rousset H. [Systemic sclerosis in men]. Rev Med Interne. 2008;29(3):181-6. French. [PubMed ID: 17976873]. https://doi.org/10.1016/j.revmed.2007.07.010.