Study of Rheumatoid Arthritis in older patients: A cross-sectional study

doi:10.21203/rs.3.rs-4843673/v1

Background: Rheumatoid Arthritis (RA) is a common chronic inflammatory arthritis causing severe disability and impacting patients' physical, psychological, and social health, as well as society due to healthcare costs and decreased productivity. This study analyzes RA in older patients focusing on clinical, radiological, immunological profiles, disease activity, severity, disability, comorbidities, and the diagnostic utility of a new serum marker, 14-3-3η.

Methodology: A cross-sectional study recruited 200 arthritis patients over sixty years old and 40 controls. Anti-CCP and serum 14-3-3η levels were measured. Descriptive analysis was performed for all variables. Quantitative variables were compared using unpaired t-test or Wilcoxon Rank Sum test, and categorical variables using Chi-Square or Fisher exact test. Spearman’s correlation coefficient assessed associations between continuous variables. ROC curves determined optimal cut-off values for serum ACCP and 14-3-3η levels.

Results: The most common complaints were joint pain (100% small and large joints, 31.7%), fatigue (71.4%), myalgia (61.4%), fever (55.56%), weight loss (46.03%), neuropathy (25.4%), and PMR-like symptoms (19.05%). Impaired ADL and IADL were noted in 17.5% and 73.2%, respectively. Impaired HMSE and GDS were found in 36.5% and 41.2%, respectively.

The mean age of RA onset was 55.8 years, and the mean RA duration was 7.8 years. The mean number of joints involved was 3.6, and EMS was 28.8 minutes. TJC and SJC means were 8.6 and 2.17, respectively. The mean VAS, CRP, ESR, DAS28ESR, and DAS28CRP were 39, 6.9, 33.3, 6.12, and 2.2, respectively. Serum ACCP and 14-3-3η means were 4.4 and 2.2, respectively. Common deformities were swan neck (30.19%), ulnar deviation (20.63%), and boutonniere (19.05%).

For ACCP, a cut-off value of ≥ 0.5098 U/mL had 77.7% sensitivity and 76.64% specificity. For 14-3-3η, a cut-off value of ≥ 1.471 U/mL had 55.56% sensitivity and 54.74% specificity. Using both markers, 88.88% of RA patients were positive for one of the tests.

Conclusion: RA is prevalent in the elderly, especially in women, and is associated with impaired CGA scores and comorbidities like hypothyroidism and osteoporosis. PMR-like symptoms are common, indicating an acute onset and severe course. DMARDS remain the main treatment. Plasma 14-3-3η is a useful diagnostic marker, especially when combined with ACCP, warranting further investigation for early RA diagnosis.

Rheumatoid Arthritis

Plasma 14-3-3η

Anti-CCP

Rheumatoid Arthritis (RA) is one of the most common chronic destructive inflammatory arthritis which causes severe disability. The disease has a substantial impact on the physical, psychological, and social health of the patients and, in turn, on society in terms of health care costs and decreased productivity. Community studies point to a prevalence of 0.5–0.75%, in India^1,2. The worldwide prevalence rate of RA is estimated to be around 0.5–1.0% of the adult population in developed countries. It tends to increase with age. And it is higher in females than in males³.

Rheumatoid Arthritis is a systemic inflammatory disease which manifests its greatest impact in multiple joints of the body that are lined with synovium. It is a specialized tissue responsible for maintaining the nutrition and lubrication of the joint. The inflammatory process primarily affects the synovium, but can also affect other organs. The inflamed synovium leads to erosions of the cartilage and bone leading to joint deformity over time.

The distribution of synovial joints affected is characteristic. It typically affects the bilateral small joints of the hands and feet symmetrically, though any synovial joint can be affected. In patients with established and aggressive disease, most of the joints will be affected over time.

Although the causes are unknown, many cases are believed to result from an interaction between genetic factors and environmental exposures. Specific HLA class II genotypes are associated with increased risk. Most attention has been given to the DR4 and DRB1 molecules of the HLA class II genes. The strongest associations have been found between RA and the DRB1*0401 and DRB1*0404 alleles. More recent investigations indicate that of the more than 30 genes studied, the strongest candidate gene is PTPN22, a gene that has been linked to several autoimmune conditions⁴.

Several modifiable risk factors have been studied in association with RA including reproductive hormonal exposures, tobacco use, dietary factors, and microbial exposures. The strongest and most consistent evidence is for an association between smoking and RA. Hormones related to reproduction have been studied extensively as potential risk factors for RA as Reproductive and breastfeeding history like oral contraceptives, hormone replacement therapy, live birth history, breastfeeding and menstrual history^5–7.

RA is believed to be the result of a faulty immune response. The initial trigger for RA is unknown. There is evidence to suggest abnormalities in components of the immune system that lead to the body developing abnormal immune and inflammatory reactions, particularly in joints. Whatever sets the pathology in motion results in a large increase in blood flow to the joint (giving heat and redness), proliferation of the synovial membrane with an increase in synovial fluid(swelling), and pain (due to stretching of pain receptors in the soft tissues around, and the bone on either side, of the joint).If the inflammation of the synovial membrane cannot be suppressed it will result in increasing damage to the joint, due to the release of protein-degrading enzymes from inflammatory and other cells, and a conversion of parts of the synovial membrane into an inflammatory tissue called pannus. It can invade the bone and cartilage at the margins of the joint. The degree of progressive damage is related to the intensity and duration of the inflammation. Damage to joints results in progressive deformity and disability⁸.

The natural history of RA varies from self-limited, non-erosive to severe, destructive disease. The onset may be acute, sub-acute or insidious. The symptoms of early and established RA often differ. In addition, during any stages of this condition, the symptoms can vary widely from person to person. Most patients with RA report some degree of morning stiffness. Later in the course of disease radiographs may show joint space narrowing, diffuse osteoporosis and eventually marginal bone erosions. The destructive changes occurring in joints affected by RA include degeneration of cartilage, bony erosions, and destruction of ligaments and tendons^9–12.RA causes widespread inflammatory arthritis and affects much more organs than the joints. Hence it is a systemic disease resulting in premature death. The release of large concentrations of proteins that drive inflammatory processes (such as tumor necrosis factor-α,TNF-α), result in constitutional symptoms. Furthermore, other body organ systems may be affected by the inflammatory process, with dryness of the eyes and mouth (Sjögren’s syndrome), and nodules (hard lumps particularly over extensor surfaces like the backs of elbows)⁸.

More significant inflammatory manifestations may lead to serious pathology, such as fibrosis in the lungs, inflammation affecting the lining of the heart and lungs (pleural and pericardial effusions), or vasculitis of sclera, peripheral neuropathy etc. It has become increasingly evident that the people with the most active RA have the greatest risk of heart disease. People with RA are more prone to infections, probably due to abnormalities in the immune system.

RA usually develops in middle aged adults; however, it may occur at childhood or old age too. RA is known to increase in incidence and prevalence up to approximately age of 85 years. The presentation, severity and prognosis of RA differ depending on the age of disease onset¹³.People with RA have been reported to experience more losses in function than people without arthritis in every domain of human activities including work, leisure and social relations giving worst Impact on health-related quality of life (HRQOL).Mortality has been found to be increased among people with diagnosed RA in multiple studies. Over the past half century, many studies have found mortality to be increased in patients with established RA in comparison with the general population. Among people with RA, the presence of RF and/or ACPA is potential markers of premature mortality¹⁴.

Ideally, RA is diagnosed early within 6 months of symptom onset, so that treatment can begin as soon as possible to slow or halt disease progression. Early diagnosis is challenging because the symptoms of early RA can be non-specific. RA is diagnosed clinically, but classified according to the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Prior to the 2010 criteria, the 1987 ACR criteria were the standard for diagnosis and study of RA¹⁵.The most frequent serological test is the measurement of rheumatoid factor (RF).Although the RF test has good sensitivity, it is not specific for RA^16,17.Citrulline is a non-standard amino acid, as it is not incorporated into proteins during protein synthesis. It can however be generated via post-transitional modification of arginine residues by the enzyme peptidylarginine deiminase (PAD)¹⁸. In 1998, Schellekens and colleagues reported that autoantibodies reactive with linear synthetic peptides containing citrulline were highly specific for RA in an ELISA based assay¹⁹.Subsequent studies demonstrated that cyclic variants of these linear peptides, termed cyclic citrullinated peptides (CCP) were as specific for RA but with a higher sensitivity than the linear peptides²⁰.Anti-CCP antibodies have been found to be present very early in the disease often with the absence of clinical symptoms. Many reports indicate that elevated levels of anti-CCP antibodies can predict the development of erosive disease. These findings suggest an important role for cyclic citrullinated peptides in the diagnosis of RA at an early stage of the disease course^21–24.

Appropriate management needs to address not only the impact on joints, but also focus on the whole patient’s body, their families and carers. New insights into the biological mechanisms have resulted drastic changes in the treatment strategies over the past decade, which have led to significant improvements in the future prospects of patients. Current treatments have a more aggressive approach aiming to suppress RA disease activity as fast as possible, as completely as possible, and as long as possible^25–27.Predicting the outcome of this disease is crucial for optimal clinical management. Patients with a high likelihood of an untoward outcome should be given appropriately aggressive treatment at an early stage to reduce progression of the disease. The ultimate goal of treatment is remission^28,29.

14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and trans membrane receptors. More than 200 signaling proteins have been reported as 14-3-3 ligands. The name 14-3-3 refers to the particular elution and migration pattern of these proteins on DEAE-cellulose chromatography and starch-gel electrophoresis. There are 7 isoforms of the 14-3-3 family of intracellular chaperone proteins (α/β, γ, δ/ζ, ε, η, θ/τ, σ). These highly conserved proteins are acidic at physiologic pH, possess a molecular weight of about 28 kDa, and share more than 50% amino acid homology between isoforms.

Structurally, they have 9 α helices with variable amino- and carboxyl-termini. Through their N-terminus, the 14-3-3 proteins either homo- or hetero-dimerize, forming a cup-like structure known as the amphipathic groove. Through this groove, 14-3-3 proteins interact with more than 200 intracellular proteins, thereby regulating an array of biological processes including protein synthesis, cellular metabolism, protein trafficking, signal transduction, and cytoskeletal transport. Of the isoforms, only 14-3-3η was present in synovial fluid with levels of at least 5-fold higher than those found in matched sera, implicating the joint as the likely source of 14-3-3η. Externalization of 14-3-3η is believed to be mediated in part through exosomes because this family of proteins has been described as a key component of these microvesicles.In the extracellular environment, at concentrations present in the serum of patients with RA, soluble 14-3-3η possesses ligand activity, preferentially activating cells of the innate immune system. Soluble 14-3-3η acts through signaling cascades such as the extracellular signal-regulated kinase and p38 pathway to up regulate proinflammatory cytokines, including interleukin 1β (IL-1β), IL 6, tumor necrosis factor-α (TNF-α), and factors that are involved in joint degradation such as MMP-9 and receptor activator of nuclear factor-κB ligand (RANKL).In future, the marker should be studied to assess the degree it will enhance the diagnostic utility, when combined with standard clinical and serological variables in RA^30,31.

This study was conducted to analyze the spectrum of RA in older patients with special emphasis on clinical, radiological, immunological profile, disease activities, severity, disability, multiple co morbidities and their managements with diagnostic utility of new serum marker 14-3-3η.

Study design: Cross sectional study

Ethics approval and consent to participate: Ethical approval was obtained from the Institutional Ethics Committee (IESC/T‐17/21.01.2015) All Indian Institute of medical Sciences (AIIMS), New Delhi, India. The study was conducted according to ethical guidelines established by the Declaration of Helsinki and Good Clinical Practice Guidelines. Informed consent was obtained from all participants.

Data and Sample: OPD and Ward of the Geriatric Medicine Department, AIIMS(All India Institute of Medical sciences), New Delhi, India, from March 2015 to October 2017.

Sample size: Community studies point to a prevalence of 0.5% to 0.75% RA, in our country. Accordingly sample size requirement will be very high. However, keeping in view of the limited availability of patients and time consumption with each patient, a convenient sample of 200 polyarthritis patients were included in this study.

Recruitment & assessment: All patients with more than one joint involvement, of both gender and age above 60 years were evaluated for screening of Rheumatoid Arthritis by EULAR criteria (Annexure-1). Diagnosed cases of RA were reviewed retrospectively including clinical, radiological and immunological assessments. Also all patients were evaluated, based on disease duration, disease activity, and severity and disability parameters.

Tender joint count (TJC), swollen joint count (SJC), and disease activity score (DAS 28) were used as a parameters of disease activity. Joint erosions were used as markers of disease severity and damage. Disability was assessed using the Indian version Health Assessment Questionnaire disability index (HAQ DI). Demographic characteristics, baseline co-morbidity and extra-articular manifestations were recorded according to pre-defined criteria.Co-morbidities were identified by rheumatology case records and by documented nature of the medicationsgiven by physicians for that co-morbidity.

A new serum marker 14-3-3η and ACPA level were assessed in all patients with polyarthritis by quantitative ELISA method. This assay employed was a quantitative sandwich enzyme immunoassay technique.

Evaluation: After fulfilling the above inclusion criteria, the cases were recruited in the study. They were evaluated as per the predesigned protocol. After obtaining consent for participation subjects were investigated though a detailed protocol. They were subjected to:

Detailed clinical evaluation:

History with focus on presenting health problems
Current medical and surgical problems unrelated to RA for which they were receiving some form of treatment
Other co-morbidities and joint deformities
Health problems of past (quiescent morbidity) which might have an impact on treatment planning.
Personal history
Reproductive and breastfeeding history
Comprehensive geriatric assessment(CGA)
Detailed physical examination (general and systemic)

Clinical Assessment-

Assessment of pain: Pain was assessed on VAS (visual analogue scale) (ANNEXURE-2). Briefly, it was a 10 cm horizontal line with ‘0’ at one end (indicative of no pain) and ‘100’ at the other end (indicative of the worst possible pain). Patient was asked to place a mark on this scale to indicate his level of pain.

Duration of early morning stiffness: Patients were asked about the time of waking and the time by which the stiffness was maximally improved. This time interval was recorded in minutes.

Number of tender and swollen joints: The ‘28 joint count’ was preferred. Assessment for tenderness and swelling in the following 28-joints was done:10 proximal inter-phalangeal joints (PIP), 10 metacarpo-phalangeal joints (MCP), 2 wrists, 2 elbows, 2 shoulders and 2 knees. Additional involved joints were also recorded. While assessing swollen joints, the swelling was attributed to synovial hypertrophy and/or effusion and not bone overgrowth. A ‘mannequin’ was a good and easy way to keep a record of joint counts (ANNEXURE-3).

Laboratory-

Erythrocyte sedimentation rate (ESR) was done by Wintergreen’s method.

C-reactive protein-(CRP)-was done.

Full blood counts: Hemoglobin, total and differential leukocyte count, platelet count.

Biochemistry: AST/ALT (SGOT/SGPT), serum albumin, creatinine.

Radiology: Plain radiographs of the B/L hands (AP view) was done in each patient. Additional radiograph of the affected joints was done if indicated.

Serology: Both IgM-RF and anti-CCP were calculated in all patients. Also serum marker 14-3-3η level was measured in all patients.

Quantification of current disease activity- Disease activity score (DAS) was the most popular tool to assess disease activity. Among the various modifications, the simplest and most commonly used was DAS28, based on 28-joint count (ANNEXURE-4). DAS28 calculator was downloaded from the IRA/das28 website.

Damage assessment: Damage was assessed clinically by noting the presence of deformities and limitation of joint movement. Radiological assessment was preferred with recording of joint space narrowing, erosions and subluxation of the affected joints. The detailed scoring system was done by a simplified scoring method for structural damage on radiographs of patients with rheumatoid arthritis with the Simple Erosion Narrowing Score, SENS (ANNEXURE-5).

Disability assessment: RA disability was being contributed both by disease activity and damage. Hence, disability was assessed using the Indian version Health Assessment Questionnaire disability index (HAQ DI) (Annexure-6).

Categorization of patients: The patients were categorized on basis of disease activity score as Low (DAS<3.2), Moderate (DAS3.2–5.1), High (DAS>5) groups. (ANNEXURE-7)

Statistical Analysis: Data was managed in MS-Excel database and analyzed using STATA. Descriptive analysis was done for all variables, frequency (percentage) for qualitative and mean±SD or median were calculated for quantitative variables. For comparison of quantitative variables between two groups, unpaired t-test or Wilcoxon Rank sum (Mann Whitney U) test was used. Categorical variables were analyzed for association using Chi Square test/ Fisher exact test. For the association of two continuous variables, Spearman’s correlation coefficient was used. The p value < 0.05 was considered significant for each analysis in study. ROC curves were constructed for serum ACCP and 14-3-3η levels to find out the best cut off value for them.

A total of 200 patients with more than one joint pain fulfilling inclusion criteria were enrolled during the study period. After screening31.5% were diagnosed as RA, which fulfilled EULAR criteria. OA knee(65.5%) constituted majority of other arthritis group. Also a total of 40 control patients with no history of joint pain were recruited in the study.

Table 1-Total Patients Distribution

Recruited patients	N(%)
RA	63(31.5)
OA knee	131(65.5)
Lupus arthritis	1(0.5)
Inflammatory polyarthritis	2(1.0)
Reactive polyarthritis	1(0.5)
Gout	2(1.0)
Psoriatic arthritis	1(0.5)
Total patients	200(100)

Control Group	40

Table 2-Demographic Characteristics of total patients

S.N	Variables	RA(N=63) Mean±SD or number f( %)	Other arthritis(n=137) Mean±SD or number f( %)	Control(n=40) Mean±SD or number f( %)
1	Age (years)	63.66(4.70)	65.60(6.17)	63.50(3.36)
2	BMI	24.31(5.55)	26.68(5.98)	24.72(4.92)
3	Gender
	Male	12(19.05)	44(332.22)	07(17.50)
	Female	51(80.95)	93(67.88)	33(82.50)
4	Educational status
	Illiterate	32(50.7)	49(35.8)	22(55)
	Primary	20(31.7)	58(42.3)	12(30)
	Under graduate	05(7.9)	14(10.2)	04(10)
	Graduate	03(4.7)	8(5.8)	0
	Post graduate	03(4.7)	8(5.8)	02(05)
5	Marital status
	Married	46(73.02)	100(72.99)	31(77.5)
	Single	01(1.59)	2(1.46)	2(5)
	Divorced	06(9.52)	2(1.46)	0
	Widowed	10(15.87)	33(24.06)	7(17.5)
6	Living arrangement
	Living alone	5(7.90)	4(2.92)	2(5)
	With spouse	0	6(4.38)	0
	In family	57(90.48)	125(91.24)	38(95)
	Old age home	4(1.59)	2(1.46)	0
7	Occupation
	Unemployed	44(69.80)	84(61.20)	30(75)
	Employed	6(9.50)	11(8.00)	4(10)
	Retired	13(20.60)	42(30.70)	6(15)
8	Personal History
	alcoholic	4(6.35)	14(10.22)	4(10)
	Smoker	6(9.52)	26(18.98)	6(15)
	Tobacco user	5(7.92)	11(8.03)	4(10)
9	Reproductive History
	Abortion	16(25.4)	10(7.3)	3(7.5)
	Poor breast feeding	11(17.4)	4(2.9)	0.0
10	Family History
	Positive	4(6.35)	-	-
11	Impaired Geriatric assessment
	ADL	11(17.5)	24(17.52)	2(5.0)
	IADL	46(73.2)	71(51.82)	3(7.5)
	HMSE	23(36.5)	41(29.93)	5(12.5)
	GDS	26(41.2)	48(35.04)	4(10.0)

Age: The mean (SD) age of patients enrolled in RA group was63.66[4.7] years. Gender: Out of total 63 RA patients,12[19.05%] were male and 51[80.09%] were female. The average BMI of RA patients was 24.31(5.5).The literate participants were 49.3%.The participants married were 73.02%.The participants living in family with spouse were 90.48%. The unemployed patients were 69.84%.The participants having history of abortion and poor breastfeeding were 25.4% and 17.4% respectively. 6.35% of the participants had positive RA family history. The patients having impaired ADL and IADL were 17.5% and 73.2% respectively. The HMSE and GDS were impaired in 36.5% and 41.2%respectively.The impaired scores were defined for ADL,IADL and HMSE being <20,8 and 24 respectively. GDS was defined impaired if≥ 5.

Table 3:Frequency of chief complaints in RA patients

Chief complaints	Frequency, n=63(%)	Chief complaints	Frequency, n=63(%)
Small joint pain	63(100)	Large joint pain	20(31.75)
Fever	35(55.56)	Cervical pain	3(4.76)
Weight loss	29(46.03)	AOE	4(6.35)
Myalgia	39(61.90)	cough	6(9.52)
Fatigue	45(71.40)	Dyspepsia	14(22.20)
Neuropathy	16(25.40)	Constipation	9(14.29)
Lymphadenopathy	2(3.17)	Palpitation	5(7.94)
Rheumatoid nodule	22(34.92)	Low backache	4(6.35)
Hepatoslenomegaly	15(21.92)	DOE	14(22.20)
PMR like symptoms	12(19.05)

The most common presenting complaints were small and large joint pain(100%and 31.7%), fatigue[71.4%], myalgia[61.4%],fever[55.56%],weight loss[46.03%],neuropathy[25.4%]and PMR like symptom[19.05%].

Table 4: Frequency of Co-morbidities in RA patients

Co morbidities	Frequency, n=63(%)	Co morbidities	Frequency, n=63(%)
Diabetes mellitus	12(19.05)	PVD	2(3.17)
Hypertension	30(47.62)	Felty’s syndrome	4(6.35)
OA of knee	14(22.20)	Oral involvement	6(9.52)
COPD	2(3.17)	Ocular involvement	3(4.76)
CAD	4(6.35)	Renal disease	3(4.76)
PAH	1(1.59)	Depression	4(6.35)
Hypothyroidism	13(20.63)	LRTI	2(3.12)
Anemia	13(20.63)	TB	2(3.12)
ILD	6(9.52)	BPH	2(3.12)
Osteopenia	7(11.11)	Cataract	2(3.12)
Osteoporosis	33(52.30)	CCF	4(6.35)
Pericarditis	1(4.59)	Vasculitis	4(6.35)

The most common comorbidities noted with RA were osteoporosis[52.3%], hypertension[47.62%], OA knee joint[22.2%], diabetes mellitus[19.05%], hypothyroidism[20.63%], anemia[20.63%] and osteopenia[11.11%].

Table 5: Frequency of Drugs in RA patients

Drugs	Frequency, n=63(%)	Drugs	Frequency, n=63(%)
Methotrexate	61(96.88)	Diuretics	10(15.87)
Sulphasalazine	58(92.06)	Beta blockers	15(23.81)
HCQ	45(71.43)	Antiplatelets	12(19.05)
Cyclophosphamide	1(1.59)	Statins	10(15.87)
Biological	4(6.35)	Nitrate	3(4.76)
Leflunamide	4(6.25)	MDI /LABA/ICS	10(15.87)
prednisolone	7(11.11)	Pregabalin	5(7.94)
NSAID	35(55.56)	Volini gel	15(23.81)
Opiod	3(4.76)	Hot water use	11(17.56)
PPI	40(63.49)	Thyroid suppl.	11(17.56)
CCB	8(12.70)	Metformine	7(11.11)
ARB	27(42.86)	Glimiperide	7(11.11)
Calcium	53(84.13)	Sitagliptine	3(4.76)
Vit D3	51(80.95)	SSRI	4(6.35)
MVT	11(17.46)	Laxative	8(12.70)
Alpha-1 blockerr	2(3.12)	ATT	1(1.59)

The most common drugs prescribed for RA were methotrexate[96.88%], sulphasalazine[92.06%], HCQ[71.43%].Others drugs were NSAID[55.56%], PPI[63.49%],RB[42.86%],Calcium[84.13%],VitD3[80.93%],diuretics[15.87%],beta blockers[23.81%] and antiplatelet[19.05%].

Table 6: Parameters in RA patients

Activities	Mean(SD),median	Activities	Mean(SD),median
Age of onset	55.8(7.62)	No of type of joint	3.6(1.04),4
Duration	7.8(5.92),6	EMS	28.8(15.8),30
TJC	8.6(4.8),8	HAQ	18.8(4.7),18
SJC	2.17(1.8),2	DI	1.56(0.39)1.5
VAS	39(18.8),30
CRP	6.9(13.2),3.2	Blood level	Mean(SD),median
ESR	33.3(25.3),28	ACCP	4.4(3.9),3.81
DAS28ESR	6.12(0.45)	14-3-3η	2.2(1.7),1.70
DAS28CRP	2.2(0.42)	Hemoglobin	11.77(1.77)

DAS categories	N=63(%)
Moderate DAS score	2(3.17))
Severe DAS score	61(96.83)

Deformities	N=63(%)
Swan neck	19(30.19)
Boutonniere	12(19.05)
Ulnar deviation	13(20.63)

X-ray B/L Hand with Wrist
	Mean(SD),median
JSN	8.5(8.9),4
Erosion	5.2(6.6),2
SENS Total	13.8(15.30),8

The mean(SD) age of onset of RA was 55.8[7.62] and duration of RA was 7.8[5.92]6.Themean(SD)/median of number of type of joint involvement and EMS were 3.6[1.04]/4 and 28.8[15.8]/30respectively.

TJC and SJC mean(SD),median noted were 8.6[4.8],8and 2.17[1.8],2 respectively.

The mean(SD),median ofVAS,CRP,ESR,DAS28ESR and DAS28ESR noted for RA participants were 39(18.8),30, 6.9(13.2),3.2, 33.3(25.3),28, 6.12(0.45) and 2.2(0.42) respectively.

Serum ACCP and 14-3-3η mean(SD),median was 4.4(3.9),3.81 and 2.2(1.7),1.70 respectively. Hemoglobin mean(SD) was11.77(1.77).

The most common deformity noted were swan neck[30.19%],ulnar deviation of hand[20.63%] and boutonniere[19.05%].

The HAQ and DI mean(SD),median were 18.8(4.7)18 and 1.56(0.39)1.5 respectively.

The mean(SD),median JSN, Erosion and SENS Total score noted were8.5(8.9),4, 5.2(6.6),2 and 13.8(15.30),8 respectively.

All RA patients were classified according to the age at onset of the RA disease into:

YORA : with disease onset before 60 years.

EORA: with disease onset after 60 years.

These two groups were compared based on demographic parameters, chief complaints, comorbidities, drug intake, disease duration, disease activity, severity and disability parameters with serum markers.

Table 7: Demographic characteristics of YORA and EORA patients

S.N	Parameters	YORA(n=47) mean±SD or number f( %)	EORA(n=16) mean±SD or number f( %)	P value
1	Age (years)	62.2(2.98)	67.87(6.50)	0.000
2	BMI	24.30(4.20)	24.62(3.98)	0.91
3	Gender
	Male	6(12.70)	6(37.50)	0.03
	Female	41(87.30)	10(62.50)
4	Educational status
	Illiterate	24(51.06)	8(50.00)	0.76
	Primary	13(27.60)	7(43.75)
	Under graduate	4(8.51)	1(6.25)
	Graduate	3(6.38)	0
	Post graduate	3(6.38)	0
5	Marital status
	Married	33(70.40)	13(81.20)	0.924
	Single	1(2.13)	0
	Divorced	5(10.64)	1(6.25)
	Widowed	8(17.02)	2(12.50)
6	Living arrangement
	Living alone	5(10.64)	0	0.489
	With spouse	0	0
	In family	41(87.27)	16(100)
	Old age home	1(2.13)	0
7	Occupation
	Unemployed	33(70.21)	11(68.75)	0.217
	Employed	6(12.77)	0
	Retired	8(17.02)	5(31.25)
8	Personal History
	Alcoholic	3(6.38)	1(6.25)	1.00
	Smoker	6(12.77)	0	0.34
	Tobacco user	4(8.51)	1(6.25)	1.00
9	Reproductive History
	Abortion	13(27.66)	3(18.75)	0.74
	Poor breast feeding	11(23.40)	0	0.052
10	Family History
	Positive	3(6.38)	1(6.25)	1.00
11	Impaired Geriatric assessment
	ADL	10(21.28)	1(6.25)	0.26
	IADL	36(76.60)	10(62.50)	0.27
	HMSE	19(40.43)	4(25)	0.371
	GDS	21(44.66)	5(31.25)	0.346

The number of female patients in YORA group was 87.3%.The mean age was 62.2(±2.98) in YORA group. The BMI noted were 24.30[4.2] and 24.62[3.98] in YORA and EORA group. The illiterate patient were 51.06% and 50 % in YORA and EORA group respectively. The poor breastfeeding history was 23.40% in YORA group[p=0.05].In YORA and EORA group, HMSE and GDS were 40.3%,25% and 44.6%,31.25% respectively. Similarly ADL/IADL impairment in both groups YORA/EORA were 21.28%/6.25% and 76.6%/62.5% respectively.

Table 8- Chief complaints of YORA and EORA patients

S.N	Parameters	YORA(n=47) mean±SD or number f( %)	EORA(n=16) mean±SD or number f( %)	P value
1	Chief complaints
	Large joint pain	18(38.30)	2(12.50)	0.86
	Fever	26(55.32)	9(56.25)	0.948
	Weight loss	20(42.55)	9(56.25)	0.34
	Myalgia	28(59.57)	11(68.75)	0.514
	Fatigue	31(65.96)	14(87.50)	0.121
	Neuropathy	14(29.70)	2(12.50)	0.205
	Lymphadenopathy	1(2.13)	1(6.25)	0.44
	Rheumatoid nodule	17(36.17)	5(31.25)	0.721
	Hepatoslenomegaly	12(25.50)	3(18.75)	0.429
	PMR like	7(14.89)	5(31.25)	0.15
	AOE	1(2.13)	3(18.80)	0.047
	Dyspepsia	1(2.13)	2(12.50)	0.156
	Constipation	1(2.13)	4(25.00)	0.219
	Palpitation	3(6.38)	2(12.50)	0.59
	Low back ache	4(8.51)	0	0.56
	DOE	10(21.28)	4(25.00)	0.739

In YORA and EORA group, fever, weight loss, myalgia, fatigue, PMR like symptom were (55.32% vs 56.25%), (42.2% vs56.25%),(59.57% vs68.75%),(65.96%vs 87.5%),(14.8% vs31.2%) respectively. AOE was significantly higher up to 18.75% in EORA group(p=0.047).

Table 9- Comorbidities of YORA and EORA patients

S.N	Parameters	YORA(n=47) mean±SD or number f( %)	EORA(n=16) mean±SD or number f( %)	P value
1	Comorbidities
	Diabetes mellitus	9(19.15)	3(18.75)	1.00
	Hypertension	20(42.55)	10(62.50)	0.16
	OA of knee	13(27.66)	1(6.25)	0.093
	COPD	2(4.24)	2(12.50)	0.265
	BA	2(4.26)	0	1.00
	CAD	1(2.13)	3(18.75)	0.047
	PAH	1(2.13)	0	1.00
	Hypothyroidism	8(17.02)	5(31.25)	0.224
	Anemia	10(21.28)	3(18.75)	1.00
	ILD	4(8.51)	2(12.50)	0.63
	Osteopenia	5(10.64)	2(12.50)	0.63
	Osteoporosis	25(53.19)	8(50.00)	0.82
	Pericarditis
	SSJ	1(2.13)	0	1.000
	PVD	2(4.26)	0	1.00
	Felty’s syndrome	4(8.51)	0	1.00
	Oral involvement	6(12.17)	0	0.324
	Occular involvement	3(6.38)	0	0.56
	Renal disease	0	1(6.25)	0.25
	Depression	4(8.51)	0	0.564
	Vasculitis	4(8.51)	0	0.54

Hypertension was 62.5%in EORA group and 42.55% in YORA group. OA knee and osteoporosis were 27.66% and 53.19% in YORA group. CAD was 18.75% in EORA group and 2.13% in YORA group (p=0.047).

Table 10- Drugs of YORA and EORA patients

S.N	Parameters	YORA(n=47) Mean±SD or number f( %)	EORA(n=16) Mean±SD or number f( %)	P value
1	Drugs
	MTX	46(97.87)	15(93.75)	0.44
	Sulphasalazine	42(89.36)	16(100)	0.317
	HCQ	34(72.30)	11(68.75)	0.78
	Wysolone	7(14.89)	00.00	0.176
	NSAID	29(61.70)	6(37.50)	0.092
	PPI	31(65.96)	9(56.25)	0.218
	CCB	6(65.96)	2(12.50)	1.00
	ARB	19(40.43)	8(50.00)	0.504
	Calcium	38(80.08)	15(93.75)	0.429
	Vit D3	37(78.72)	14(87.50)	0.79
	Diuretics	6(12.77)	4(25.00)	0.25
	Beta blockers	10(21.28)	5(31.25)	0.419
	Antiplatelets	7(14.89)	5(31.25)	0.419
	Statins	5(10.04)	5(31.25)	0.051
	Nitrate	1(2.13)	2(12.50)	0.156
	MDI /LABA/ICS	6(12.77)	4(25.00)	0.25
	Metformine	6(12.75)	1(6.25)	0.66
	Glimiperide	6(12.75)	1(3.25)	0.66
	SSRI	4(8.51)	0	0.56
	Laxative	4(8.51)	4(25)	0.186

MTX were 97.87% in YORA group and 93.75% in EORA group. Sulphasalazine and HCQ were 89.36% and 72.3%in YORA group respectively. Calcium and Vit-D3 were80.08 %and 78.72% in YORA group.

Table 11- Parametersof YORA and EORA patients

S.N	Parameters	YORA(n=47) mean±SD or number f( %)	EORA(n=16) mean±SD or number f( %)	P value
1	Activities	Mean(SD),med	Mean(SD),med
	Duration(years)	9.55(5.77),8	2.8(2.5),2	0.000
	EMS	29.23(15.8),30	26.68(16.11),25	0.40
	TJC	9.90(5.0),8	6.3(3.2),5.5	0.035
	SJC	2.40(1.90),2	1.5(1.31),1	0.085
	VAS	39.87(17.97),33	37.5(20.97),25	0.27
	CRP	8.22(15.68),4.1	3.2(2.66),2.25	0.053
	ESR	35.10(27.90),30	28.3(18.8),25	0.51
	DAS28ESR	6.12(0.46),6	5.9(0.36),6	0.066
	DAS28CRP	2.33(0.43),2	2.04(0.32)1.9	0.0316

2	Deformities
	Swan neck	15(31.91)	4(25)	0.75
	Boutonniere	11(23.40)	1(6.25)	0.267
	Ulnar deviation	13(27.66)	0	0.027

3	Disability
	HAQ	19.6(4.2),20	16.3(5.6),15	0.014
	DI	1.64(0.35),1.66	1.35(0.47),1.25	0.014

4	XrayB/L Hand
	JSN	9.36(9.33),8	6.1(7.5),4	0.18
	Erosion	5.7(6.78),4	3.7(6.04),1	0.16
	SENS Total	15.12(15.8),10	9.9(13.4),4	0.18

5	Blood level
	ACCP	4.77(4.1),3.8	3.4(3.35),2.3	0.351
	14-3-3η	2.4(1.97),1.7	1.9(0.8)1.7	0.843
	Haemoglobin	11.7(1.68)	11.61(1.91)	0.7913

The mean (SD),median duration disease was 9.55(5.77),8 years in YORA group and 2.8(2.5),2 years in EORA group(p=0.000).

The mean(SD) TJC was 9.9(5)in YORA group and6.3(3.2) in EORA group.

The mean±SD SJC was 2.40±1.9 in YORA group and 1.5±1.31 in EORA group.

CRP(mean ±SD, median) was 8.2±15.8,4.1 in YORA group and 3.2±2.66,2.25 in EORA group(p=0.05).

DASCRP28 score mean ±SD, median was 2.3±0.4,2 in YORA group and 2.04±0.32,1.9 in EORA group (p=0.031).

Ulnar deviation deformity was 27.66% in YORA group (p=0.027).

The disability HAQ score mean±SD was 19.6±4.2 in YORA group and 16.3±5.6 in EORA group (p=0.014).

Similarly DI was 1.64±0.35 in YORA group and1.35±0.47 in EORA group (p=0.014).

SENS total x ray erosion score mean ±SD, median was 15.12±15.8,10 in YORA group and9.9±13.4,4 in EORA group.

ACCP and 14-3-3η mean±SD score was 4.77±4.1,3.8 and 2.4±1.97,1.7 in YORA group as compared to 3.4±3.35,2.3 and 1.9±0.8,1.7 in EORA group respectively.

Table 12:Frequency of parameters in other arthritis patients

Chief complaints	Frequency,n=137(%)	Chief complaints	Frequency,n=137(%)
Fever	16(11.68)	Pedal oedema	4(2.92)
Weight loss	13(9.49)	Dysphagia	2(1.46)
Myalgia	16(11.86)	Diarrhoea	1(0.73)
Fatigue	45(32.95)	Syncope	2(1.46)
Neuropathy	25(18.25)	Ascites	1(0.73)
Lymhadenopathy	3(2.19)	Shoulder pain	5(3.65)
AOE	7(5.11)	Palpitation	10(7.03)
Cough	18(13.14)	Low back ache	21(15.33)
Dyspepsia	39(28.47)	Cervical pain	2(1.46)
Constipation	33(24.09)

Comorbidities	Frequency,n=137(%)	Comorbidities	Frequency,n=137(%)
Diabetes mellitus	37(27.01)	SNHL	5(3.65)
Hypertension	89(64.96)	AF	3(2.19)
BA	8(5.84)	CLD	2(1.46)
COPD	9(6.57)	Piles	2(1.44)
CAD	18(13.14)	Renal disease	15(10.95)
PAH	3(2.19)	Depression	21(15.33)
Hypothyroidism	15(10.95)	LRTI	12(8.76)
Anemia	14(10.12)	TB	7(5.11)
ILD	3(2.19)	BPH	14(10.22)
Osteopenia	34(24.92)	Cataract	15(10.95)
Osteoporosis	30(21.96)	CCF	5(3.65)
Sick sinus syndrome	3(2.19)	Glaucoma	2(1.46)
Spondylosis	9(6.57)	Migraine	5(3.65)

The most common chief complaints associated with other arthritis group was fatigue32.95%,neuropathy18.25%,dyspepsia28.47%,constipation24.09%,myalgia11.8%,low backache15.33% and fever11.68%.

The most common comorbidities associates were hypertension 64.96%,diabetes mellitus27.01%,hypothyroidism10.95%,anemia10.12%depression15.33%,osteoporosis21.96%,renal disease10.95% and coronary artery disease13.14%.

Table 13:Frequency of drugs intake in other arthritis patients

Drugs	Frequency,n=137(%)	Drugs	Frequency,n=137(%)
NSAID	88(64.23)	Diuretics	38(27.74)
HCQ	3(2.19)	Beta blockers	37(27.01)
CCB	46(33.58)	Statins	36(26.28)
ARB	63(45.99)	Nitrate	7(5.11)
Antiplatelets	44(32.12)	MDI /LABA/ICS	15(10.95)
Prednisolone	5(3.65)	Pregabalin	24(17.52)
Antihistaminics	5(3.65)	Diclofenacgel	84(61.31)
Opiod	32(23.65)	Hot/cold water use	63(45.99)
PPI	102(74.45)	Thyroid suppl.	11(8.03)
Calcium	99(72.26)	Metformine	33(24.09)
Vit D3	94(68.61)	Glimiperide	30(21.92)
MVT	23(16.79)	Sitagliptine	11(8.03)
Alpha-1 blockerr	13(9.49)	SSRI	33(24.09)
Knee cap	30(21.90)	Laxative	26(18.98)
Physiotherapy	35(25.55)	ATT	3(2.19)
		MTX	1(0.73)

The most common drugs prescribed was NSAID64.23%, ARB45.99%, CCB33.58%, antiplatelets32.12%,opiods23.65%,diuretics27.74%,beta blockers27.01%, statins26.28%, pregabalin17.52%, and hot/cold application45.99%.

Table 14:Frequency of parameters in other arthritis patients

Parameters	Frequency,n(%)	parameters	Mean(SD),median
X ray B/L knee OA grading	N=131(%)	Age of onset of OA
Grade 1	17(13.00)		58.18(7.22)
Grade 2	76(58.00)
Grade 3	32(24.4)	Duration ofOA knee	7.41(6.03),6
Grade 4	6(4.6)
		VAS	41(19.32),58

OA knee right>left	N=131(%),median	Blood level
	102(77.86)	ACCP	0.72(1.54),0.36
		14-3-3η	1.45(0.56),1.41
		Hb	12.42(1.85)

On the basis ofX ray B/L knee, OA grading was done. It classified patients into 4 groups. From grade 1to 4 patients were 12.97%,58.01%,24.42% and 4.58% respectively.

The preponderance of OA knee is more on right side by 77.89% than left side.

The mean(SD) age of onset of OA knee was 68.18(7.22)years.

The mean±SD, median duration of OA knee and VAS score was 7.41±6.03,6 and 41(19.32),58 respectively.

The mean±SD, median ACCP,14-3-3η and Hb levels were 0.72(1.54),0.36,

1.45(0.56),1.41 and 12.42(1.85) respectively.

Table 15- Association of parameters in different groups

S.N	Variables	RA(N=63) mean±SD or number f (%)	Other arthritis(n=137)mean±SDor number f (%)	Control(n=40)mean±SD or number f (%)	pvalue
1	PersonalHistory
	Alcohol user	4(6.35)	14(10.22)	4(10)	0.74
	Smoker	6(9.52)	26(18.98)	6(15)	0.232
	Tobacco user	5(7.92)	11(8.03)	4(10)	0.899
2	ReproductiveHistory
	Abortion	16(25.4)	10(7.3)	3(7.5)	0.0001
	Poor breast feeding	11(17.4)	4(2.92)	0	0.000

3	Impaired Geriatric assessment
	ADL	11(17.5)	24(17.52)	2(5)	0.123
	IADL	46(73.2)	71(51.82)	3(7.5)	0.000
	HMSE	23(36.5)	41(29.93)	5(12.5)	0.025
	GDS	26(41.2)	48(35.04)	4(10)	0.001

4	Comorbidities
	Hypothyroidism	13(20.63)	15(10.95)	0	0.002
	Osteoporosis	33(52.28)	30(21.9)	4(10.0)	0.000

5	Blood level	Mean(sd),med	Mean(sd),med	Mean(sd),med
	ACCP	4.5(3.9),3.81	0.72(1.54),0.36	0.90(0.96),0.7	0.00,0.00
	14-3-3η	2.2(1.7),1.7	1.45(0.56),1.41	1.19(0.64),1.25	0.0087,0.0008
	Hb	11.77(1.77)	12.42(1.85)	12.05(1.75)	0.011,0.342

On comparing the parameters in different three groups of patients, alcohol, smoking and tobacco users, no significant statistical difference was noted. However on comparing history of abortion and poor breast feeding, RA group had25.4% and 17.4% frequency compared to 7.3% and 2.92% in other arthritis group respectively(p=<0.05).

The RA group had higher impaired IADL,HMSE and GDS frequency of 73.2%,36.5%and 41.2% respectively(p=<0.05).

On comparing the comorbidities like hypothyroidism and osteoporosis in all groups, RA group had very high frequency rate of 20.63% and 52.28% compared to 10.95% and 21.9% in other arthritis groups respectively (p=<0.05).

The Mean(SD),median value of serum ACCP was extremely higher 4.5(3.9),3.81 in RA group, 0.72(1.54),0.36 in other arthritis group and 0.90(0.96),0.7 in control group respectively (p=<0.05).

Similarly for serum 14-3-3η marker, Mean(SD),median was higher 2.2(1.7),1.7 in RA group,1.45(0.56),1.41 in other arthritis group and 1.19(0.64),1.25 in control group respectively (p=<0.05).

The Mean(SD) of blood hemoglobin level was lower 11.77(1.77) in RA group and 12.42(1.85) in other arthritis group respectively(p=<0.05).

The ROC was constructed to determine a cut off for ACCP level to detect Rheumatoid Arthritis from non-Rheumatoid Arthritis patients. In the graph the ability of ACCP to detect RA individuals was assessed. From the ROC given, a cut off value of ≥ 0.723 U/mL has a sensitivity of 76.19% and specificity of 75.71% to detect RA individuals[95% CI= 0.76515-0.89721] with corresponding LR positivity of 3.13. The area under the curve is 0.831, hence ability of ACCP to diagnose RA is fair.

The ROC was constructed to determine a cut off for ACCP level to detect Rheumatoid Arthritis from other Arthritis patients. In thegraph the ability of ACCPto detect RA individuals was assessed. From the ROC given, a cut off value of ≥ 0.5098U/mL has a sensitivity of 77.7% and specificity of 76.64% to detect RA individuals[ 95% CI=0.79266-0.91537] with corresponding LR positivity of 3.3. The area under the curve is 0.854, hence ability of ACCPto diagnose RA is fair.

The ROC was constructed to determine a cut off for 14-3-3η level to detect Rheumatoid Arthritis from non-Rheumatoid Arthritis patients. In the graph the ability of 14-3-3η to detect RA individuals was assessed. From the ROC given, a cut off value of ≥ 1.445 ng/mL has a sensitivity of 57.14.% and specificity of 56.50% to detect RA individuals[95%CI=0.54212-0.72539] with corresponding LR positivity of 1.31.The area under the curve is 0.6338, hence ability of 14-3-3ηto diagnose RA is fair.

The ROC was constructed to determine a cut off for 14-3-3ηlevel to detect Rheumatoid Arthritis from other Arthritis patients. In the graph the ability of 14-3-3η to detect RA individuals was assessed. From the ROC given, a cut off value of ≥ 1.471 U/mL has a sensitivity of 55.56% and specificity of 54.74% to detect RA individuals [95% CI=0.51984-0.71142] with corresponding LR positivity of 1.22. The area under the curve is 0.6156, hence ability of ACCP to diagnose RA is fair.

Serum 14-3-3η did not associate with C-reactive protein, rythrocyte sedimentation rate, Disease Activity Score, SEN total score or DI (p value >0.05). When 14-3-3η and ACCP were used in combination, 56 out of 63 RA patients (88.88%) were positive for one of the test, when cut off value of ≥ 0.723 U/mL for ACCP and a cut off value of ≥ 1.445 ng/mL for 14-3-3η was used.

This was a hospital-based, cross-sectional observational study of small sample size to assess spectrum of Rheumatoid Arthritis in older patients with emphasis on clinical, radiological, immunological profile, disease activities, severity, disability, multiple comorbidities and their managements with diagnostic utility of new serum marker 14-3-3η. The Rheumatoid arthritis (RA) is one of the most common chronic destructive inflammatory arthritis causing severe disability. The course of the disease is highly variable and has a substantial impact on the physical, psychological, and social health of the patients and, in turn, on society in terms of health care costs and decreased productivity. Community studies point to a prevalence of 0.5% to 0.75%, in India^1,2.The issue of whether RA arising in the Elderly onset population (EORA) is a distinct disease from younger onset RA (YORA) is not settled yet^13,36.Also most of EORA patients have comorbid diseases that increase the level of functional impairment, causing the management challenging. Hence the main goal should be at induction of remission and maintenance of drug control with improved the physical capacity and good quality of life with multidimensional treatment and rehabilitating modalities³⁵.

14-3-3η is a conserved regulatory protein interacting with more than 200 intracellular proteins thereby regulating array of biological processes. It is found 5 times higher in synovial fluid than matched serum. Externalization of 14-3-3η in serum was found to be higher in RA disease. By mediating through signaling cascades, it up regulates proinflammatory cytokines and by ligand activities it preferentially activates cells of innate immune system.

The result showed overall M:F ratio of 4:1 in RA population. It is similar to an Italian study reported a female/male ratio of 1.6 : 1for EORA and 4.4 : 1 for subjects with younger onset RA^42,43.A striking female preponderance characterizes many autoimmune diseases and estrogen activated humoral immunity. Sex steroids contribute to the expression of autoimmune diseases⁴³.It is well known that women are affected approximately three times as often as men, but gender differences have been diminishing in the studies of the older age group⁴³.In this study male: female ratio was 1:1.66 in EORA group.

Half of the patients in RA group were illiterate and unemployed. Approximately more than three fourth of the patients were married and living with family member and spouse. Around three fourth of the patients had impaired IADL and 20% had impaired ADL. It reflected poor functionality and disability in the study group, as RA is chronic destructive disease causing severe disability. Around 40% of RA patients had poor GDS score and this could be explained due to disabling and challenging nature of illness.

The most common symptoms were joints pain and stiffness with other constitutional symptoms like fatigue, myalgia, fever, weight loss, rheumatoid nodules, lymphadenopathy and neuropathy similar to previous literatures⁴⁴.

In contrast to classical clinical picture of symmetrical small joint involvement in RA, 20% patients also had larger joint involvement in elderly.

PMR like symptoms were found in around 20% of elderly RA patients similar to other study^32,33. The most frequently associated co morbid diseases (past or current) were DM(19%),HTN(47%),OA knee(14%), osteoporosis(52%), anemia(20%), cardiorespiratory diseases and depression, which were similar to literatures^44-48.

Hypothyroidism(20%) was found in RA subjects, which was similar to the study by Enas A. Elattara⁴⁹.In that study, the most common thyroid dysfunction was hypothyroidism, which was found in 36(24%) RA patients, followed by subclinical hypothyroidism in six(4%) patients, whereas subclinical hyperthyroidism was present in two (1.3%) patients.

Regarding the RA therapy, methotrexate(96%) and sulphasalazine(92%) were used more than other DMARD and biological, possibly due to their high cost benefit ratio than others. In our elderly RA patients, the use of biologic therapy and combination DMARD therapy were less frequently observed because of the presence of high comorbidities and poor financial status. However, It was found similar to the other population studies^32,36.

Most common pain killers prescribed in RA patients were NSAID(55%) with PPI(66%) compared to opioids (5%),because of its anti-inflammatory properties. Also it could be taken on requirement basis without much sedative and vomiting side effects. More than 80% of RA patients were on calcium and Vitamin D3 supplementation for prophylaxis and management of osteoporosis. Other drugs were prescribed for co-morbidities like DM, HTN, cardiovascular disease, peripheral neuropathy, impaired bowel habits. SSRI were common prescription for associated depression. Physical therapy was suggested for more than 20% of patients^32,36.The mean age(SD) of onset and duration of RA were 55.8(7.62) and 7.8(5.92),6 years, indicating more number of younger onset RA with long progression of disease.

With regards to early morning stiffness, its mean(SD),median was 28.8(15.8),30 min, indicating high disease activity at the time of recruitment. The mean(SD) for number of tender joint count out of 28 was 8.6(4.8),8.The mean(SD) for DAS28 score was 6.12(0.45), indicating high disease activity score or poor improvement from baseline, when following the EULAR criteria for improvement in disease activity, giving impression of overall poor medication control or adherence. Majority of patients were not in clinical remission. (ANNEXURE-7)

However, It could not be ruled out a possible selection bias towards the recruitment of more severe cases of RA as they were all recruited in a tertiary care setting. The classical rheumatoid hand deformities were found in more than 20% of patients, with DI Mean(SD),median was 1.56(0.39)1.5, showing high disability in older Indian RA patients. The total Simplified Erosion Narrowing Score (SENS) mean(SD),median out of 62 on B/L x-ray of hand was 13.8(15.30),8, suggesting high hand joint deformity, indicating poor chronic drug control and persistent slow progression of joints erosion in older RA subjects^40,41.

RA patients were further classified and compared in two groups; YORA and EORA on the basis of onset of age, before and after 60 years. Differential diagnostic possibilities for EORA were PMR, pseudo gout, reflex sympathetic dystrophy and osteoarthritis, which must be excluded before labeling definite diagnosis of EORA⁵⁰.Since EORA is difficult to diagnose exactly, it takes a long time to be sure of the definite diagnosis. Meanwhile, it was found that the disease duration was longer in YORA [9.55(5.77),8] than in EORA [2.8(2.5),2] with p value of 0.00.It suggested EORA patients had more acute onset of disease than YORA patients. A striking female preponderance was found in both groups^42,43.Theclassical clinical picture of RA was similar in both groups, might be due to smaller sample size, except AOE which was found higher in EORA 18.75% vs 2.1% in YORA with a statistical significant p value of 0.047.Whereas EORA patients had more common constitutional features such as fatigue, weight loss, myalgia, fever and lymphadenopathy like previous literature^32,36.

A substantial proportion of EORA patients had PMR like symptoms including bilateral aching and prolonged morning stiffness involving neck or torso, shoulders or arms, hips or thighs, that occur in episodic attacks at different times during the patients follow up. The occurrence of peripheral arthritis particularly in both hands might lead to some difficulties in the differential diagnosis between PMR and EORA. They had a different clinical condition from classical RA to a closely similar condition of PMR. A diagnosis of PMR or RA could therefore be made in the same patient at a different time depending on the clinical expression of the disease. Moreover, in other studies the patients were considered to have PMR, manifesting the broader clinical spectrum of this disease at the end of the period of observation.

However PMR like symptoms are found more in EORA, 31.25%vs 14.89% in YORA group, it was similar to other studies^51-56.

Hypertension, ILD were higher in EORA group but DM, SSJ, felty’syndrom, osteoporosis, anemia were higher in YORA group, can be explained by low sample size and long duration of disease³².CAD was significantly higher in EORA group with statistically significant p value similar to other studies^44-48.

Hypothyroidism was significantly higher in EORA group31% vs 21%,with no significant p-value, similar to other studies⁴⁹. Regarding therapy; sulfasalazine was used more common in EORA (100%) than YORA patient, however MTX and HCQ are used more common in YORA patients, as side effect profiles were higher and difficult to manage in co-morbid elderly³⁶.

Data concerning methotrexate prescription for EORA were lacking. One study analyzed the safety of oral methotrexate 7.5 mg/week in 33 elderly patients (mean age 78.8 years) with RA. The investigators concluded that low-dose methotrexate treatment in older subjects appears safe and simple follow-up of liver and renal function can eliminate the main risks⁵⁷.Another study compared the efficacy and toxicity of methotrexate 7.5–15 mg/week in patients 65 years of age and in younger subjects. Significant differences were not found⁵⁸.

Sulfasalazine exhibited relatively little renal toxicity. It had been shown to have clinically and statistically significant effectiveness with respect to RA disease activity but its action on radiological progression seems modest⁵⁹.In fact, Drosos⁶⁰ suggests sulfasalazine as an alternative to methotrexate in the older age group only in patients with mild to moderate forms of RA. The large size of sulfasalazine pills and their gastrointestinal toxicity could represent important problems for the elderly⁶¹.The elimination half-life of sulfasalazine was greater in older subjects. Furthermore, in elderly slow acetylators, the half-life of sulfasalazine increases from 13 to 20 hours, influencing the serum concentration of sulfapyridine, a sulfasalazine component that appears to be strictly related to the appearance of adverse effects⁶².Calcium and Vitamin D3 supplementations were higher in EORA group, can be explained by low sample size³².NSAIDS were used higher 61% in YORA group than 37% in EORA group, because of the higher risk of adverse events in elderly age group¹⁵.

Corticosteroid use was lower in both groups as the place of systemic corticosteroids in the treatment of EORA was a subject for debate. Their efficacy least in the short-term was counterbalanced by their multiple adverse effects. The elderly were particularly liable to complications of corticosteroids after months like diabetes mellitus, cardiovascular effects, cataracts, mood disturbances and osteoporosis. Oral corticosteroid therapy for >6 months increases the risk of new-onset diabetes in the elderly³⁶.The same pharmacological resources are available for treating EORA as for younger populations with RA (namely, analgesics, NSAIDs, corticosteroids, DMARDs and anti-cytokine drugs). However, the increased risk of adverse reactions as a result of advancing age means more caution is required when prescribing these drugs and, subsequently, more attention is required during follow-up of patients.

DAS28CRP was higher in YORA group than EORA group, with statistical significant difference of p value <0.05.Similarly HAQ and DI score was higher in YORA group than EORA group, with statistical significant difference of p value <0.05, could be explained by longer duration of disease of in YORA group.

This study demonstrated that YORA group had more active and more disabling disease course and affected more female than EORA group. Erosions were more prevalent in YORA groups than EORA and also HAQ disability index was increased in YORA compared to EORA (p=0.014).Joint deformities were significantly high in YORA groups than EORA group.

In this study elevated levels of ESR, CRP, hemoglobin, Serum markers 14-3-3η and ACCP were not significant in YORA group than EORA group, differs from previous literature because of the small number of sample size included.^63,64,41Different opinions had been reported in the literature concerning the long-term outcome of EORA. Onset of RA in the elderly was considered a poor prognostic factor by several investigators. However, It was reported lower joint scores and higher health assessment ratings in EORA patients compared with YORA patients⁶⁵.

Abortion and poor breast feeding history in patients with rheumatoid arthritis on comparison with other arthritis and control group was found statistically significant(p=0.001),suggesting hormones related to reproductive and breastfeeding history could be a potential risk factor for onset RA in future life^5-7.However in this study, no association had been found on several modifiable risk factors like smoking, tobacco and alcohol to RA disease, but strong association has been found out in previous study, difference might be because of small sample size and denial of sharing the addiction habit openly by patients in this sociodemo graphic structure^5-7.

Significant statistical association had been found for serum marker ACCP and 14-3-3η for RA disease in comparison to other arthritis and control group, which was similar to previous literature^30,31,39.The value for the cut off level of serum 14-3-3η for detection of RA was higher than the study no.18 and at that cut off level, sensitivity and specificity was lower than study no.18 but similar to study no. 66,might be due to low sample size, unequal number of patients in each group, prolonged duration of disease, interference of serum value by methotrexate, as majority of patients were on the drug or might be due to different brand of ELISA kit used whose lower level of detection was kept at high value^30,66.Also Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, SEN total score and DI, similar to previous study^30,67,68.Although the value of cut off level of serum ACCP for detection of RA was lower than the study no.18, might be due to different brand of ELISA kit used. At that cut off, sensitivity and specificity was similar to other study³⁰.

14-3-3η was an early RA plasma marker that was modifiable with standard DMARD therapy. Its changes were independent of CRP and corresponded with improvement in clinical variables at one year followingdiagnosis^66-68.

As there are no any serum markers that can independently predict joint damage progression in ACCP negative RA patients, although ESR, CRP,DAS and TJC can independently predict joint damage progression in ACCP positive RA patients.

Hence, there is a need for new complementary diagnostic markers that can assist clinicians in better identifying higher risk patients. 14-3-3η is a soluble diagnostic RA marker involved in the path physiology of the disease and marks joint damage in subjects⁶⁶.

Therefore, this novel marker should demand further examination for clinical insight into early RA diagnosis and patient management in large sample size.

The second most common arthropathies in elderly patients attending Geriatric OPD and ward in our hospital is Rheumatoid Arthritis after Osteoarthritis. RA has striking female preponderance. Majority of them are illiterate, married, unemployed and living in family with spouse. Majority of RA patients have impaired Geriatric assessment. Abortion and poor breast feeding history have significant association in patients with RA. The most common symptoms are multiple small and large joint pains with stiffness and other constitutional symptoms. PMR like symptoms are also predominant in elderly. Multiple comorbidities are common in RA patients; however hypothyroidism and osteoporosis are significantly associated with RA. Elderly onset RA has more acute onset. Patients have severe course of disease activities, disability and deformity. DMARDS are mainstay of treatment.

Plasma 14-3-3η is a novel soluble mechanistic complementary marker to ACCP in RA diagnosis when compared with other arthropathies and control patients. This study therefore supports continuing evaluation of the diagnostic utility of this biomarker. Through earlier and more accurate diagnosis of RA, patients can be provided earlier access to disease-modifying therapy to preserve joint function and minimize the personal costs. This novel marker should be further examined for clinical insights into early RA diagnosis and patient management, in both ACCP positive and negative large sample size.

Ethics approval and consent to participate: Ethical approval was obtained from the Institutional Ethics Committee (IESC/T‐17/21.01.2015) of All Indian Institute of medical Sciences (AIIMS), New Delhi, India. The study was conducted according to ethical guidelines established by the Declaration of Helsinki and Good Clinical Practice Guidelines. Informed consent was obtained from all participants.

Consent for publication: Not applicable

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. All data generated or analysed during this study are included in this published article and its supplementary information files

Competing interests: The authors declare that they have no competing interests

Funding: This work was supported by the Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi as the postgraduate dissertation of Dr. Ramesh Kumar Sah.

Authors' contributions: Ramesh Kumar Sah was the Principal Investigator of this study, overseeing all aspects of the research. Aparajit Ballav Dey and Uma Kumar were responsible for the study design. Avinash Chakrawarty was involved in the data analysis, while S. N. Dwivedi developed the methodology and assisted with the statistical analysis. Chandan Das performed the radiological analysis of the reports. Ramesh Kumar Sah interpreted the data and drafted the initial manuscript. All authors critically revised the manuscript, ensured the accuracy of the final content, and read and approved the final manuscript.

Acknowledgements: The authors are grateful to the patients for their consent and support to carry out this research work.

Authors' information (optional): Dr Ramesh Kumar Sah is an eminent and renowned geriatrician, celebrated for his exceptional contributions to elderly care in India. With diverse area of experience, he has pioneered innovative treatments and practices that have significantly improved the quality of life for countless seniors. His dedication to patient-centered care, combined with his extensive research and compassionate approach, has earned him widespread recognition and respect in the medical community. Dr. Ramesh’s work extends beyond clinical practice; he is a prolific author, esteemed lecturer, and an active advocate for the health and well-being of the elderly, making him a leading figure in geriatric medicine. Dr. Ramesh's contributions to geriatric medicine inspire peers and positively impact countless lives.

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No competing interests reported.

Study of Rheumatoid Arthritis in older patients: A cross-sectional study

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Abstract

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