The journey of rheumatoid arthritis patients: a review of reported lag times from the onset of symptoms

Figures & data

Figure 1 Flow diagram of study selection.

Figure 2 Reported lag times in rheumatoid arthritis patients.

Table 1 Characteristics of the studies providing data relevant to our analysis

Study	Country	No. of patients	Symptoms to first physician visit (Lag1; months)	Initial visit to rheumatology referral (Lag2; months)	Referral to diagnosis (Lag3; months)	Diagnosis to DMARD initiation (Lag4; months)
Cho et al^Citation27	Korea	98	2
			5.75
			42
Irvine et al^Citation28	UK	74	4
Sokka and Pincus^Citation47	USA	232	5.1
Ayas and Nur^Citation36	UK	269	6
				3
Lacaille et al^Citation37	Canada	27,710		2.2 (IQR 0.7–6.4)		30% prior to or at the time of diagnosis and 70% within 2.2 months after diagnosis(IQR 0.76–6.6)
Clemente et al^Citation19	Spain	865	14
Feldman et al^Citation48	Canada	13,237	2.6 (IQR 0.9–7.6)
Kumar et al^Citation29	UK	169	3.25 in RF-positive patients compared to 1 in RF-negative patients	0.5 (IQR 0.25–2.5)
			5.75 (IQR 3–13.5)
Badsha et al^Citation49	United Arab Emirates	100	14.4 (average)
			19.2 (average)
Ankjær-Jensen^Citation50	Denmark	NA			5.6
Kiely et al^Citation26	UK and Ireland	808	4 (IQR 2–9)	1 (IQR 1–2)	1 (IQR 0–2)
			5 (IQR 3–12)
			8 (IQR 4–13)
Koh et al^Citation51	Singapore	386	8.4±9.0
Fathi et al^Citation52	Egypt	196	24.1±44.2
			31.5±50.0
van der Linden et al^Citation30	The Netherlands	598	0.6	2
			3.4
Robinson and Taylor^Citation46	New Zealand	128	1.7 (IQR 0.93–3.17) in urgent patients; 3.8 (IQR 1.5–11) in semi-urgent patients
			4.1 (IQR 2.7–8.1) in urgent patients; 6.9 (IQR 4.6–18.8) in semi-urgent patients
			4 (IQR 3–7.23) in urgent patients; 7.3 (IQR 4.4–18) in semi-urgent patients
Blanco et al^Citation53	Spain	915	6.3±11.3			2.3±10.2
					4.0±13.5
Rodríguez-Polanco et al^Citation16	Venezuela	272	13			1
			5.5		5
			24
Jamal et al^Citation17	Canada	204	3.03 (IQR 1.02–8.04)	2.01 (IQR 1.02–4.01)	0.0	0.0 (IQR 0.00–0.99)
			6.35 (IQR 3.29–12.01)
Raza et al^Citation54	Pan Europe	482	6 (IQR 3.3–16.55)
Verschueren et al^Citation55	Belgium	182	5.5 (IQR 3.08–9.75)
Zafar et al^Citation56	United Arab Emirates	100	7.8
			12.5
Nanji et al^Citation34 Kimura et al^Citation31	Canada Japan	151 296	4	0.8
			5 2.2 (IQR 0.11–1)	1.25 (IQR 0.1–0.67)
			6.72 (IQR 0.36–2.313)
Gόmez Caballero et al^Citation57	Spain	183	11.3±13.2
			10.2±12.7
			11.1±12.8
Natalia et al^Citation32	Argentina	316	1 (IQR 0.3–2)		0.8 (IQR 0.2–12.17)
			3 (IQR 1.2–7)
			5.5 (IQR 1–12.17)
Doornum et al^Citation25	Australia	135	5.4 (IQR 2.9–10.8)
				1.1 (IQR 0.3–1.8)
				0
			3.26 (same research, but no IQR)
Fautrel et al^Citation33	France	813	0.5	1
De Cock et al*,^Citation58	Belgium	69				0.25 (IQR 1)
			6.75 (IQR 29.5)
Zonana Nacach et al^Citation22	Mexico	98	2.9	6.6
			9.9
Gibson et al^Citation59	Australia	177	44.4
Widdifield et al^Citation35	Canada	1,086		2
De Cock et al^Citation23	Belgium	156	2.5 (IQR)	1.75 (IQR)		0.25 (IQR)
			5.75 (IQR)
Sørensen and Hetland^Citation60	Denmark	13,721	4
Benaglio et al^Citation61	Italy	513	3.5
Ješe et al^Citation21	Slovenia	87	2.47 (IQR 1.1–6.3)	3.17 (IQR 1.5–6.5)
			3.6 (IQR 1.9–6.9)
Widdifield et al^Citation20	Canada	2,430	5.7	2.2		1.8
			10.9
			>13.3
Hussain et al^Citation14	Saudi Arabia	250	6.2±5.5	30.2±16.0

Notes: Lag times are median values in month. Values are also presented as mean ± SD wherever available.

* The article had provided enough data to calculate IQR values.

Abbreviation: IQR, interquartile range; DMARD, disease-modifying antirheumatic drug; RF, rheumatoid factor; NA, not available.

Table 2 Factors associated with delays in the diagnosis and treatment of rheumatoid arthritis

Reference	Location; patients (research time)	Factor studied	Findings	Author recommendation
Lard et al^Citation62	N/A; 142 F + 82 M (1993–1999)	1. Gender	1. More delay in women as compared to men (median of 93 vs 58 days)	GPs should be made aware that early detection and early referral of patients with RA are crucial for early treatment
Xibillé-Friedmann et al^Citation63	México; 530 (2002)	1. PCP	1. Only 20% of the PCP referrals are confirmed as RA 2. PCPs do not utilize the laboratory and X-ray technologies effectively, leading to a delay in accurate diagnosis 3. Even diagnosed cases were referred with a huge delay of 3 years	A vigorous effort in educating PCP is needed to achieve early diagnosis and referral of RA cases
Neill et al^Citation64	Ireland; N/A (2011)	1. PCP	1. PCPs lack knowledge on diagnosis and importance of timely treatment of RA 2. Diagnostic uncertainty and shortage of rheumatologists lead to delay in referral from PCPs	Diagnostics facility and training of PCPs
Widdifield et al^Citation65	Canada; 27,127 (1997–2008)	1. Age 2. SES 3. Having a male PCP 4. Measures of poor access	1. Increasing age, lower SES, and having a male PCP limits timely access to rheumatologists 2. Measures of poor access (poor continuity of primary care, density, and proximity to rheumatologists) negatively impacted rates of encounters with a rheumatologist	Proactive, tailored approaches are needed to provide rheumatology care to such populations
Panchal^Citation66	UK; 189 (2012)	1. Ethnicity	1. Black minorities experienced more delay as compared to Caucasians	There may be a range of ethnically specific culturally centered reasons for such delay
Zafar et al^Citation56	United Arab Emirates; N/A (2006)	1. Public awareness	1. A positive and statistically significant reduction in the lag time to both diagnosis and the initiation of DMARD therapy was achieved in 5 years of launching a public awareness campaign	This difference in lag time may in part be attributed to the inception of the patient support groups, coupled with the general drive toward increasing public awareness about RA
Delaurier et al^Citation67	Canada; N/A (2009–2010)	1. Rheumatologist appointment	1. Most patients with RA are still not receiving an appointment to a rheumatologist in a timely manner	Effective triage tools to decrease these delays should be instituted
Grygielska^Citation68	Poland; 1,000 (2009–2010)	1. Geographical factor 2. Gender 3. Age	1. Inhabitants of rural area are diagnosed earlier than inhabitants of big cities 2. Men were diagnosed earlier than women 3. Respondents with first symptoms in younger age were diagnosed later than older patients
Molina et al^Citation69	USA; 1,209 (2014)	1. SES	1. Lower SES leads to significant delay in DMARD treatment (8.5 vs 6.1 years for middle and upper SES patients), both of which were independently associated with worse clinical outcomes
Barnabe et al^Citation70	Canada; 1,142 (2012)	1. Severity of disease activity 2. Serology results (anti-CCP antibody-positive patients) 3. Lower income levels 4. Ethnicity 5. Underlying comorbidities	1. Higher number of swollen joints, elevated acute-phase reactants, and worse patient global scores decrease time to diagnosis 2. Positive serology results are associated with delays in time to diagnosis in multivariate analysis. The reasons for this unanticipated finding are unclear. One potential reason is that some triage units may delay assigning a priority to the patient for an appointment until the serology results are available, which will delay the time to diagnosis. In addition, availability of anti-CCP testing is restricted in some regions of Canada, despite its utility in diagnosis and prognosis of RA. 3. Patients with lower income levels are at risk of delays in diagnosis 4. Did not find any evidence of discrimination in time to diagnosis based on ethnicity or underlying health comorbidities
Sung et al^Citation71	Korea; 714 (2014)	1. Age 2. Education 3. Income 4. Disease activity	1. Older onset age, higher education level and higher income lead to early diagnosis 2. DAS28 remained similar but hand joints were more eroded in delayed diagnosis
Widdifield et al^Citation72	Canada; 2,430 (2015)	1. PCP	1. Approximately 1 in 3 PCP referrals to rheumatologists were referred for a systemic inflammatory rheumatic disease	Understanding the referral patterns of PCPs can identify opportunities to improve PCP management of patients prior to rheumatology referral
Simons et al^Citation73	UK; 32 F + 6 M (2015)	1. Perceived causes of symptoms 2. Presentation, location, and experience of symptoms 3. Perceived impact of symptoms on daily life 4. Self-management of symptoms 5. GP-related drivers and barriers	1. Factors prompting GP consultation included: –a sudden and severe symptom onset – symptoms resistant to self-management strategies – symptoms not easing – symptoms disrupting daily activities – the perception that symptoms were unusual and could not be explained 2. Numbers of patients were trying to identify external causative factors, or felt that joint pain and stiffness were simply part of getting older and as a result they would delay or avoid seeking medical attention. Others mentioned “knocks” and other injuries as a possible cause, specifically when experiencing symptoms in a single joint. They would delay help-seeking if they suspected injury as a causal factor 3. RA patients interviewed within a year of diagnosis, described using over-the-counter medications prior to, or instead of, seeking medical advice or while awaiting a formal diagnosis
Molina^Citation74	USA; 1,209 (1996–2009)	1. Potential health barriers 2. Distance to the rheumatologist 3. SES	1. All the 3 factors were independently associated with disease activity, joint damage, and physical disability 2. Distance was not significantly correlated with DMARD lag and was inversely associated with these clinical measures, suggesting that patients who live closer to the rheumatologist have more severe RA. This result was unexpected 3. On average, patients with lower SES waited 8.5 years after the onset of RA symptoms to begin DMARD treatment, compared to those in the middle and upper SES tertiles who waited ~6.16 years
Peerboom et al^Citation75	Belgium; 94 (2015)	1. Pain 2. PCP	1. Pain is the foremost related symptom at the onset and the most important reason to visit the GP, accelerating diagnosis 2. 25% of patients needed >5 visits before ERA was detected
Mølbæk et al^Citation76	Denmark; 11 (2014)	1. Nature and severity of symptoms	1. When symptoms were obvious to patients, there was a shorter delay between symptom onset and contacting their GP. In cases where symptoms gradually worsened or were difficult to interpret, there was a longer delay 2. Participants with a high degree of body awareness appeared to be good at detecting when something was not normal, and they responded quickly to their symptoms 3. For those who regarded the doctor as a resource to which they were entitled and who were not worried about getting a diagnosis, there was a shorter delay 4. Diffuse symptoms seemed to confuse GPs and can contribute to physician delay in the investigation process 5. The presence of other diseases can result in a prolonged period before referral to a rheumatologist 6. The results showed that the greater the awareness of the patient’s body, the better the disease recognition, the fewer barriers to contacting the GP and the shorter the delay in doing so
Pratt et al^Citation77	UK; 173 (2011–2014)	1. Serology results (anti-CCP antibody-positive patients)	1. Retrospective analysis to determine whether time to treatment following symptom onset differs between RA patients according to autoantibody status 2. ACPA+/RF+ patients experienced significantly longer symptom duration before DMARD initiation 3. This accounted for delays in their presentation to primary care following symptom onset 4. In contrast, ACPA−/RF− patients were significantly more likely to experience delays in DMARD initiation after presenting to secondary care 5. Causes of treatment delays in early RA differ according to patients’ autoantibody status
Hussain et al^Citation14	Saudi Arabia; 250 (2016)	1. Early referral to rheumatology 2. Presence of early symptoms (hand/wrist involvement, fatigue) 3. Geographic distribution	1. Nonrheumatologists offered diagnoses in 24.4% of cases, while rheumatologists diagnosed 75.6% 2. The absence of early hand/wrist involvement and fatigue were associated with delayed RA diagnosis (long lag2; p<0.01). Moreover, geographic distribution influenced RA diagnosis, with rural patients experiencing a greater delay than urban patients (p<0.0001)	RA diagnosis can be accelerated by encouraging early referral to rheumatologists

Abbreviations: M, male; F, female; N/A, not available; GP, general practitioner; RA, rheumatoid arthritis; PCP, primary care physician; SES, socioeconomic status; DMARD, disease-modifying antirheumatic drug; CCP, cyclic citrullinated peptide; DAS28, disease activity score; ERA, early rheumatoid arthritis; ACPA, anti-citrullinated protein antibody; RF, rheumatoid factor.

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