bmj openrozeena garner mbbs mrcp (rheum) 2, rakesh kumari mbbs md mrcp (rheum) 2, peter lanyon dm...

For peer review only

Prevalence, risk factors and associations of Primary

Raynaud’s Phenomenon: Systematic review and meta-

analysis of observational studies

Journal: BMJ Open

Manuscript ID: bmjopen-2014-006389

Article Type: Research

Date Submitted by the Author: 15-Aug-2014

Complete List of Authors: Garner, Rozeena; Queens Medical Centre, Rheumatology Kumari, Rakesh; Queens Medical Centre, Rheumatology Lanyon, Peter; Nottingham University Hospital, Rheumatology; Queens

Medical Centre, Rheumatology Doherty, Michael ; University of Nottingham, Academic Rheumatology Zhang, Weiya; University of Nottingham, Academic Rheumatology; Nottingham University, Academic Rheumatology

<b>Primary Subject Heading</b>:

Epidemiology

Secondary Subject Heading: Rheumatology

Keywords: RHEUMATOLOGY, EPIDEMIOLOGY, STATISTICS & RESEARCH METHODS

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Prevalence, risk factors and associations of Primary Raynaud’s Phenomenon: Systematic

review and meta-analysis of observational studies

Rozeena Garner MBBS MRCP (Rheum) 2, Rakesh Kumari MBBS MD MRCP (Rheum)

2, Peter

Lanyon DM FRCP MRCGP DRCOG2, Michael Doherty MA MD FRCP

1, 2, Weiya Zhang BMed

MEpi PhD1

1Academic Rheumatology, University of Nottingham, UK;

2Department of Rheumatology,

Queens Medical Centre, UK

Correspondence to:

Dr Weiya Zhang

Academic Rheumatology

Clinical Sciences Building

Nottingham City Hospital

Nottingham NG5 1PB

UK

Telephone: +44 (0)115 823 1756

Fax: +44 (0)115 823 1757

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Email: [email protected]

Keywords: Primary Raynaud’s phenomenon, prevalence, incidence, risk factors, systematic

review

Word Count: Abstract: 243, main text: 2685

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Abstract

Objective: To systematically review the literature with regard to the prevalence, incidence,

risk factors and associations of primary Raynaud’s phenomenon (PRP).

Method: A systematic review of the literature of observational studies for PRP was

undertaken using five electronic databases. Any studies reporting prevalence, incidence and

risk factors of PRP were collected. Relative risk or odds ratio (OR) and 95% confidence

interval (CI) were extracted or calculated to present the association between risk factors

and PRP. Random effects model was used to pool the results.

Results: 33 articles assessing a total of 33, 733 participants were included in this analysis (2

cohort, 17 cross-sectional and 14 case-control studies). The mean prevalence of PRP was

4.85% (95% CI 2.08%, 8.71%) in the general population. The annual mean incidence of PRP

was 0.25% (95% CI 0.17, 0.33). Risk factors and associations for PRP included female gender

(OR 1.65, 95% CI 1.42, 1.91), family history (OR 16.6, 95% CI 7.44, 36.8), smoking (OR 1.27,

95% CI 1.06, 1.53), manual occupation (OR 2.66 95% CI 1.73, 4.08), migraine (OR 4.02, 95%

CI 2.62, 6.17), cardiovascular disease (OR 1.69, 95% CI 1.22, 2.34) and marital status (OR

0.60, 95% CI 0.43, 0.83). The definition of PRP varied considerably between studies.

Conclusion: This is the first systematic review of the prevalence, incidence, risk factors and

associations of PRP. Further study using uniform strict criteria for the condition is required

to confirm these findings, particularly the possible association with cardiovascular disease.

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Strengths and limitations of this study

• This is the first meta-analysis of the literature for the global epidemiology of primary

Raynaud’s phenomenon (PRP).

• The prevalence and incidence of PRP in different countries were estimated. Female

gender, positive family history, smoking and migraines were found to be the major risk

factors for PRP.

• The lack of original data restricted an adequate estimation of the age-effect on PRP.

• Different definitions of PRP handicapped a comparison between countries

INTRODUCTION

In the 19th century, Maurice Raynaud first described Raynaud’s phenomenon (RP) as an

episodic, symmetrical, vasospastic disorder resulting in classic triphasic colour change,

trophic changes limited to the skin and uncomfortable sensory symptoms of the extremities

in the absence of arterial occlusion.[1] Further criteria have been suggested to distinguish

Primary Raynaud’s phenomenon (PRP) from secondary Raynaud’s phenomenon which

include detail regarding symptom duration, negative autoimmune serology, normal serum

inflammatory markers and capillaroscopy, and the clinical absence of any underlying

disease.[1-4] Use of colour charts to aid diagnosis has also been used.[4, 5] Despite this,

there is no unifying definition that is used worldwide for PRP.

There have been a number of studies performed in various countries reporting the

prevalence of PRP. The reported prevalence ranges from less than 1% up to 20%

depending on definitions and population selected.[6] In contrast, few studies have

examined the incidence of PRP and the true burden of PRP in the general population

remains unclear. PRP is thought to be more common in women, particularly when it

develops at a young age.[7] There are also reports of a hereditary component and links

with other vasospastic conditions such as migraine.[8-11] It is uncertain whether other co-

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morbidities or risk factors particularly related to vascular diseases such as ischaemic heart

disease and/or smoking have an association with PRP.

The primary objective of this study was to perform a systematic review of observational

studies to summarise the literature with regard to the prevalence, incidence and risk

factors/associations of PRP. The secondary objective was to examine the current definitions

used to define PRP worldwide.

METHODS

1: Literature search – data sources and search strategy

A systematic literature search was undertaken in June 2011 using five databases: Medline,

Embase, Cinahl, Amed and Pubmed. The search terms for “Raynauds” or “Raynauds

disease” were combined with the terms “epidemiology” , “prevalence”, “risk” or “incidence”

to generate the citations (see Appendix 1). “Cross sectional”, “case-control” or “cohort”

studies and “systematic review” were also applied for types of studies.

Abstracts were reviewed and the full papers were sought where abstracts were felt to be

relevant. Any duplicate articles were excluded (Figure 1). Where there was difficulty in

article retrieval, the authors were contacted via email. The literature search and abstract

review was completed by RG and validated by WZ.

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Figure 1: Flow chart diagram showing results of systematic literature search

Initial search: n=2378

n = 1911

n = 97

Final number of relevant articles

Definite= 33

Further exclusion after paper

retrieval: n = 64

See box 2 for exclusion reasons

Duplicates = 467

Reviews, Case reports, Non-RP,

treatment, progression etc = 1814


Box 1: Exclusion reasons for 1814 papers

Review (219), Case report (34), Letter (14), Webpage (5), Animal studies unrelated to RP (4), Connective tissue disease

(602), Vibration induced disease (169), Diagnosis/investigation of RP (11), Secondary progression from primary RP (4),

drugs related to RP (53), RA/inflammatory arthritis (21), Other musculoskeletal (37), Fibromyalgia (9)Genetics not

related to RP (11), Autoantibodies (13), Treatment involving sympathectomy (45), Opthalmology studies (14), Psychiatric

conditions (11), Haematological disease (14), Infectious disease (24), cardiovascular disease (64), Respiratory disease

(17), Gastrointestinal disease (27), Renal disease (27), Dermatological (30), Endocrinological disease (31), Neurological

disease (43), Cancer (106), Drugs not related to RP (63), Vascular intervention (64), Laser Doppler flowmetry (8), Breast

implant rupture (4)Other: including motor vehicles, dentists, seafarers, fishermen, aircrafts, breast feeding (17)


Letter to editor (1)

Review (5)

Diagnosis/Investigation of RP (14)

Secondary RP (39)

Treatment RP (1)

Same patient sample as is already included in another study used (3)

Case only study (1)

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2: Inclusion and Exclusion Criteria

Inclusion criteria: studies reporting the prevalence and/or incidence of PRP; studies

reporting potential risk factors associated with PRP; studies reporting human data on PRP in

people of any age; studies in any language (4 articles required translation – 1 Japanese, 1

Turkish, 1 French, 1 Italian).

Exclusion criteria (Figure 1): studies assessing treatment of PRP; studies involving

participants with Raynauds secondary to other diseases; studies assessing Raynauds in a

specific occupation e.g., people using vibration tools; unpublished material, case reports,

editorials, letters or reviews.

3. Data extraction and quality assessment

Study characteristics including age range, gender ratio and total number of participants in

the study were documented. The study design, country, setting (i.e. hospital or community

based) were also assessed and noted. If more than one article used the same study

population, the article where the data was felt to be presented most clearly was used in the

study. The definition of PRP and instruments used to confirm the condition were also

documented. The number of cases of PRP out of the number of people studied in a certain

time in the general population was documented as unadjusted crude prevalence. Incidence

figures were documented if the number of new cases of PRP in the population at risk

studied over a given period of time was stated.

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Risk factors and associations in the form of relative risk (RR) or Odds ratio (OR) were

extracted or calculated for the following:

o Constitutional: age, gender

o Environmental: employment, education, marital status, sex hormone

medications

o Genetic: family history in 1st

degree relatives

o Associations: smoking, alcohol, cardiovascular disease, migraine

An independent reviewer (RK) assessed a random selection of articles to ensure quality of

data extraction. The checklist for the Meta-analysis of Observational Studies in

Epidemiology (MOOSE) was followed to report the findings.[12]

4. Statistical analysis

Individual data for prevalence and incidence were derived from the original report either

directly or indirectly from the information provided in each study. Individual data for RR or

OR for risk factors or associations with PRP were extracted from the original report or

calculated using the available data given in the study. The fixed effects model was used to

combine the data if they were homogenous, otherwise the random effects model was used

if the data were heterogeneous.[13] Heterogeneity was examined using Forrest plots,

Cochran Q tests and I2

statistic as a measure for inconsistency due to chance.[14, 15]

Publication bias was assessed using funnel plots and Eggers test.[16] All analyses were

undertaken using StatsDirect© Version 2.7.9.

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RESULTS

1: Study characteristics

2378 citations were found in the initial literature search. 467 duplicates were removed and

1871 citations were excluded as they did not meet the inclusion criteria (Figure 1). The final

number of studies available for analysis was 33 (33, 733 subjects). There were 2 cohort

studies[17, 18] (1, 632 subjects), 17 cross-sectional studies[6, 19-34] (25, 797 subjects) and

14 case-control studies[7-11, 35-43] (6, 304 subjects) (Table 1). Data for incidence and

prevalence were taken from cohort and cross-sectional studies respectively. Data for risk

factors were taken from all studies as long as the results were reported.

Age ranges across different study designs were as follows: case-control (16-79 years), cohort

(18-81 years), cross sectional (12-84 years). 67% of the studies involved participants

recruited in a community based setting. The majority of studies were conducted in Europe

(18)[6, 9, 17, 20, 22, 24, 25, 27, 28, 30, 31, 33-35, 37, 39-41] or the USA (10)[7-8, 10-11, 18-

19, 21, 36, 38, 42], however other countries of origin included Japan (2)[23, 26], New

Zealand (1)[32] and Israel (1)[43]. One comparison study included participants from USA and

France.[29]

Participants were surveyed by means of phone, face-to-face interview, and/or postal

questionnaire. 26 studies included a physical examination which also included blood testing

(including serology), nail fold capillaroscopy and use of colour chart/photographs (Table 1)

10 studies used specific criteria to define PRP (3 studies Allen & Brown[8, 19, 30], 3 Leroy &

Medsger[9, 34, 35], 4 UK Scleroderma Study Group[6, 20, 31-32]). The remaining studies

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used a combination of cold sensitivity, varying degrees of colour change and sensory

symptoms via questionnaire or interview to define PRP. Colour charts or photographs to

indicate colour change were used in 12 studies[6-7, 9-10, 17-18, 23, 26-27, 29, 31, 33] and

nailfold capillaroscopy was performed as part of the examination in 10 studies.[8-9, 17, 29,

34, 35, 37, 39-41] In 15 studies, blood testing including serology and/or inflammatory

markers were performed.[6, 8-9, 11, 22, 28, 31, 34-35, 37-42]

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Table 1: Characteristics of studies

Cohort Cross-sectional Case-control All studies

No. of studies 2 17 14 33

No. of subjects 1632 25797 6304 33733

Age 18 – 81 12-84 16-79 12-84

Setting

Community-based 2 14 5 21

Hospital-based 0 2 9 11

Community & hospital 0 1 0 1

Region of study

USA 1 2 7 10

Europe 1 11 6 18

France & USA 0 1 0 1

Japan 0 2 0 2

New Zealand 0 1 0 1

Israel 0 0 1 1

Diagnosis*

Questionnaire 0 5 2 7

Questionnaire + Examination 2 9 12 23

* Diagnosis was classified as questionnaire based or, questionnaire and examination based diagnosis. The former include phone survey, postal questionnaire and face to

face interview whereas the latter include clinical examination, blood testing including serology, use of colour chart/photographs and capillaroscopy in addition to the

questionnaire. Colour chart/photographs were used in 12 studies (cohort 2, cross sectional 7, case control 3) and capillaroscopy used in 10 studies(Cohort 1, cross sectional

2, case control 7).

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2: Prevalence of PRP

The overall prevalence for definite PRP varied from 1.6 – 7.2% in 6 cross sectional studies in

the general population (women: 2.1-15.8% and men 0.8-6.5%).[19, 21, 23, 25, 29, 31] The

pooled prevalence was 4.85% (95% CI 2.08%, 8.71%) (Figure 2), with 5.74% (95% CI 2.74,

9.75) in women and 4.12% (95% CI 1.60, 7.74) in men.

The overall prevalence for possible PRP ranges from 3.98% to 12.7% (women: 4.5-17.9% and

men: 3.4-7.2%) in three cross sectional studies.[24, 32-33] The prevalence in specific

populations varies depending on the studies (Table 2)

In 6 studies assessing the general population we found the lowest prevalence of PRP in

Japan with an overall prevalence of 1.6 (2.1% in women, 1.1% in men).[23] Highest overall

prevalence figures were found in the USA with a median prevalence of 7.5% (7.8% in

women, 5.8% in men,).[19, 21] A study from France also showed high prevalence figures of

11.75% in women and 6.5% in men (median values).[29] (Table 3)

Five studies reported prevalence of PRP by age.[6, 26-28, 32] Leppert (1987) reported that

prevalence in 4 age bands 18-29, 30-39, 40-49 and 50-59 were 11%, 16%, 14% and 16%

respectively. The other four other studies (Iwata (1987), Voulgari (2000) Purdie (2009) and

Jones (2003) also failed to find any increase or decrease in PRP with age.

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Figure 2: Funnel plot and Forest plot showing the pooled prevalence of definite Primary Raynauds Phenomenon for 5 general population studies

Funnel plot for publication bias Egger’s assymetric test p=0.22

0.00 0.02 0.04 0.06 0.080.012

0.009

0.006

0.003

0.000

Prevalence

Standard error

Forest plot for heterogeneity, I2=98.2% (95% CI = 97.6, 98.6)

p for heterogeneity < 0.0001

0.00 0.02 0.04 0.06 0.08 0.10

combined 0.05 (0.02, 0.09)

Onbasi 2005 0.06 (0.04, 0.08)

Ivorra 2001 0.03 (0.02, 0.06)

Harada 1991 0.01 (0.01, 0.02)

Fraenkel 1999 0.08 (0.07, 0.09)

Brand 1997 0.07 (0.06, 0.08)

Prevalence (95% confidence interval)

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Table 2: Prevalence of Primary Raynaud’s Phenomenon in 17 studies

First Author Country Setting Sample Size

Mean Age (Range

/ SD)

% Female

Prevalence

Overall (%)

Female (%) Male (%)

Prevalence of definite primary raynaud’s phenomenon in general population studies

Brand 1997 Boston, USA Com 4182 51.8 52.2 7.2 7.8 6.5

Fraenkel 1999 Boston, USA Com 1525 53.9 52.5 7.8 9.6 5.8

Harada 1991 Ehime, Japan Hosp 3873 20 – 70 51.6 1.6 2.1 1.1

Ivorra 2001 Valencia, Spain Com 276 54.4 74.3 3.3 3.4 2.8

Maricq 1997 South Carolina, USA Com 432 18+ NS NS 3.4 0.8

Toulon, France Com 189 18+ NS NS 11.4 2.8

Nyons, France Com 345 18+ NS NS 5.8 6.2

Grenoble, France Com 272 18+ NS NS 12.1 6.4

Tarentaise, France Com 296 18+ NS NS 15.8 6.3

Onbasi 2005 Van, Turkey Com 768 29.2 ( 10.4) 46.6 5.9 7.0 4.9

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Prevalence of possible primary raynaud’s phenomenon in general population studies

Heslop 1983 Southampton, UK Com 450 20 - 59 50.9 12.7 17.9 7.2

Purdie 2009 New Zealand Com 234 18+ 56.8 11.5 17.3 4.0

Sahin 2003 Van, Turkey Hosp 251 28.9 53.4 3.98 4.5 3.4

Prevalence of primary raynauds phenomenon in specific population studies

Prevalence of primary raynauds phenomenon in single gender only population studies

Leppert 1987 Vasteras, Sweden Com 2705 18-59 100 - 15.6 -

Olsen 1978 Copenhagen, Denmark Com 67 21-50 100 - 22.4 -

Tzilalis 2011 Athens, Greece Com 3912 18-28 0 - - 0.18

Prevalence of primary raynauds phenomenon in studies using hospital personnel

Cakir 2008 Edirne, Turkey Com 1414 27.2 59.3 3.6 4.8 1.9

Gallo 1994 Milan, Italy Com 1920 15-84 68 4.2 4.5 3.9

Iwata 1987 Japan C&H 1470 18-59 56.8 4.8 6.5 2.5

Voulgari 2000 Ioannina, Greece Com 500 33.7 (6.2) 77.8 5.2 6.4 0.9

Prevalence of primary raynauds phenomenon in studies assessing children

Jones 2003 Manchester, UK Com 716 12-15 50.8 14.9 17.6 12.2

Com Community, Hosp Hospital, C&H Community and hospital

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Table 3: Regional variation of prevalence of primary raynaud’s phenomenon for general population studies

Country No. Of Studies No. Of

Participants

Prevalence %

Male Female Total

USA† 3 6139 5.8 7.8 7.5

France† 1 1102 6.3 11.75 -

Spain 1 276 2.8 3.4 3.3

Turkey 1 768 4.9 7.0 5.9

Japan 1 3873 1.1 2.1 1.6

TOTAL 6 12158

† Median values calculated for prevalence. USA gender figures include data from Maricq 1997 (France & USA). Total USA prevalence figure includes data

from 2 USA only studies

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3: Incidence of Primary Raynauds Phenomenon

Only two studies reported incidence rates.[17-18] Carpentier et al reported an annual

incidence rate of 0.25% (95% CI 0.17, 0.33), with 0.24% in women and 0.26% in men and

Suter et al reported a 7-year incidence of 1.87% (2.2% in women and, 1.5% in men). Neither

study provided 95%CIs.

4: Risk factors and associations

In 18 studies (23, 197 participants), there was a positive association between female gender

and PRP (OR 1.65, 95% CI 1.42, 1.91).[6-7, 9, 18-27, 31-33, 35, 42] Family history, assessed in

2 studies looking at 1st degree relatives, also had a positive significant association with PRP

(OR 16.6, 95%CI 7.44, 36.8).[8-9] No significant association was found with education

beyond primary school age.[6, 35] (Table 4). Manual occupation (not including vibration

tool use) had an OR of 2.66 (95% CI 1.73, 4.08) in 1 study of 3873 participants.[23] In 4

studies, marriage had an OR of 0.60 (95% CI 0.43, 0.83).[6-7, 21, 35] Smoking was found to

have an association in 9 studies giving a pooled OR of 1.27 (95% CI 1.06, 1.53).[7, 9-11, 18,

20-21, 30, 42] Alcohol use,[21, 42] participants with positive Helicobacter Pylori

investigations[37, 39] and those with conditions such as diabetes,[21] hypertension[11, 21]

and hypercholesterolaemia[21] did not have a significant association with PRP.

Migraine had a positive significant association with a pooled OR of 4.02 (95% CI 2.62, 6.17)

in 6 studies.[6, 9-11, 20, 43] One study of 3442 participants reported a positive association

of cardiovascular disease with PRP with an OR of 1.69 (95% CI 1.22, 2.34).[42]

Cardiovascular disease in this study included a history of ischaemic heart disease,

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intermittent claudication, congestive cardiac failure and cerebrovascular disease. A single

study using 81 participants did not show a positive significant association of coronary heart

disease with PRP.[38]

A positive association was found in participants taking oestrogen replacement therapy alone

in two studies with an OR of 2.34 (95% CI 1.42, 3.84).[21, 36] However no significant

association was found in combined oestrogen and progesterone replacement therapy[36] in

postmenopausal women or in oral contraceptive pill[10-11] use in two other studies. A

study by Smyth et al looking at allele frequencies of known polymorphisms of candidate

vasoactive mediator genes (eNOS, BKRG, ET01 and ETA receptor genes) did not show any

association.[9] Shemirani et al looked at clotting factors in participants with PRP and found a

significant association with methyltetrahydrofolate reductase C677T mutations (OR 0.4, 95%

CI 0.2, 0.9) but no difference in other thrombosis-associated alleles (FVLeiden, prothrombin

G20210A).[40]

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Table 4: Association of Raynaud’s Phenomenon with demographic, environmental, comorbid illness and pharmacological factors

Risk Factor No. of studies (No. of patients) OR 95% CI I2

% (95% CI)

Cochran Q P value

Female 18 (23197) 1.65 1.42, 1.91 17.2 (0, 53) 0.2476

Family History of RP 2 (421) 16.6 7.44, 36.8 - 0.3399

Marital Status* 4 (2650) 0.60 0.43, 0.83 16.9 (0,73) 0.3067

Education† 2 (891) 1.52 0.89, 2.59 - 0.2431

Manual occupation 1 (3873) 2.66 1.73, 4.08 - -

Smoking 9 (8501) 1.27 1.06, 1.53 6.2 (0.8, 57.1) 0.3835

Alcohol 2 (4967) 0.33 0.02, 5.37 - < 0.0001

Migraine‡ 6 (2595) 4.02 2.62, 6.17 35.9 (0, 73.6) 0.1675

Diabetes 1 (1525) 0.51 0.2, 1.27 - -

Hypertension 2 (1711) 1.00 0.67, 1.48 - 0.4606

Hypercholesterolaemia 1 (1525) 0.86 0.53, 1.40 - -

Coronary Heart Disease 1 (81) 0.58 0.1, 3.31 - -

Cardiovascular disease+ 1 (3442) 1.69 1.22, 2.34 - -

H. Pylori¥ 2 (265) 0.91 0.51, 1.63 - 0.0735

OCP 2 (268) 0.69 0.34, 1.38 - 0.8821

Oestrogren replacement therapy± 2(1242 2.34 1.42, 3.84 - 0.8092

RP Raynaud’s phenomenon, H. Pylori Helicobacter Pylori, OCP Oral contraceptive pill

*Marital status reference used are single/separated/widowed/divorced apart from Fraenkel 1998 and Keil 1991 where the reference used is widowed/separated/divorced

† Reference for educaXon used is primary school (De Angelis 2008) and < 12years education (Voulgari 2000)

‡ O’Keefe (1992) did not report whether their calculation for OR was adjusted/unadjusted. All other reported calculations for OR are unadjusted.

+ Cardiovascular disease includes history of angina, myocardial infarction, coronary insufficiency, intermittent claudication, congestive cardiac failure, stroke and transient

ischemic attack

¥ Positive investigation for Helicobacter pylori uses urea breath test (Savarino 2000) and serology (Herve 2006)

± Adjusted for age BMI alcohol cigarettes and B adrenoreceptor antagonists in study by Fraenkel (1998)

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DISCUSSION

This is the first meta-analysis of the literature for the prevalence, incidence, risk factors and

associations of PRP. Overall the pooled mean prevalence of PRP in the general population

was 4.85% (95% CI 2.08%, 8.71%) (Figure 2) and the mean incidence was 0.25% (95% CI

0.17, 0.33) per annum.[17] Major risk factors/associations of PRP include female gender,

family history of PRP, migraine, smoking, cardiovascular disease, manual occupation,

oestrogren replacement therapy and possibly marital status. (Table 4).

Variations in prevalence were observed between countries (Table 3) though this could

reflect use of different diagnostic criteria rather than real differences in prevalence. Almost

all studies demonstrate a higher prevalence of PRP in women. This may be due to a

relationship with female hormones as two studies found an association between PRP and

use of oestrogen replacement therapy alone,[21, 36] although no association was found

between combined oestrogen and progesterone replacement or the oral contraceptive

pill.[10-11, 36] In contrast, prevalence of PRP does not increase with age in all published

studies with a wide age range of participants from 12 years up to 84 years. This accords

with the clinical observation that PRP usually starts in teenage years and that later

development, which is far less common, is characteristic of secondary RP. While the former

may be driven predominantly by genetic risk factors, later onset “primary” Raynaud’s may

be predominantly influenced by environmental exposures such as vascular microtrauma

from manual usage and vibrating tools. In terms of other environmental factors we did find

a weak negative association between marital status and PRP with an OR of 0.60 (95%CI 0.43,

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0.83) in those that are married vs. single/separated/widowed/divorced.[6-7, 21, 35]

However, there is no plausible biological explanation for this and the reported data may not

be free from confounding bias.

The association of cardiovascular disease and autoimmune disease is well documented and

thought to be due to accelerated atherosclerosis as a result of chronic inflammation,

treatment such as glucocorticoids as well as the traditional risk factors for cardiovascular

disease.[44-50] A link between cardiovascular disease and PRP has been shown in only one

study[42] and a reason for this association is not known. It is unlikely to be due to an

inflammatory process or related to medication and with PRP having predominance for the

female population and onset at a young age it not clear if traditional cardiovascular risk

factors play a part. However, smoking was found to have positive association with PRP in

our study (OR 1.27, 95% CI 1.06, 1.53). It is well known that smoking is one of three

(smoking, hypertension and hyperlipidaemia) main risk factors for cardiovascular and

cerebrovascular disease.[51-57] Smoking may be the same risk factor for PRP and CVD.

Whether smoking causes PRP first then CVD is an interesting question which deserves

further research. More interestingly, we found a very strong association between migraine

and PRP (OR 4.02, 95%CI 2.62, 6.17). It has been previously shown that migraine is due to a

cascade of vascular and neural events.[44-45] However, a review by Rosamund suggested

migraine was not shown to be linked with coronary heart disease but possibly shares a

common underlying pathophysiology with Raynaud’s phenomenon and other vasospastic

disorders such as variant angina.[58-59] It is thought there may be other factors that may

affect the underlying mechanism for these vasospastic conditions as episodes occur at

different times with differing precipitants.[60-61] Further study may help clarify whether

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PRP is a benign vasospastic disorder or whether there is underlying pathology affecting the

vascular wall associated with traditional risk factors seen in cardiovascular disease.

There are number of caveats to this study. Firstly, it was striking that there was no uniform

definition for diagnosis of PRP. Only 39% of studies looking at prevalence had a precise

definition for PRP, thereby reducing the number of studies we used to assess pooled

prevalence. We feel that an amalgamation of the generally more commonly used definitions

would ensure that the diagnosis is clear by assessing symptoms, using colour chart or

photographs for confirmation of colour change and carefully exclude underlying conditions

including checking for digital infarcts/ulceration, nailfold capillaroscopy and assessing

autoimmune screen and inflammatory markers. Secondly, as our objective was to

specifically examine the epidemiology of PRP a large proportion of studies were excluded

because they focused on secondary Raynaud’s phenomenon, especially related to

connective tissue diseases and vibration white finger. In addition we also excluded studies

that looked at investigation or treatment of PRP. This left only a small number of studies to

assess. From the studies included, there was a great deal of variation in the population of

participants used. 9 out of the 17 studies used investigated participants in the general

population whereas the remainder examined specific populations such as single gender,

children or hospital/medical personnel. Furthermore, there was considerable variation in

the risk factors addressed in each study and this may have affected the significance and

association, or lack of association between the risk factors and PRP. We tried to extract as

many risk factors from each study as possible to use in our analysis. In the future, a larger

multinational population study may help us to get a better understanding of the disease.

This would be particularly useful if standardised criteria were used to include participants in

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the studies, using strict definition for PRP (as mentioned previously) and data was collected

in a similar fashion assessing a wide variety of possible risk factors (particularly related to

cardiovascular disease and vasospastic disoders) for more accurate data analysis.

CONCLUSION

This first systematic review summarises the burden of PRP in the general population using

published literature. It is not a rare condition (prevalence 4.85% and annual incidence

0.25%). It starts at a young age, is more common in women and associates with a family

history and with smoking. In addition, people with PRP are 4 times more likely to have

migraine than those without this condition.

ACKNOWLEDGEMENT: Our sincere thank you to Joanna Ramowski and Helen Richardson for

article retrieval and support. Also special thank you to Anu Suokas, Karin Tatsumoa,

Professor Tiraje Truncer, Ana Valdes and Maggie Wheeler for language translation.

AUTHOR CONTRIBUTIONS

Study conception and design: Dr Zhang, Professor Doherty, Dr Lanyon, Dr Garner

Acquision of data: Dr Garner, Dr Kumari, Dr Zhang

Statistical Analysis: Dr Garner, Dr Zhang

Analysis and interpretation of data: Dr Garner, Dr Zhang, Professor Doherty, Dr Lanyon

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Manuscript preparation and final approval of manuscript: Dr Garner, Dr Zhang, Professor

Doherty, Dr Lanyon

Funding No funding

Competing interests None

Ethical approval and patient consent Not required

Data sharing statement No unpublished data were used in this study. No additional data

available.

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Supplementary file

Appendix 1: Medline/Embase/Cinahl/AMED search strategy

Any field

No limitations

1: Randomised control trial (exploded)

2: Double blind (exploded)

3: Single blind (exploded)

4: Placebo (exp)

5: Comparative study (exp)

6: 1 OR 2 OR 3 OR 4 OR 5

7: meta-analysis or systematic review

8: metanalysis exp

9: quantitative review

10: quantitative overview

11: statistical pool

12: 7 or 8 or 9 or 10 or 11

13: Cohort studies exp

14: cohort stud

15: exp prospective studies

16: prospective stud

17: relative risk

18: incidence exp

19: 13 or 14 or 15 or 16 or 17 or 18

20: exp case- control studies

21: case control stud

22: exp retrospective studies

23: retrospective stud

24: exp odds ratio

25: odds ratio

26: 20 or 21 or 22 or 23 or 24 or 25

27: exp cross sectional

28: cross sectional

29: exp risk

30: prevalence exp

31: 27 or 28 or 29 or 30

32: Raynaud Disease

33: Raynaud

34: 32 or 33

35: Epidemiology

36: 19 or 26 or 31 or 35

37: 34 and 36 (incidence or risk or prevalence or epidemiology) and raynauds

38: 32 and 35 (raynauds and epidemiology)

39: 30 and 32 ( prevalence and raynaud disease)

40: 18 and 32 (incidence and raynaud disease)

41: 12 and 33 (systematic review and raynauds disease)

42: 6 and 32 (RCT and Raynauds disease)

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PubMed search strategy

#43 Search (#6) AND #33 RCT and Raynauds disease

#42 Search (#12) AND #33 systematic review and raynauds disease

#41 Search (#18) AND #33 incidence and raynaud disease

#40 Search (#30) AND #33 prevalence and raynaud disease

#39 Search (#33) AND #36 raynauds and epidemiology

#38 Search (#35) AND #37 (incidence or risk or prevalence or epidemiology) and raynauds #37 Search (((#19) OR #26) OR #31) OR #36 #36 Search Epidemiology #35 Search (#33) OR #34 #34 Search Raynaud #33 Search Raynauds Disease #31 Search (((#27) OR #28) OR #29) OR #30 #30 Search prevalence #29 Search risk #28 Search "cross sectional"[All Fields] #27 Search cross sectional #26 Search (((((#20) OR #21) OR #22) OR #23) OR #24) OR #25 #25 Search "odds ratio"[All Fields] #24 Search odds ratio #23 Search "retrospective studies"[All Fields] #22 Search retrospective studies #21 Search "case control"[All Fields] #20 Search case control #19 Search (((((#13) OR #14) OR #15) OR #16) OR #17) OR #18 #18 Search incidence #17 Search relative risk #16 Search "prospective studies"[All Fields] #15 Search prospective studies #14 Search "cohort studies"[All Fields] #13 Search cohort studies #12 Search ((((#7) OR #8) OR #9) OR #10) OR #11 #11 Search statistical pool #10 Search quantitative overview #9 Search quantitative review #8 Search systematic review #7 Search meta-analysis #6 Search ((((#1) OR #2) OR #3) OR #4) OR #5 #5 Search comparative study #4 Search placebo #3 Search single blind #2 Search double blind #1 Search randomised control trials

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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 4

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

4,5

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years

considered, language, publication status) used as criteria for eligibility, giving rationale. 6-7

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5, Supplementary material – appendix 1

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

5-7

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

7-8

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

7-8

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 7-8

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of

consistency (e.g., I2) for each meta-analysis.

8

Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

8

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

6, 9

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

9-11

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

12-19

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 13

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 13

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 12-19

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

20-23

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

20-23

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 20-23

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

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For more information, visit: www.prisma-statement.org.

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Prevalence, risk factors and associations of Primary

Raynaud’s Phenomenon: Systematic review and meta-

analysis of observational studies

Journal: BMJ Open

Manuscript ID: bmjopen-2014-006389.R1

Article Type: Research

Date Submitted by the Author: 11-Dec-2014

Complete List of Authors: Garner, Rozeena; Queens Medical Centre, Rheumatology Kumari, Rakesh; Queens Medical Centre, Rheumatology Lanyon, Peter; Nottingham University Hospital, Rheumatology; Queens

Medical Centre, Rheumatology Doherty, Michael ; University of Nottingham, Academic Rheumatology Zhang, Weiya; University of Nottingham, Academic Rheumatology; Nottingham University, Academic Rheumatology

<b>Primary Subject Heading</b>:

Epidemiology

Secondary Subject Heading: Rheumatology

Keywords: RHEUMATOLOGY, EPIDEMIOLOGY, STATISTICS & RESEARCH METHODS


BMJ Open on M

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Prevalence, risk factors and associations of Primary Raynaud’s Phenomenon: Systematic 1

review and meta-analysis of observational studies 2

3


2, Peter 4


1, 2, Weiya Zhang BMed 5

MEpi PhD1 6


2Department of Rheumatology, 7

Queens Medical Centre, UK 8

9

10

Correspondence to: 11

Dr Weiya Zhang 12

Academic Rheumatology 13

Clinical Sciences Building 14

Nottingham City Hospital 15

Nottingham NG5 1PB 16

UK 17

Telephone: +44 (0)115 823 1756 18

Fax: +44 (0)115 823 1757 19

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Email: [email protected] 1

2

Keywords: Primary Raynaud’s phenomenon, prevalence, incidence, risk factors, systematic 3

review 4

Word Count: Abstract: 244, main text: 3133 5

6

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Abstract 1

Objective: To systematically review the literature with regard to the prevalence, incidence, 2

risk factors and associations of primary Raynaud’s phenomenon (PRP). 3

Method: A systematic review of the literature of observational studies for PRP was 4

undertaken using five electronic databases. Any studies reporting prevalence, incidence and 5

risk factors of PRP were collected. Relative risk or odds ratio (OR) and 95% confidence 6

interval (CI) were extracted or calculated to present the association between risk factors 7

and PRP. Random effects model was used to pool the results. 8

Results: 33 articles assessing a total of 33, 733 participants were included in this analysis (2 9

cohort, 17 cross-sectional and 14 case-control studies). The pooled prevalence of PRP was 10

4.85% (95% CI 2.08%, 8.71%) in the general population. The pooled annual incidence of PRP 11

was 0.25% (95% CI 0.19, 0.32). Risk factors and associations for PRP included female gender 12

(OR 1.65, 95% CI 1.42, 1.91), family history (OR 16.6, 95% CI 7.44, 36.8), smoking (OR 1.27, 13

95% CI 1.06, 1.53), manual occupation (OR 2.66 95% CI 1.73, 4.08), migraine (OR 4.02, 95% 14

CI 2.62, 6.17), cardiovascular disease (OR 1.69, 95% CI 1.22, 2.34) and marital status 15

(married) (OR 0.60, 95% CI 0.43, 0.83). The definition of PRP varied considerably between 16

studies. 17

Conclusion: This is the first systematic review of the prevalence, incidence, risk factors and 18

associations of PRP. Further study using uniform strict criteria for the condition is required 19

to confirm these findings, particularly the possible association with cardiovascular disease. 20

21

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1

Strengths and limitations of this study 2

• This is the first meta-analysis of the literature for the global epidemiology of primary 3

Raynaud’s phenomenon (PRP). 4

• The prevalence and incidence of PRP in different countries were estimated. Female 5

gender, positive family history, smoking and migraines were found to be the major risk 6

factors for PRP. 7

• The lack of original data restricted an adequate estimation of the age-effect on PRP. 8

• Different definitions of PRP handicapped a comparison between countries 9

10

INTRODUCTION 11

In the 19th century, Maurice Raynaud first described Raynaud’s phenomenon (RP) as an 12

episodic, symmetrical, vasospastic disorder resulting in classic triphasic colour change, 13

trophic changes limited to the skin and uncomfortable sensory symptoms of the extremities 14

in the absence of arterial occlusion.[1] Further criteria have been suggested to distinguish 15

Primary RP (PRP) from secondary RP which include detail regarding symptom duration, 16

negative autoimmune serology, normal serum inflammatory markers and capillaroscopy, 17

and the clinical absence of any underlying disease.[1-4] Use of colour charts to aid 18

diagnosis has also been used.[4, 5] Despite this, there is no unifying definition that is used 19

worldwide for PRP. 20

21

There have been a number of studies performed in various countries reporting the 22

prevalence of RP. The reported prevalence ranges from less than 1% (in men) and up to 23

20% (in women) depending on definitions and population selected.[6] In contrast, few 24

studies have examined the incidence of PRP and the true burden of PRP in the general 25

population remains unclear. PRP is thought to be more common in women, particularly 26

when it develops at a young age.[7] There are also reports of a hereditary component and 27

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links with other vasospastic conditions such as migraine.[8-11] It is uncertain whether other 1

co-morbidities or risk factors particularly related to vascular diseases such as ischaemic 2

heart disease and/or smoking have an association with PRP. 3

4

The primary objective of this study was to perform a systematic review of observational 5

studies to summarise the literature with regard to the prevalence, incidence and risk 6

factors/associations of PRP. The secondary objective was to examine the current definitions 7

used to define PRP worldwide. 8

METHODS 9

1: Literature search – data sources and search strategy 10

A comprehensive systematic literature search was undertaken in June 2011 and re-run in 11

October 2014 using five databases: Medline, Embase, Cinahl, Amed and Pubmed. The 12

search terms for “Raynauds” or “Raynauds disease” were combined with the terms 13

“epidemiology” , “prevalence”, “risk” or “incidence” to generate the citations (see Appendix 14

1 for full details of search strategy). “Cross sectional”, “case-control” or “cohort” studies and 15

“systematic review” were also applied for types of studies. 16

Abstracts were reviewed and the full papers were sought where abstracts were felt to be 17

relevant. Any duplicate articles were excluded (Figure 1). Where there was difficulty in 18

article retrieval, the authors were contacted via email. The literature search and abstract 19

review was completed by RG and validated by WZ. Reference lists of the review articles 20

were also examined for relevant studies. 21

22

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2: Inclusion and Exclusion Criteria 1

Inclusion criteria: studies reporting the prevalence and/or incidence of PRP; studies 2

reporting potential risk factors associated with PRP; studies reporting human data on PRP in 3

people of any age; studies in any language (4 articles required translation – 1 Japanese, 1 4

Turkish, 1 French, 1 Italian). 5

Exclusion criteria (Figure 1): studies assessing treatment of PRP; studies involving 6

participants with RP secondary to other diseases; studies assessing RP in a specific 7

occupation e.g., people using vibration tools; unpublished material, case reports, editorials, 8

letters or reviews. 9

3. Data extraction and quality assessment 10

Study characteristics including age range, gender ratio and total number of participants in 11

the study were documented. The study design, country, setting (i.e. hospital or community 12

based) were also assessed and noted. If more than one article used the same study 13

population, the article where the data was felt to be presented most clearly was used in the 14

study. The definition of PRP and instruments used to confirm the condition were also 15

documented. The number of cases of PRP out of the number of people studied in a certain 16

time in the general population was documented as unadjusted crude prevalence. Incidence 17

figures were documented if the number of new cases of PRP in the population at risk 18

studied over a given period of time was stated. 19

Individual odds ratio (OR), relative risk (RR) or hazard ratio (HR) and their 95%confidence 20

interval (CI) were extracted or calculated for the following: 21

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o Constitutional: age, gender 1

o Environmental: employment, education, marital status, sex hormone 2

medications 3


degree relatives 4

o Associations: smoking, alcohol, cardiovascular disease, migraine 5

6

All studies were reviewed by RG to assess study quality and for data extraction and were 7

validated by WZ. An independent reviewer (RK) assessed a random selection of articles to 8

ensure quality of data extraction. Study quality was assessed according to study design 9

(cohort, cross-sectional and case control), setting (community or hospital), sample size, case 10

definition, exposure definition, confounding factors and adjustment. Quality scoring for 11

studies was not performed as it is not possible or fair to assign equal weight to different 12

quality aspects related to the study. However, current consensus standards of reporting 13

meta-analysis of observational studies in epidemiology (MOOSE) [12] were followed, and 14

subgroup/sensitivity analysis was undertaken to examine the changes of the estimate 15

according to different quality aspects 16

4. Statistical analysis 17

Individual data for prevalence and incidence were derived from the original report either 18

directly or indirectly from the information provided in each study. The pooled proportion 19

was calculated as the back-transform of the weighted mean of the transformed proportion, 20

using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird 21

(1986) weights for the random effects model. [13, 14] Cumulative incidence and 95%CI were 22

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transformed into incidence rate data (i.e., incidence per 100 person-years) and pooled 1

incidence rate was estimated. Individual data for OR, RR and HR were pooled to present 2

the overall relative risk of all observational studies, as well as separately for each specific 3

risk measure or study design as appropriate. Random-effects mode was used to pool the 4

data.[15] Heterogeneity was examined using Forest plots, Cochran Q tests and I2

statistic as 5

a measure for inconsistency due to chance.[16, 17] Publication bias was assessed using 6

funnel plots and Eggers test or the Harbord test if the number of studies included in the 7

meta-analysis was too small (≤4).[18] All analyses were undertaken using StatsDirect© 8

Version 2.7.9. 9

10

RESULTS 11

1: Study characteristics 12

2378 citations were found in the initial literature search. 467 duplicates were removed and 13

1871 citations were excluded as they did not meet the inclusion criteria (Figure 1). The final 14

number of studies available for analysis was 33 (33, 733 subjects). There were 2 cohort 15

studies[19, 20] (1, 632 subjects), 17 cross-sectional studies[6, 21-36] (25, 797 subjects) and 16

14 case-control studies[7-11, 37-45] (6, 304 subjects) (Table 1). Data for incidence and 17

prevalence were taken from cohort and cross-sectional studies respectively. Data for risk 18

factors were taken from all studies as long as the results were reported. 19

Age ranges across different study designs were as follows: case-control (16-79 years), cohort 20

(18-81 years), cross sectional (12-84 years). 67% of the studies involved participants 21

recruited in a community based setting. The majority of studies were conducted in Europe 22

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(18)[6, 9, 19, 22, 24, 26, 27, 29, 30, 32, 33, 35-37, 39, 41-43] or the USA (10)[7-8, 10-11, 20-1

21, 23, 38, 40, 44], however other countries of origin included Japan (2)[25, 28], New 2

Zealand (1)[34] and Israel (1)[45]. One comparison study included participants from USA and 3

France.[31] 4

Participants were surveyed by means of phone, face-to-face interview, and/or postal 5

questionnaire. 26 studies included a physical examination which also included blood testing 6

(including serology), nail fold capillaroscopy and use of colour chart/photographs (Table 1) 7

10 studies used specific criteria to define PRP (3 studies [8, 21, 32] Allen & Brown[1], 3[9, 8

36, 37]Leroy & Medsger[2], 4[6, 22, 33-34] UK Scleroderma Study Group[4]). The remaining 9

studies used a combination of cold sensitivity, varying degrees of colour change and sensory 10

symptoms via questionnaire or interview to define PRP. Colour charts or photographs to 11

indicate colour change were used in 12 studies[6-7, 9-10, 19-20, 25, 28-29, 31, 33, 35] and 12

nailfold capillaroscopy was performed as part of the examination in 10 studies.[8-9, 19, 31, 13

36, 37, 39, 41-43] In 15 studies, blood testing including serology and/or inflammatory 14

markers were performed.[6, 8-9, 11, 24, 30, 33, 36-37, 39-44] 15

Studies with clear definition of PRP or clear exclusion criteria for secondary RP were 16

categorised as “definite PRP” in this study. Studies with less clear definition of PRP were 17

categorised as “possible PRP”. Studies with clear definition of secondary RP were excluded.18

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2: Prevalence of PRP 1

The overall prevalence for definite PRP varied from 1.6 – 7.2% in 6 cross sectional studies in 2

the general population (women: 2.1-15.8% and men 0.8-6.5%).[21, 23, 25, 27, 29, 33] The 3

pooled prevalence was 4.85% (95% CI 2.08%, 8.71%) (Figure 2), with 5.74% (95% CI 2.74, 4

9.75) in women and 4.12% (95% CI 1.60, 7.74) in men. We used the Harbord test to detect 5

publication bias (1.59 92.5% CI -21.6,24.8, P=0.87) 6

The overall prevalence for possible PRP ranges from 3.98% to 12.7% (women: 4.5-17.9% and 7

men: 3.4-7.2%) in three cross sectional studies.[26, 34-35] The prevalence in specific 8

populations varies depending on the studies (Table 2) 9

In 6 studies assessing the general population we found the lowest prevalence of PRP in 10

Japan with an overall prevalence of 1.6 (2.1% in women, 1.1% in men).[25] Highest overall 11

prevalence figures were found in the USA with a median prevalence of 7.5% (7.8% in 12

women, 5.8% in men,).[21, 23] A study from France also showed high prevalence figures of 13

11.75% in women and 6.3% in men (median values).[31] (Table 3) 14

Five studies reported prevalence of PRP by age.[6, 28-30, 34]. Three did not find any age-related 15

prevalence (Leppert1987, Iwata 1987 and Voulgari 2000). Purdie (2009) reported a higher 16

prevalence of PRP in younger compared to older age groups, whereas Fraenkel (1999) reported 17

higher prevalence in older age groups in men (adjusted OR=2.3, 95%CI 1.0 to 5.2 highest vs. lowest 18

tertile) but not in women (adjusted OR=0.9, 95%CI 0.4 to 1.6). Jones (2003) also showed a slight 19

increase in prevalence by age in yearly increments between ages 12-15 years. 20

21

22

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3: Incidence of Primary Raynauds Phenomenon

Only two studies reported incidence rates.[19-20] Carpentier et al reported an annual

incidence rate of 0.25% (95% CI 0.17, 0.33), with 0.24% in women and 0.26% in men and

Suter et al reported a 7-year incidence of 1.87% (2.2% in women and, 1.5% in men), which

was converted to an annual incidence rate of 0.26% (95%CI 0.17, 0.39). The pooled annual

incidence rate of these two studies was therefore 0.25% (95%CI 0.19, 0.32).

4: Risk factors and associations

In 18 studies (23, 197 participants), there was a positive association between female gender

and PRP (OR 1.65, 95% CI 1.42, 1.91).[6-7, 9, 20-29, 33-35, 37, 44] Family history, assessed in

2 studies looking at 1st degree relatives, also had a positive significant association with PRP

(OR 16.6, 95%CI 7.44, 36.8).[8-9] No significant association was found with education

beyond primary school age.[6, 37] (Table 4). Manual occupation (not including vibration

tool use) had an OR of 2.66 (95% CI 1.73, 4.08) in 1 study of 3873 participants.[25] In 4

studies, being married was associated with a lower risk of PRP with OR of 0.60 (95% CI 0.43,

0.83) compared with being single/divorced/widowed.[6-7, 23, 37] Smoking was found to

have an association in 9 studies giving a pooled OR of 1.27 (95% CI 1.06, 1.53).[7, 9-11, 20,

22-23, 32, 44] Alcohol use,[23, 44] participants with positive Helicobacter Pylori

investigations[39, 41] and those with conditions such as diabetes,[23] hypertension[11, 23]

and hypercholesterolaemia[23] did not have a significant association with PRP.

Migraine had a positive significant association with a pooled OR of 4.02 (95% CI 2.62, 6.17)

in 6 studies.[6, 9-11, 22, 45] One study of 3442 participants reported a positive association

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of cardiovascular disease with PRP with an OR of 1.69 (95% CI 1.22, 2.34).[44]

Cardiovascular disease in this study included a history of ischaemic heart disease,

intermittent claudication, congestive cardiac failure and cerebrovascular disease. A single

study using 81 participants did not show a positive significant association of coronary heart

disease with PRP.[40]

A positive association was found in participants taking oestrogen replacement therapy alone

in two studies with an OR of 2.34 (95% CI 1.42, 3.84).[23, 38] However no significant

association was found in combined oestrogen and progesterone replacement therapy[38] in

postmenopausal women or in oral contraceptive pill[10-11] use in two other studies. A

study by Smyth et al looking at allele frequencies of known polymorphisms of candidate

vasoactive mediator genes (eNOS, BKRG, ET01 and ETA receptor genes) did not show any

association.[9] Shemirani et al looked at clotting factors in participants with PRP and found a

significant association with methyltetrahydrofolate reductase C677T mutations (OR 0.4, 95%

CI 0.2, 0.9) but no difference in other thrombosis-associated alleles (FVLeiden, prothrombin

G20210A).[42]

DISCUSSION

This is the first meta-analysis of the literature for the prevalence, incidence, risk factors and

associations of PRP. Overall the pooled mean prevalence of PRP in the general population

was 4.85% (95% CI 2.08%, 8.71%) (Figure 2) and the mean incidence was 0.25% (95% CI

0.17, 0.33) per annum.[19] Major risk factors/associations of PRP include female gender,

family history of PRP, migraine, smoking, cardiovascular disease, manual occupation,

oestrogren replacement therapy and possibly marital status. (Table 4).

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Variations in prevalence were observed between countries (Table 3) though this could

reflect use of different diagnostic criteria rather than real differences in prevalence. The

heterogeneity of prevalence figures may also reflect the differences in the way the studies

were conducted, the selection of participants (e.g., age and gender), and the disease

definition. All studies (except for Maricq 1997) demonstrate a higher prevalence of PRP in

women. This may be due to a relationship with female hormones as two studies found an

association between PRP and use of oestrogen replacement therapy alone,[23, 38] although

no association was found between combined oestrogen and progesterone replacement or

the oral contraceptive pill.[10-11, 38] In contrast, prevalence of PRP does not increase with

age in five published studies with a wide age range of participants from 12 years up to 84

years.[6, 28-30, 34] This accords with the clinical observation that PRP usually starts in

teenage years and that later development, which is far less common, is characteristic of

secondary RP. While the former may be driven predominantly by genetic risk factors, later

onset “primary” Raynaud’s may be predominantly influenced by environmental exposures

such as vascular microtrauma from manual usage and vibrating tools. In terms of other

environmental factors we did find a weak negative association between marital status and

PRP with an OR of 0.60 (95%CI 0.43, 0.83) in those that are married vs.

single/separated/widowed/divorced.[6-7, 23, 37] However, there is no plausible biological

explanation for this and the reported data may not be free from confounding bias.

The association of cardiovascular disease and autoimmune disease is well documented and

thought to be due to accelerated atherosclerosis as a result of chronic inflammation,

treatment such as glucocorticoids as well as the traditional risk factors for cardiovascular

disease.[46-52] A link between cardiovascular disease and PRP has been shown in only one

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study[44] and a reason for this association is not known. It is unlikely to be due to an

inflammatory process or related to medication and with PRP having predominance for the

female population and onset at a young age it not clear if traditional cardiovascular risk

factors play a part. However, smoking was found to have positive association with PRP in

our study (OR 1.27, 95% CI 1.06, 1.53). It is well known that smoking is one of three

(smoking, hypertension and hyperlipidaemia) main risk factors for cardiovascular and

cerebrovascular disease.[53-59] Smoking may be the same risk factor for PRP and CVD.

Whether smoking causes PRP first then CVD is an interesting question which deserves

further research. More interestingly, we found a very strong association between migraine

and PRP (OR 4.02, 95%CI 2.62, 6.17). It has been previously shown that migraine is due to a

cascade of vascular and neural events.[46-47] However, a review by Rosamund suggested

migraine was not shown to be linked with coronary heart disease but possibly shares a

common underlying pathophysiology with Raynaud’s phenomenon and other vasospastic

disorders such as variant angina.[60-61] It is thought there may be other factors that may

affect the underlying mechanism for these vasospastic conditions as episodes occur at

different times with differing precipitants.[62-63] Further study may help clarify whether

PRP is a benign vasospastic disorder or whether there is underlying pathology affecting the

vascular wall associated with traditional risk factors seen in cardiovascular disease.

There are number of caveats to this study. Firstly, it was striking that there was no uniform

definition for diagnosis of PRP. Only 39% of studies looking at prevalence had a precise

definition for PRP, thereby reducing the number of studies we used to assess pooled

prevalence. It is possible that the variation in definition of PRP together with the way

participants were recruited and assessed may have led to under- or over-estimation of the

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true prevalence of PRP in the general population. We feel that an amalgamation of the

generally more commonly used definitions would ensure that the diagnosis is clear by

assessing symptoms, using colour chart or photographs for confirmation of colour change

and carefully exclude underlying conditions including checking for digital infarcts/ulceration,

nailfold capillaroscopy and assessing autoimmune screen and inflammatory markers.

Secondly, as our objective was to specifically examine the epidemiology of PRP a large

proportion of studies were excluded because they focused on secondary Raynaud’s

phenomenon, especially related to connective tissue diseases and vibration white finger. In

addition we also excluded studies that looked at investigation or treatment of PRP. This left

only a small number of studies to assess. From the studies included, there was a great deal

of variation in the population of participants used. 9 out of the 17 studies used investigated

participants in the general population whereas the remainder examined specific populations

such as single gender, children or hospital/medical personnel. Furthermore, there was

considerable variation in the risk factors addressed in each study and this may have affected

the significance and association, or lack of association between the risk factors and PRP. We

tried to extract as many risk factors from each study as possible to use in our analysis. In the

future, a larger multinational population study may help us to get a better understanding of

the disease. This would be particularly useful if standardised criteria were used to include

participants in the studies, using strict definition for PRP (as mentioned previously) and data

was collected in a similar fashion assessing a wide variety of possible risk factors

(particularly related to cardiovascular disease and vasospastic disoders) for more accurate

data analysis.

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CONCLUSION

This first systematic review summarises the burden of PRP in the general population using

published literature. It is not a rare condition (prevalence 4.85% and annual incidence

0.25%). It starts at a young age, is more common in women and associates with a family

history and with smoking. In addition, people with PRP are 4 times more likely to have

migraine than those without this condition.

ACKNOWLEDGEMENT: Our sincere thank you to Joanna Ramowski and Helen Richardson for

article retrieval and support. Also special thank you to Anu Suokas, Karin Tatsumoa,

Professor Tiraje Truncer, Ana Valdes and Maggie Wheeler for language translation.

AUTHOR CONTRIBUTIONS

Study conception and design: Dr Zhang, Professor Doherty, Dr Lanyon, Dr Garner

Acquision of data: Dr Garner, Dr Kumari, Dr Zhang

Statistical Analysis: Dr Garner, Dr Zhang

Analysis and interpretation of data: Dr Garner, Dr Zhang, Professor Doherty, Dr Lanyon

Manuscript preparation and final approval of manuscript: Dr Garner, Dr Zhang, Professor

Doherty, Dr Lanyon

Funding No funding

Competing interests None

Ethical approval and patient consent Not required

Data sharing statement No unpublished data were used in this study. No additional data

available.

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No. of subjects 1632 25797 6304 33733

Age 18 – 81 12-84 16-79 12-84

Setting




Region of study

USA 1 2 7 10

Europe 1 11 6 18


Japan 0 2 0 2

New Zealand 0 1 0 1

Israel 0 0 1 1

Diagnosis*






2, case control 7).

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Age Mean (SD)/

Range

% Female

Prevalence

Overall (%)

Female (%) Male (%)






Maricq 1997* South Carolina, USA Com 2086/432 18+ NS NS 3.4 0.8

Toulon, France Com 1998/189 18+ NS NS 11.4 2.8

Nyons, France Com 1996/345 18+ NS NS 5.8 6.2

Grenoble, France Com 2069/272 18+ NS NS 12.1 6.4

Tarentaise, France Com 2000/296 18+ NS NS 15.8 6.3


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Prevalence of possible primary Raynaud’s phenomenon in general population studies




Prevalence of primary Raynaud’s phenomenon in specific population studies

Prevalence of primary Raynaud’s phenomenon in single gender only population studies




Prevalence of primary Raynaud’s phenomenon in studies using hospital personnel



Iwata 1987 Japan C&H 1470 18-59 56.8 4.8 6.5 2.5


Prevalence of primary Raynaud’s phenomenon in studies assessing children



*This study involved two stage sampling

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Table 3: Regional variation of prevalence of primary raynaud’s phenomenon for general population studies including prevalence rates for males and 1

females 2

3


Participants

Prevalence %

Male Female Total

USA† 3 6139 5.8 7.8 7.5

France† 1 1102 6.3 11.75 -

Spain 1 276 2.8 3.4 3.3

Turkey 1 768 4.9 7.0 5.9

Japan 1 3873 1.1 2.1 1.6

TOTAL 6 12158

† Median values calculated for prevalence. USA gender figures include data from Maricq 1997 (France & USA). Total USA prevalence figure includes data 4

from 2 USA only studies 5

6

7

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Table 4: Risk factors of Raynaud’s Phenomenon 1

Risk Factor No. of studies (No. of

participants)

Pooled OR 95% CI I2

% (95% CI)∞

P (heterogeneity)

Female 18 (23197) 1.65 1.42, 1.91 17.2 (0, 53) 0.25


Marital Status* 4 (2650) 0.60 0.43, 0.83 16.9 (0,73) 0.31

EducaWon† 2 (891) 1.52 0.89, 2.59 - 0.24


Smoking 9 (8501) 1.27 1.06, 1.53 6.2 (0.8, 57.1) 0.38

Alcohol 2 (4967) 0.33 0.02, 5.37 - < 0.0001

Migraine‡ 6 (2595) 4.02 2.62, 6.17 35.9 (0, 73.6) 0.17

Diabetes 1 (1525) 0.51 0.2, 1.27 - -

Hypertension 2 (1711) 1.00 0.67, 1.48 - 0.46




H. Pylori¥ 2 (265) 0.91 0.51, 1.63 - 0.07

OCP 2 (268) 0.69 0.34, 1.38 - 0.88


RP Raynaud’s phenomenon, H. Pylori Helicobacter Pylori, OCP Oral contraceptive pill 2

∞ The I2 values are stated where more than three studies were assessed 3

*Marital status reference used are single/separated/widowed/divorced apart from Fraenkel 1998 and Keil 1991 where the reference used is widowed/separated/divorced 4

† Reference for education used is primary school (De Angelis 2008) and < 12years education (Voulgari 2000) 5

‡ O’Keefe (1992) did not report whether their calculaWon for OR was adjusted/unadjusted. All other reported calculaWons for OR are unadjusted. 6

+ Cardiovascular disease includes history of angina, myocardial infarction, coronary insufficiency, intermittent claudication, congestive cardiac failure, stroke and transient 7

ischemic attack 8

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¥ Positive investigation for Helicobacter pylori uses urea breath test (Savarino 2000) and serology (Herve 2006) 1

± Adjusted for age BMI alcohol cigarettes and B adrenoreceptor antagonists in study by Fraenkel (1998) 2

3

4

Figure 1: Flow chart diagram showing results of systematic literature search 5

6

7

8

9

10

11

12

Figure 2: Forest plot showing the pooled prevalence of definite Primary Raynauds Phenomenon for 5 general population studies 13

14

15

16





related to RP (11), Autoantibodies (13), Treatment involving sympathectomy (45), Ophthalmology studies (14),

Psychiatric conditions (11), Haematological disease (14), Infectious disease (24), cardiovascular disease (64), Respiratory

disease (17), Gastrointestinal disease (27), Renal disease (27), Dermatological (30), Endocrine disease (31), Neurological


implant rupture (4)Others: including motor vehicles, dentists, seafarers, fishermen, aircrafts, breast feeding (17)



Review (5)


Secondary RP (39)

Treatment RP (1)


Case only study (1)

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REFERENCES


Sci 1932;183(2):187-200.


1992;10:485-488.





1988;15(3):454-459.






Rheumatism 1996;39(7):1189-1191.








(Moose) group. JAMA 2000;283:2008-2012.

13 DerSimonian R, Laird N. Meta-analysis in Clinical Trials. Controlled Clinical Trials 1986;7:177-188.

14 Stuart A, Ord JK. Kendall's Advanced Theory of Statistics (6th edition). London: Edward Arnold

1994.






2003;327:557-60.


test. BMJ 1997;315:629-34.



44(5):1023-1028.











Cardioangiol 1994;42(1-2):65-71.

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2003;48(12):3518-352.






Invest 1978;38(8):761-764.


Rheumatol 2005;24(4):365-369.









Clin Rheumatol 2008;14(4):206-210.






















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2008;26:673-9.




Dis. 2003;46(1):11-29.





123.














2005;45[Suppl 1]:S3-S13. 62 Rosamond W. Are migraine and coronary heart disease associated? An epidemiologic review.




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Prevalence, risk factors and associations of Primary Raynaud’s Phenomenon: Systematic 1

review and meta-analysis of observational studies 2

3


2, Peter 4


1, 2, Weiya Zhang BMed 5

MEpi PhD1 6


2Department of Rheumatology, 7

Queens Medical Centre, UK 8

9

10

Correspondence to: 11

Dr Weiya Zhang 12

Academic Rheumatology 13

Clinical Sciences Building 14

Nottingham City Hospital 15

Nottingham NG5 1PB 16

UK 17

Telephone: +44 (0)115 823 1756 18

Fax: +44 (0)115 823 1757 19

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Email: [email protected] 1

2

Keywords: Primary Raynaud’s phenomenon, prevalence, incidence, risk factors, systematic 3

review 4

Word Count: Abstract: 244, main text: 3133 5

6

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Abstract 1

Objective: To systematically review the literature with regard to the prevalence, incidence, 2

risk factors and associations of primary Raynaud’s phenomenon (PRP). 3

Method: A systematic review of the literature of observational studies for PRP was 4

undertaken using five electronic databases. Any studies reporting prevalence, incidence and 5

risk factors of PRP were collected. Relative risk or odds ratio (OR) and 95% confidence 6

interval (CI) were extracted or calculated to present the association between risk factors 7

and PRP. Random effects model was used to pool the results. 8

Results: 33 articles assessing a total of 33, 733 participants were included in this analysis (2 9

cohort, 17 cross-sectional and 14 case-control studies). The pooled prevalence of PRP was 10

4.85% (95% CI 2.08%, 8.71%) in the general population. The pooled annual incidence of PRP 11

was 0.25% (95% CI 0.19, 0.32). Risk factors and associations for PRP included female gender 12

(OR 1.65, 95% CI 1.42, 1.91), family history (OR 16.6, 95% CI 7.44, 36.8), smoking (OR 1.27, 13

95% CI 1.06, 1.53), manual occupation (OR 2.66 95% CI 1.73, 4.08), migraine (OR 4.02, 95% 14

CI 2.62, 6.17), cardiovascular disease (OR 1.69, 95% CI 1.22, 2.34) and marital status 15

(married) (OR 0.60, 95% CI 0.43, 0.83). The definition of PRP varied considerably between 16

studies. 17

Conclusion: This is the first systematic review of the prevalence, incidence, risk factors and 18

associations of PRP. Further study using uniform strict criteria for the condition is required 19

to confirm these findings, particularly the possible association with cardiovascular disease. 20

21

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1

Strengths and limitations of this study 2

• This is the first meta-analysis of the literature for the global epidemiology of primary 3

Raynaud’s phenomenon (PRP). 4

• The prevalence and incidence of PRP in different countries were estimated. Female 5

gender, positive family history, smoking and migraines were found to be the major risk 6

factors for PRP. 7

• The lack of original data restricted an adequate estimation of the age-effect on PRP. 8

• Different definitions of PRP handicapped a comparison between countries 9

10

INTRODUCTION 11

In the 19th century, Maurice Raynaud first described Raynaud’s phenomenon (RP) as an 12

episodic, symmetrical, vasospastic disorder resulting in classic triphasic colour change, 13

trophic changes limited to the skin and uncomfortable sensory symptoms of the extremities 14

in the absence of arterial occlusion.[1] Further criteria have been suggested to distinguish 15

Primary RP (PRP) from secondary RP which include detail regarding symptom duration, 16

negative autoimmune serology, normal serum inflammatory markers and capillaroscopy, 17

and the clinical absence of any underlying disease.[1-4] Use of colour charts to aid 18

diagnosis has also been used.[4, 5] Despite this, there is no unifying definition that is used 19

worldwide for PRP. 20

21

There have been a number of studies performed in various countries reporting the 22

prevalence of RP. The reported prevalence ranges from less than 1% (in men) and up to 23

20% (in women) depending on definitions and population selected.[6] In contrast, few 24

studies have examined the incidence of PRP and the true burden of PRP in the general 25

population remains unclear. PRP is thought to be more common in women, particularly 26

when it develops at a young age.[7] There are also reports of a hereditary component and 27

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links with other vasospastic conditions such as migraine.[8-11] It is uncertain whether other 1

co-morbidities or risk factors particularly related to vascular diseases such as ischaemic 2

heart disease and/or smoking have an association with PRP. 3

4

The primary objective of this study was to perform a systematic review of observational 5

studies to summarise the literature with regard to the prevalence, incidence and risk 6

factors/associations of PRP. The secondary objective was to examine the current definitions 7

used to define PRP worldwide. 8

METHODS 9

1: Literature search – data sources and search strategy 10

A comprehensive systematic literature search was undertaken in June 2011 and re-run in 11

October 2014 using five databases: Medline, Embase, Cinahl, Amed and Pubmed. The 12

search terms for “Raynauds” or “Raynauds disease” were combined with the terms 13

“epidemiology” , “prevalence”, “risk” or “incidence” to generate the citations (see Appendix 14

1 for full details of search strategy). “Cross sectional”, “case-control” or “cohort” studies and 15

“systematic review” were also applied for types of studies. 16

Abstracts were reviewed and the full papers were sought where abstracts were felt to be 17

relevant. Any duplicate articles were excluded (Figure 1). Where there was difficulty in 18

article retrieval, the authors were contacted via email. The literature search and abstract 19

review was completed by RG and validated by WZ. Reference lists of the review articles 20

were also examined for relevant studies. 21

22

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2: Inclusion and Exclusion Criteria 1

Inclusion criteria: studies reporting the prevalence and/or incidence of PRP; studies 2

reporting potential risk factors associated with PRP; studies reporting human data on PRP in 3

people of any age; studies in any language (4 articles required translation – 1 Japanese, 1 4

Turkish, 1 French, 1 Italian). 5

Exclusion criteria (Figure 1): studies assessing treatment of PRP; studies involving 6

participants with RP secondary to other diseases; studies assessing RP in a specific 7

occupation e.g., people using vibration tools; unpublished material, case reports, editorials, 8

letters or reviews. 9

3. Data extraction and quality assessment 10

Study characteristics including age range, gender ratio and total number of participants in 11

the study were documented. The study design, country, setting (i.e. hospital or community 12

based) were also assessed and noted. If more than one article used the same study 13

population, the article where the data was felt to be presented most clearly was used in the 14

study. The definition of PRP and instruments used to confirm the condition were also 15

documented. The number of cases of PRP out of the number of people studied in a certain 16

time in the general population was documented as unadjusted crude prevalence. Incidence 17

figures were documented if the number of new cases of PRP in the population at risk 18

studied over a given period of time was stated. 19

Individual odds ratio (OR), relative risk (RR) or hazard ratio (HR) and their 95%confidence 20

interval (CI) were extracted or calculated for the following: 21

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o Constitutional: age, gender 1

o Environmental: employment, education, marital status, sex hormone 2

medications 3


degree relatives 4

o Associations: smoking, alcohol, cardiovascular disease, migraine 5

6

All studies were reviewed by RG to assess study quality and for data extraction and were 7

validated by WZ. An independent reviewer (RK) assessed a random selection of articles to 8

ensure quality of data extraction. Study quality was assessed according to study design 9

(cohort, cross-sectional and case control), setting (community or hospital), sample size, case 10

definition, exposure definition, confounding factors and adjustment. Quality scoring for 11

studies was not performed as it is not possible or fair to assign equal weight to different 12

quality aspects related to the study. However, current consensus standards of reporting 13

meta-analysis of observational studies in epidemiology (MOOSE) [12] were followed, and 14

subgroup/sensitivity analysis was undertaken to examine the changes of the estimate 15

according to different quality aspects 16

4. Statistical analysis 17

Individual data for prevalence and incidence were derived from the original report either 18

directly or indirectly from the information provided in each study. The pooled proportion 19

was calculated as the back-transform of the weighted mean of the transformed proportion, 20

using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird 21

(1986) weights for the random effects model. [13, 14] Cumulative incidence and 95%CI were 22

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transformed into incidence rate data (i.e., incidence per 100 person-years) and pooled 1

incidence rate was estimated. Individual data for OR, RR and HR were pooled to present 2

the overall relative risk of all observational studies, as well as separately for each specific 3

risk measure or study design as appropriate. Random-effects mode was used to pool the 4

data.[15] Heterogeneity was examined using Forest plots, Cochran Q tests and I2

statistic as 5

a measure for inconsistency due to chance.[16, 17] Publication bias was assessed using 6

funnel plots and Eggers test or the Harbord test if the number of studies included in the 7

meta-analysis was too small (≤4).[18] All analyses were undertaken using StatsDirect© 8

Version 2.7.9. 9

10

RESULTS 11

1: Study characteristics 12

2378 citations were found in the initial literature search. 467 duplicates were removed and 13

1871 citations were excluded as they did not meet the inclusion criteria (Figure 1). The final 14

number of studies available for analysis was 33 (33, 733 subjects). There were 2 cohort 15

studies[19, 20] (1, 632 subjects), 17 cross-sectional studies[6, 21-36] (25, 797 subjects) and 16

14 case-control studies[7-11, 37-45] (6, 304 subjects) (Table 1). Data for incidence and 17

prevalence were taken from cohort and cross-sectional studies respectively. Data for risk 18

factors were taken from all studies as long as the results were reported. 19

Age ranges across different study designs were as follows: case-control (16-79 years), cohort 20

(18-81 years), cross sectional (12-84 years). 67% of the studies involved participants 21

recruited in a community based setting. The majority of studies were conducted in Europe 22

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(18)[6, 9, 19, 22, 24, 26, 27, 29, 30, 32, 33, 35-37, 39, 41-43] or the USA (10)[7-8, 10-11, 20-1

21, 23, 38, 40, 44], however other countries of origin included Japan (2)[25, 28], New 2

Zealand (1)[34] and Israel (1)[45]. One comparison study included participants from USA and 3

France.[31] 4

Participants were surveyed by means of phone, face-to-face interview, and/or postal 5

questionnaire. 26 studies included a physical examination which also included blood testing 6

(including serology), nail fold capillaroscopy and use of colour chart/photographs (Table 1) 7

10 studies used specific criteria to define PRP (3 studies [8, 21, 32] Allen & Brown[1], 3[9, 8

36, 37]Leroy & Medsger[2], 4[6, 22, 33-34] UK Scleroderma Study Group[4]). The remaining 9

studies used a combination of cold sensitivity, varying degrees of colour change and sensory 10

symptoms via questionnaire or interview to define PRP. Colour charts or photographs to 11

indicate colour change were used in 12 studies[6-7, 9-10, 19-20, 25, 28-29, 31, 33, 35] and 12

nailfold capillaroscopy was performed as part of the examination in 10 studies.[8-9, 19, 31, 13

36, 37, 39, 41-43] In 15 studies, blood testing including serology and/or inflammatory 14

markers were performed.[6, 8-9, 11, 24, 30, 33, 36-37, 39-44] 15

Studies with clear definition of PRP or clear exclusion criteria for secondary RP were 16

categorised as “definite PRP” in this study. Studies with less clear definition of PRP were 17

categorised as “possible PRP”. Studies with clear definition of secondary RP were excluded. 18

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2: Prevalence of PRP 1

The overall prevalence for definite PRP varied from 1.6 – 7.2% in 6 cross sectional studies in 2

the general population (women: 2.1-15.8% and men 0.8-6.5%).[21, 23, 25, 27, 29, 33] The 3

pooled prevalence was 4.85% (95% CI 2.08%, 8.71%) (Figure 2), with 5.74% (95% CI 2.74, 4

9.75) in women and 4.12% (95% CI 1.60, 7.74) in men. We used the Harbord test to detect 5

publication bias (1.59 92.5% CI -21.6,24.8, P=0.87) 6

The overall prevalence for possible PRP ranges from 3.98% to 12.7% (women: 4.5-17.9% and 7

men: 3.4-7.2%) in three cross sectional studies.[26, 34-35] The prevalence in specific 8

populations varies depending on the studies (Table 2) 9

In 6 studies assessing the general population we found the lowest prevalence of PRP in 10

Japan with an overall prevalence of 1.6 (2.1% in women, 1.1% in men).[25] Highest overall 11

prevalence figures were found in the USA with a median prevalence of 7.5% (7.8% in 12

women, 5.8% in men,).[21, 23] A study from France also showed high prevalence figures of 13

11.75% in women and 6.3% in men (median values).[31] (Table 3) 14

Five studies reported prevalence of PRP by age.[6, 28-30, 34]. Three did not find any age-related 15

prevalence (Leppert1987, Iwata 1987 and Voulgari 2000). Purdie (2009) reported a higher 16

prevalence of PRP in younger compared to older age groups, whereas Fraenkel (1999) reported 17

higher prevalence in older age groups in men (adjusted OR=2.3, 95%CI 1.0 to 5.2 highest vs. lowest 18

tertile) but not in women (adjusted OR=0.9, 95%CI 0.4 to 1.6). Jones (2003) also showed a slight 19

increase in prevalence by age in yearly increments between ages 12-15 years. 20

21

22

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3: Incidence of Primary Raynauds Phenomenon 1

Only two studies reported incidence rates.[19-20] Carpentier et al reported an annual 2

incidence rate of 0.25% (95% CI 0.17, 0.33), with 0.24% in women and 0.26% in men and 3

Suter et al reported a 7-year incidence of 1.87% (2.2% in women and, 1.5% in men), which 4

was converted to an annual incidence rate of 0.26% (95%CI 0.17, 0.39). The pooled annual 5

incidence rate of these two studies was therefore 0.25% (95%CI 0.19, 0.32). 6

7

4: Risk factors and associations 8

In 18 studies (23, 197 participants), there was a positive association between female gender 9

and PRP (OR 1.65, 95% CI 1.42, 1.91).[6-7, 9, 20-29, 33-35, 37, 44] Family history, assessed in 10

2 studies looking at 1st degree relatives, also had a positive significant association with PRP 11

(OR 16.6, 95%CI 7.44, 36.8).[8-9] No significant association was found with education 12

beyond primary school age.[6, 37] (Table 4). Manual occupation (not including vibration 13

tool use) had an OR of 2.66 (95% CI 1.73, 4.08) in 1 study of 3873 participants.[25] In 4 14

studies, being married was associated with a lower risk of PRP with OR of 0.60 (95% CI 0.43, 15

0.83) compared with being single/divorced/widowed.[6-7, 23, 37] Smoking was found to 16

have an association in 9 studies giving a pooled OR of 1.27 (95% CI 1.06, 1.53).[7, 9-11, 20, 17

22-23, 32, 44] Alcohol use,[23, 44] participants with positive Helicobacter Pylori 18

investigations[39, 41] and those with conditions such as diabetes,[23] hypertension[11, 23] 19

and hypercholesterolaemia[23] did not have a significant association with PRP. 20

Migraine had a positive significant association with a pooled OR of 4.02 (95% CI 2.62, 6.17) 21

in 6 studies.[6, 9-11, 22, 45] One study of 3442 participants reported a positive association 22

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of cardiovascular disease with PRP with an OR of 1.69 (95% CI 1.22, 2.34).[44] 1

Cardiovascular disease in this study included a history of ischaemic heart disease, 2

intermittent claudication, congestive cardiac failure and cerebrovascular disease. A single 3

study using 81 participants did not show a positive significant association of coronary heart 4

disease with PRP.[40] 5

A positive association was found in participants taking oestrogen replacement therapy alone 6

in two studies with an OR of 2.34 (95% CI 1.42, 3.84).[23, 38] However no significant 7

association was found in combined oestrogen and progesterone replacement therapy[38] in 8

postmenopausal women or in oral contraceptive pill[10-11] use in two other studies. A 9

study by Smyth et al looking at allele frequencies of known polymorphisms of candidate 10

vasoactive mediator genes (eNOS, BKRG, ET01 and ETA receptor genes) did not show any 11

association.[9] Shemirani et al looked at clotting factors in participants with PRP and found a 12

significant association with methyltetrahydrofolate reductase C677T mutations (OR 0.4, 95% 13

CI 0.2, 0.9) but no difference in other thrombosis-associated alleles (FVLeiden, prothrombin 14

G20210A).[42] 15

16

DISCUSSION 17

This is the first meta-analysis of the literature for the prevalence, incidence, risk factors and 18

associations of PRP. Overall the pooled mean prevalence of PRP in the general population 19

was 4.85% (95% CI 2.08%, 8.71%) (Figure 2) and the mean incidence was 0.25% (95% CI 20

0.17, 0.33) per annum.[19] Major risk factors/associations of PRP include female gender, 21

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family history of PRP, migraine, smoking, cardiovascular disease, manual occupation, 1

oestrogren replacement therapy and possibly marital status. (Table 4). 2

Variations in prevalence were observed between countries (Table 3) though this could 3

reflect use of different diagnostic criteria rather than real differences in prevalence. The 4

heterogeneity of prevalence figures may also reflect the differences in the way the studies 5

were conducted, the selection of participants (e.g., age and gender), and the disease 6

definition. All studies (except for Maricq 1997) demonstrate a higher prevalence of PRP in 7

women. This may be due to a relationship with female hormones as two studies found an 8

association between PRP and use of oestrogen replacement therapy alone,[23, 38] although 9

no association was found between combined oestrogen and progesterone replacement or 10

the oral contraceptive pill.[10-11, 38] In contrast, prevalence of PRP does not increase with 11

age in five published studies with a wide age range of participants from 12 years up to 84 12

years.[6, 28-30, 34] This accords with the clinical observation that PRP usually starts in 13

teenage years and that later development, which is far less common, is characteristic of 14

secondary RP. While the former may be driven predominantly by genetic risk factors, later 15

onset “primary” Raynaud’s may be predominantly influenced by environmental exposures 16

such as vascular microtrauma from manual usage and vibrating tools. In terms of other 17

environmental factors we did find a weak negative association between marital status and 18

PRP with an OR of 0.60 (95%CI 0.43, 0.83) in those that are married vs. 19

single/separated/widowed/divorced.[6-7, 23, 37] However, there is no plausible biological 20

explanation for this and the reported data may not be free from confounding bias. 21

The association of cardiovascular disease and autoimmune disease is well documented and 22

thought to be due to accelerated atherosclerosis as a result of chronic inflammation, 23

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treatment such as glucocorticoids as well as the traditional risk factors for cardiovascular 1

disease.[46-52] A link between cardiovascular disease and PRP has been shown in only one 2

study[44] and a reason for this association is not known. It is unlikely to be due to an 3

inflammatory process or related to medication and with PRP having predominance for the 4

female population and onset at a young age it not clear if traditional cardiovascular risk 5

factors play a part. However, smoking was found to have positive association with PRP in 6

our study (OR 1.27, 95% CI 1.06, 1.53). It is well known that smoking is one of three 7

(smoking, hypertension and hyperlipidaemia) main risk factors for cardiovascular and 8

cerebrovascular disease.[53-59] Smoking may be the same risk factor for PRP and CVD. 9

Whether smoking causes PRP first then CVD is an interesting question which deserves 10

further research. More interestingly, we found a very strong association between migraine 11

and PRP (OR 4.02, 95%CI 2.62, 6.17). It has been previously shown that migraine is due to a 12

cascade of vascular and neural events.[46-47] However, a review by Rosamund suggested 13

migraine was not shown to be linked with coronary heart disease but possibly shares a 14

common underlying pathophysiology with Raynaud’s phenomenon and other vasospastic 15

disorders such as variant angina.[60-61] It is thought there may be other factors that may 16

affect the underlying mechanism for these vasospastic conditions as episodes occur at 17

different times with differing precipitants.[62-63] Further study may help clarify whether 18

PRP is a benign vasospastic disorder or whether there is underlying pathology affecting the 19

vascular wall associated with traditional risk factors seen in cardiovascular disease. 20

There are number of caveats to this study. Firstly, it was striking that there was no uniform 21

definition for diagnosis of PRP. Only 39% of studies looking at prevalence had a precise 22

definition for PRP, thereby reducing the number of studies we used to assess pooled 23

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prevalence. It is possible that the variation in definition of PRP together with the way 1

participants were recruited and assessed may have led to under- or over-estimation of the 2

true prevalence of PRP in the general population. We feel that an amalgamation of the 3

generally more commonly used definitions would ensure that the diagnosis is clear by 4

assessing symptoms, using colour chart or photographs for confirmation of colour change 5

and carefully exclude underlying conditions including checking for digital infarcts/ulceration, 6

nailfold capillaroscopy and assessing autoimmune screen and inflammatory markers. 7

Secondly, as our objective was to specifically examine the epidemiology of PRP a large 8

proportion of studies were excluded because they focused on secondary Raynaud’s 9

phenomenon, especially related to connective tissue diseases and vibration white finger. In 10

addition we also excluded studies that looked at investigation or treatment of PRP. This left 11

only a small number of studies to assess. From the studies included, there was a great deal 12

of variation in the population of participants used. 9 out of the 17 studies used investigated 13

participants in the general population whereas the remainder examined specific populations 14

such as single gender, children or hospital/medical personnel. Furthermore, there was 15

considerable variation in the risk factors addressed in each study and this may have affected 16

the significance and association, or lack of association between the risk factors and PRP. We 17

tried to extract as many risk factors from each study as possible to use in our analysis. In the 18

future, a larger multinational population study may help us to get a better understanding of 19

the disease. This would be particularly useful if standardised criteria were used to include 20

participants in the studies, using strict definition for PRP (as mentioned previously) and data 21

was collected in a similar fashion assessing a wide variety of possible risk factors 22

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(particularly related to cardiovascular disease and vasospastic disoders) for more accurate 1

data analysis. 2

3

CONCLUSION 4

This first systematic review summarises the burden of PRP in the general population using 5

published literature. It is not a rare condition (prevalence 4.85% and annual incidence 6

0.25%). It starts at a young age, is more common in women and associates with a family 7

history and with smoking. In addition, people with PRP are 4 times more likely to have 8

migraine than those without this condition. 9

10

ACKNOWLEDGEMENT: Our sincere thank you to Joanna Ramowski and Helen Richardson for 11

article retrieval and support. Also special thank you to Anu Suokas, Karin Tatsumoa, 12

Professor Tiraje Truncer, Ana Valdes and Maggie Wheeler for language translation. 13

14

AUTHOR CONTRIBUTIONS 15

Study conception and design: Dr Zhang, Professor Doherty, Dr Lanyon, Dr Garner 16

Acquision of data: Dr Garner, Dr Kumari, Dr Zhang 17

Statistical Analysis: Dr Garner, Dr Zhang 18

Analysis and interpretation of data: Dr Garner, Dr Zhang, Professor Doherty, Dr Lanyon 19

Manuscript preparation and final approval of manuscript: Dr Garner, Dr Zhang, Professor 20

Doherty, Dr Lanyon 21

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Funding No funding 1

Competing interests None 2

Ethical approval and patient consent Not required 3

Data sharing statement No unpublished data were used in this study. No additional data 4

available. 5

6

7

8

9

10

11

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No. of subjects 1632 25797 6304 33733

Age 18 – 81 12-84 16-79 12-84

Setting




Region of study

USA 1 2 7 10

Europe 1 11 6 18


Japan 0 2 0 2

New Zealand 0 1 0 1

Israel 0 0 1 1

Diagnosis*






2, case control 7).

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Age Mean (SD)/

Range

% Female

Prevalence

Overall (%)

Female (%) Male (%)






Maricq 1997* South Carolina, USA Com 2086/432 18+ NS NS 3.4 0.8

Toulon, France Com 1998/189 18+ NS NS 11.4 2.8

Nyons, France Com 1996/345 18+ NS NS 5.8 6.2

Grenoble, France Com 2069/272 18+ NS NS 12.1 6.4

Tarentaise, France Com 2000/296 18+ NS NS 15.8 6.3


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Prevalence of possible primary Raynaud’s phenomenon in general population studies




Prevalence of primary Raynaud’s phenomenon in specific population studies

Prevalence of primary Raynaud’s phenomenon in single gender only population studies




Prevalence of primary Raynaud’s phenomenon in studies using hospital personnel



Iwata 1987 Japan C&H 1470 18-59 56.8 4.8 6.5 2.5


Prevalence of primary Raynaud’s phenomenon in studies assessing children



*This study involved two stage sampling

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Table 3: Regional variation of prevalence of primary raynaud’s phenomenon for general population studies including prevalence rates for males and 1

females 2

3


Participants

Prevalence %

Male Female Total

USA† 3 6139 5.8 7.8 7.5

France† 1 1102 6.3 11.75 -

Spain 1 276 2.8 3.4 3.3

Turkey 1 768 4.9 7.0 5.9

Japan 1 3873 1.1 2.1 1.6

TOTAL 6 12158

† Median values calculated for prevalence. USA gender figures include data from Maricq 1997 (France & USA). Total USA prevalence figure includes data 4

from 2 USA only studies 5

6

7

8

9

10

11

12

13

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Table 4: Risk factors of Raynaud’s Phenomenon 1

Risk Factor No. of studies (No. of

participants)

Pooled OR 95% CI I2

% (95% CI)∞

P (heterogeneity)

Female 18 (23197) 1.65 1.42, 1.91 17.2 (0, 53) 0.25


Marital Status* 4 (2650) 0.60 0.43, 0.83 16.9 (0,73) 0.31

EducaWon† 2 (891) 1.52 0.89, 2.59 - 0.24


Smoking 9 (8501) 1.27 1.06, 1.53 6.2 (0.8, 57.1) 0.38

Alcohol 2 (4967) 0.33 0.02, 5.37 - < 0.0001

Migraine‡ 6 (2595) 4.02 2.62, 6.17 35.9 (0, 73.6) 0.17

Diabetes 1 (1525) 0.51 0.2, 1.27 - -

Hypertension 2 (1711) 1.00 0.67, 1.48 - 0.46




H. Pylori¥ 2 (265) 0.91 0.51, 1.63 - 0.07

OCP 2 (268) 0.69 0.34, 1.38 - 0.88


RP Raynaud’s phenomenon, H. Pylori Helicobacter Pylori, OCP Oral contraceptive pill 2

∞ The I2 values are stated where more than three studies were assessed 3

*Marital status reference used are single/separated/widowed/divorced apart from Fraenkel 1998 and Keil 1991 where the reference used is widowed/separated/divorced 4

† Reference for education used is primary school (De Angelis 2008) and < 12years education (Voulgari 2000) 5

‡ O’Keefe (1992) did not report whether their calculation for OR was adjusted/unadjusted. All other reported calculations for OR are unadjusted. 6

+ Cardiovascular disease includes history of angina, myocardial infarction, coronary insufficiency, intermittent claudication, congestive cardiac failure, stroke and transient 7

ischemic attack 8

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¥ Positive investigation for Helicobacter pylori uses urea breath test (Savarino 2000) and serology (Herve 2006) 1

± Adjusted for age BMI alcohol cigarettes and B adrenoreceptor antagonists in study by Fraenkel (1998) 2

3

4

Figure 1: Flow chart diagram showing results of systematic literature search 5

6

7

8

9

10

11

12

13 Figure 2: Forest plot showing the pooled prevalence of definite Primary Raynauds Phenomenon for 5 general population studies14





related to RP (11), Autoantibodies (13), Treatment involving sympathectomy (45), Ophthalmology studies (14),

Psychiatric conditions (11), Haematological disease (14), Infectious disease (24), cardiovascular disease (64), Respiratory

disease (17), Gastrointestinal disease (27), Renal disease (27), Dermatological (30), Endocrine disease (31), Neurological


implant rupture (4)Others: including motor vehicles, dentists, seafarers, fishermen, aircrafts, breast feeding (17)



Review (5)


Secondary RP (39)

Treatment RP (1)


Case only study (1)

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REFERENCES


Sci 1932;183(2):187-200.


1992;10:485-488.





1988;15(3):454-459.






Rheumatism 1996;39(7):1189-1191.








(Moose) group. JAMA 2000;283:2008-2012.

13 DerSimonian R, Laird N. Meta-analysis in Clinical Trials. Controlled Clinical Trials 1986;7:177-188.

14 Stuart A, Ord JK. Kendall's Advanced Theory of Statistics (6th edition). London: Edward Arnold

1994.






2003;327:557-60.


test. BMJ 1997;315:629-34.



44(5):1023-1028.











Cardioangiol 1994;42(1-2):65-71.

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2003;48(12):3518-352.






Invest 1978;38(8):761-764.


Rheumatol 2005;24(4):365-369.









Clin Rheumatol 2008;14(4):206-210.






















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2008;26:673-9.




Dis. 2003;46(1):11-29.





123.














2005;45[Suppl 1]:S3-S13.

62 Rosamond W. Are migraine and coronary heart disease associated? An epidemiologic review.




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Figure 1: Flow chart diagram showing results of systematic literature search

Initial search: n=2378

n = 1911

n = 97

Final number of relevant articles

Definite= 33

Further exclusion after paper

retrieval: n = 64


Duplicates = 467

Reviews, Case reports, Non-RP,

treatment, progression etc = 1814


aSee table 1 for exclusion reasons

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Figure 2: Forest plot showing the pooled prevalence of definite Primary Raynauds Phenomenon for 5 general population studies

0.00 0.02 0.04 0.06 0.08 0.10

combined 0.05 (0.02, 0.09)

Onbasi 2005 0.06 (0.04, 0.08)

Ivorra 2001 0.03 (0.02, 0.06)

Harada 1991 0.01 (0.01, 0.02)

Fraenkel 1999 0.08 (0.07, 0.09)

Brand 1997 0.07 (0.06, 0.08)

Prevalence (95% confidence interval)

Forest plot for heterogeneity, I2=98.2% (95% CI = 97.6, 98.6)

p for heterogeneity < 0.0001

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MOOSE Checklist

Prevalence, risk factors and associations of Primary Raynaud’s Phenomnon:

Systematic review and meta-analysis of observational studies

Criteria Brief description of how the criteria were handled in the

meta-analysis

Reporting of background should

include

√ Problem definition Primary Raynaud’s phenomenon (PRP) has been studied in

various countries with variation in prevalence rates reported.

There has been no previous systematic review of the literature

assessing the global epidemiology of PRP. (pages 4-5)

√ Hypothesis statement Primary Raynaud’s phenomenon is a universal condition, more

common in females, and is associated with family history,

migraines, vascular/autoimmune disorders. (pages 4-5)

√ Description of study outcomes 1: Prevalence of PRP

2: Incidence of PRP

3: Risk factors/associations

(pages 5-7)

√ Type of exposure or intervention

used

Age, gender, family history, comorbidities and other putative

risk factors.

(pages 6-7)

√ Type of study designs used Included studies: cross sectional studies to assess prevalence,

case-control studies assessing associations/risk factors, cohort

studies

Excluded: studies involving participants with raynauds

symptoms secondary to other disease or specific occupation.

Case reports, editorials, letters and reviews also excluded.

(page 6, 23)

√ Study population Participants who suffered with symptoms suggesting primary

raynauds phenomenon only – any secondary cause of raynauds

symptoms were not included. Studies included those that

reported human data of any age group.

(page 6)

Reporting of search strategy should

include

√ Qualifications of searchers Experienced epidemiologist (MSc) and systematic reviewers

(PhD). (page 1)

√ Search strategy, including time

period included in the synthesis

and keywords

Databases: PubMed, EMBASE, MEDLINE, CINAHL, AMED

Time period: 1945 to 2011, further up to date search performed

from 1945 to 2014

see methods (page 5) and Appendix 1 for full search strategy

including keywords

√ Databases and registries searched PubMed, EMBASE, MEDLINE, CINAHL, AMED

(page 5)

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√ Search software used, name and

version, including special features

Please see above plus Reference Manager Network 10

√ Use of hand searching hand-searched references of papers reviewed in the study for

additional references. (page 5)

√ List of citations located and those

excluded, including justifications

Please see flow chart (see figure 1, cited page 6, See PDF files

named “Figures 1 & 2_Primary Raynauds systematic review”,

see also page 23)

√ Method of addressing articles

published in languages other than

English

We requested translation for four articles (please see

acknowledgements section, page 16 and also page 6)

√ Method of handling abstracts and

unpublished studies

We excluded abstracts and have no intention to include

unpublished studies (page 6, 23)

√ Description of any contact with

authors

We contacted authors for studies we were unable to get from

the local libraries and the inter library loan (page 5)

Reporting of methods should include

√ Description of relevance or

appropriateness of studies

assembled for assessing the

hypothesis to be tested

Please see methods section for inclusion and exclusion criteria

(page 6)

√ Rationale for the selection and

coding of data

Please see page 6 for data extraction

Data extracted included the following: study characteristics

including age range, gender ratio and total number of

participants, study design, country, setting, number of cases of

PRP, incidence figures if provided were documents, risk

factors and association in the form of odds ratio were extracted

(see table 4 on page 22 for full list of risk factors)

√ Assessment of confounding Confounding was assessed by study design and methods to

adjust for. Subgroup analysis was undertaken to compare

crude and adjusted estimates. (page 7-8)

√ Assessment of study quality,

including blinding of quality

assessors; stratification or

regression on possible predictors

of study results

Data was blind abstracted by the first reviewer (RG). The

second reviewer (RK) extracted data independently and

agreement was reached by involving the third reviewer (WZ).

(page 7)

√ Assessment of heterogeneity Heterogeneity was examined using Forest plots, Cochran Q

tests and I2 statistic as a measure for inconsistency due to -

chance. (pages 7-8)

√ Description of statistical methods

in sufficient detail to be replicated

This has been described in the methods section, please see

pages 5-8

All analyses were undertake using StatsDirect© Version 2.7.9

√ Provision of appropriate tables

and graphics Figure 1: Flow chart diagram showing results of

systematic literature search (figure legend page 23, See PDF file named “Figures 1 & 2_Primary Raynauds systematic

review. Uploaded separately as advised by editorial office) Figure 2: Forest plot showing the pooled prevalence of definite

Primary Raynauds Phenomenon for 5 general population

studies (figure legend page 23, See PDF file named “Figures

1 & 2_Primary Raynauds systematic review. Uploaded

separately as advised by editorial office)

Table 1 characteristics of studies (page 18)

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Table 2 Prevalence of PRP in 17 studies (pages 19/20)

Table 3: Regional variation of prevalence of primary raynaud’s

phenomenon for general population studies including

prevalence rates for males and females

(page 21)

Table 4 Association of PRP with demographic, environmental,

comorbid illness and pharmacological factors (Pages 22/23)

Reporting of results should include

√ Graph summarizing individual

study estimates and overall

estimate

Figure 2 (figure legend page 23, See PDF file named

“Figures 1 & 2_Primary Raynauds systematic review.

Uploaded separately as advised by editorial office), table 2

(pages 19/20), table 3 (page 21), table 4 (Pages 22/23), see also

appendix 1

√ Table giving descriptive

information for each study

included

Table 1 (page 18)

√ Results of sensitivity testing

Figure 2 (figure legend page 23, See PDF file named

“Figures 1 & 2_Primary Raynauds systematic review.

Uploaded separately as advised by editorial office), table 2

(pages 19/20), table 3 (page 21), table 4 (Pages 22/23), see also

appendix 1

√ Indication of statistical

uncertainty of findings

95% confidence intervals were presented where possible

(pages 10-12, 22)

Reporting of discussion should

include

√ Quantitative assessment of bias Regarding the association between marital status and PRP we

discuss that there is no plausible biological explanation for this

and the reported data may not be free from confounding bias.

We discuss the lack of uniform definition for the diagnosis of

PRP resulting in a number of studies including participants that

could very well suffer with secondary raynauds phenomenon.

We therefore excluded a number of studies in order to assess

only PRP. Together with variation in which participants were

invited into the studies, the populations used and assessed

thereafter also may have under/over-estimated the results.

There was also a great deal of variety in the risk factors that

were assessed in the individual studies therefore we were not

able to assess risk factors for all the studies involved in the

review (pages 12-15)

√ Justification for exclusion Our inclusion and exclusion criteria are stated in the

methods section (please see page 6, also see page 23). We

discuss our exclusion criteria in the discussion section,

mentioning how our study was to assess the prevalence of

Primary RP and therefore had to exclude a large

proportion of studies as they focused on secondary

underlying disease or causes for RP symptoms such as

connective tissue diseases and occupation involving

exposure to vibration tools.In addition we also excluded

studies that looked at investigation or treatment of PRP.

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√ Assessment of quality of

included studies

Quality assessment of our studies is discussed in more

detail in the methods section (please see pages 6-7).

We included studies from all countries, in all languages,

using participants from the general population and from

selected populations but only using those who suffered

with symptoms of Primary RP. There was variation in the

way the author’s defined PRP, their assessment/interview

of participants and in the risk factors they assessed. All

studies were reviewed by one investigator (RG), a sample

of studies were reviewed by a second investigator (RK),

and agreement was reached by involving the third

reviewer (WZ) for any queries/discrepancies.

(pages 6-7)

Reporting of conclusions should

include

√ Consideration of alternative

explanations for observed

results

Variation in prevalence results in individual studies may

be due to differences in the way studies were conducted

and data collected. (pages 12-13)

√ Generalization of the

conclusions

We report figures for prevalence and incidence for

primary raynauds phenomenon and positive association

with women, family history, smoking and migraine and

cardiovascular disease. As this is a meta-analysis of

many studies from different countries. The

generalizability is better than a single study for a single

population. (pages 12-15)

√ Guidelines for future research We recommend future studies using standardised criteria,

strict definition for PRP and data collected in a similar

fasion to assess possible risk factors (pages 15-16)

√ Disclosure of funding source No funding was required (page 17)

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TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

3

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 4,5

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

4,5

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

This is only for

RCTs, not

relevant for this

review

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

5-7

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5, Supplementary material – appendix 1

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

5-7

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

6-7

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Prevalence

Risk factors

Association

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5-7, no funding

required

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

6-8

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 6-8

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I

2) for each meta-analysis.

7-8

Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

7-8

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

Subgroup

analysis

Sensitivity

analysis 7-8

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

6, Figure 1 flow chart, (figure legend

page 23, See

PDF file named

“Figures 1 &

2_Primary

Raynauds

systematic

review.

Uploaded

separately as

advised by

editorial office)

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

8-9, see table 1 page 18

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Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Study design

Setting

Sample size

Confounding

adjustment

Pages 6-8

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

8-12, 18-23, see also (figure 2 legend

page 23, See

PDF file named

“Figures 1 &

2_Primary

Raynauds

systematic

review.

Uploaded

separately as

advised by

editorial office),

see also

supplementary

file

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 8-12, 22-23

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 8-12, (figure 2

legend page 23,

See PDF file

named “Figures 1

& 2_Primary

Raynauds

systematic

review.

Uploaded

separately as

advised by

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editorial office)

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

8-12, see also supplementary file

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

12-15

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

12-15

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

13-15

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

No funding required.

RG time half day

per week from

the NHS

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

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bmj openrozeena garner mbbs mrcp (rheum) 2, rakesh kumari mbbs md mrcp (rheum) 2, peter lanyon dm...

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