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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Objective

To assess the risk factors for progression of hand osteoarthritis (OA).

Methods

In a systematic review of cohort studies, medical literature databases were searched up to May 2012 for articles reporting data on the association between risk factors and hand OA progression. The quality of these studies was assessed by 2 independent reviewers using a criteria scoring system of 16 items, and studies were dichotomized into those with scores of 69% or over and those with scores under 69%. Best evidence synthesis was used to determine the level of evidence per risk factor.

Results

In total, 14 articles that fulfilled the selection criteria were included, of which 8 were high quality. The most frequently investigated risk factors were age, sex, radiographic features (e.g., erosive OA), and scintigraphy. Progression was mostly defined by radiographic criteria, but also clinical progression as an outcome was described. Most of the investigated risk factors showed limited or inconclusive evidence for an association with hand OA progression. Limited evidence according to the best evidence synthesis with most available studies was present for the association between a positive scintigraphic scan and radiographic progression (up to 2.8 times more progression than negative joints).

Conclusion

Limited evidence is available for a positive association between an abnormal scintigraphic scan and radiographic hand OA progression. These data suggest that a positive scintigraphic scan as an inclusion criterion for studies that aim to show structural modification can increase the power of such studies. Future longitudinal studies with a well-defined baseline population are needed to search for risk factors of hand OA progression.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Hand osteoarthritis (OA) is a prevalent heterogeneous disorder that can lead to considerable clinical burden and impact on health-related quality of life (1, 2). Over time, the disorder is slowly progressive, although in some patients the progression can be rapid (3, 4). Several risk factors for the development of hand OA have been reported (5); however, data about risk factors for the disease course in hand OA are scarce and concern mostly radiographic progression. Moreover, the data are controversial, since definitions for progression (6, 7), the followup time, and source populations (8, 9) differ. An explanation for the lack of data could be time and cost investments. Research of the disease course of hand OA is further complicated by the combined assessment of the development and progression of hand OA in longitudinal studies that report on the risk factors for progression of hand OA in persons with and without hand OA at baseline and therefore combine progressive and incident hand OA in their assessment (8–14). In this situation, it is not possible to study risk factors for the progression of hand OA.

The recognition of potential risk factors for the progression of hand OA can be beneficial. When risk factors allow the identification of patients at high risk for progression, these patients can be included in interventional studies for disease-modifying drugs for the treatment of OA. Given the opinion of the regulatory agencies that a delay in structural progression of OA can be a claim for OA-modifying drugs (15), it would be especially important when modifiable risk factors are recognized, since this could have consequences for therapy. Finally, the recognition of risk factors for the progression of hand OA could increase our understanding of the underlying pathophysiology of this condition. We performed a systematic review that included studies reporting on the risk factors contributing to hand OA progression, since the available evidence has not been summarized systematically before.

Significance & Innovations

  • This study reports on risk factors contributing to progression of hand osteoarthritis (OA), since the available evidence has not been summarized systematically before.

  • Limited evidence according to the best evidence synthesis with most available studies was present for a positive association between an abnormal scintigraphic scan and radiographic hand OA progression. These data suggest that a positive scintigraphy as an inclusion criterion for studies that aim to show structural modification can increase the power of such studies.

  • This systematic review is important, since it gives insight into what risk factors for hand OA progression have already been investigated. Future high-quality studies on risk factors for hand OA progression, especially clinical progression, are needed to determine modifiable factors in symptomatic patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Identification of studies.

Longitudinal studies with baseline determinants that were studied in relation to the progression of hand OA were searched in medical literature databases (PubMed, EMBase, and the Cumulative Index to Nursing and Allied Health Literature) by a medical librarian (JWMP) up to May 2012 (see Supplementary Appendix A for the exact search strings, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.21851/abstract). Thesaurus terms and free text for the concepts “hand,” “osteoarthritis,” and “progression” were used. Additional articles (lateral references) were searched in the reference lists of the identified articles.

Inclusion and exclusion criteria.

The selection of titles, abstracts, and articles was performed independently by 2 reviewers (WYK and MK). In the case of disagreement, consensus was reached after discussion. First, all retrieved titles were screened, subsequently selected abstracts were retrieved for detailed review, and finally, full-text articles of the remaining references were read.

Studies were included if they fulfilled the following criteria: 1) patients with clinical or radiographic hand OA, 2) the baseline determinants were studied in relation to the radiographic or clinical progression of hand OA, 3) a followup duration of at least 1 year, and 4) the study design was a cohort study in which the determinants were measured at baseline.

Animal studies, studies with patients ages <18 years, reviews, abstracts, letters to the editor, case reports, case series, cross-sectional studies, and studies reporting on musculoskeletal diseases other than hand OA and studies in other languages besides English and Dutch were excluded. If the determinants for progression were investigated in the placebo group of intervention studies, these studies were included. None of the final selected publications were in Dutch.

Data extraction.

Standardized forms were used by both reviewers independently to extract information about the following data: 1) study population (population size, patient characteristics, setting and time period of the study, age, and sex), 2) the followup time and participation rate of the persons who completed the followup time of the study (at least 1 year of followup and an 80% participation rate), 3) the type of risk factor as determinant (distribution and mean), 4) the outcome (methods of hand OA assessment and progression, blinding, and reproducibility), and 5) the effect measures and outcomes (relative risk/ratio [RR] or odds ratio [OR]).

Assessment of study quality.

The quality of the studies was evaluated by both reviewers independently using 19 criteria based on previous systematic reviews in prognostic factors in the field of musculoskeletal disorders (16–19). The criteria were adapted to evaluate studies on the association between risk factors and hand OA progression (see Supplementary Appendix B, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.21851/abstract). When a criterion was fulfilled in the article, a 1 was given to indicate that the criterion was present; otherwise, a 0 was given to indicate that the criterion was absent. A 0 was also given when no information about the specific criterion was mentioned in the article. Any differences were solved by discussion. A maximum quality score of 16 could be given for cohort studies and 17 for nested case–control studies, and the scores were based on methodologic criteria, such as the definition of study population, selection bias, description of the followup, assessments of risk factors, and the outcome and its analysis. The total quality scores per study were calculated as a percentage of the maximum score. The reliability of the criteria list was measured using Cronbach's alpha (reflecting the internal consistency of the criteria list, based on the 16 criteria used for the included studies), which was 0.83.

Rating the level of evidence.

Since the studies in this systematic review were heterogeneous and often reported no effect sizes, a pooled-effect estimate could not be calculated. Therefore, evidence was summarized using the best evidence synthesis based on the guidelines of the Cochrane Back Review Group for systematic reviews (20), which is a method to summarize evidence in observational studies if the study population, assessment of exposure and outcomes, and data analyses are heterogenic. The best evidence synthesis has 5 levels of evidence (Table 1), and more weight is given to studies with a cohort design where exposure truly precedes outcomes. The next preferred design is the nested case–control study. A study was considered to be of high quality if the total quality score was ≥69% (the median of the quality scores).

Table 1. Best evidence synthesis used in this review (20)
Evidence levelCriteria
StrongConsistent findings (≥80%) in at least 2 high-quality cohorts
ModerateOne high-quality cohort and consistent findings (≥80%) in 1 or more low-quality cohorts
LimitedFindings of 1 cohort or consistent findings in 1 or more low-quality cohorts
InconclusiveInconsistent findings irrespective of study quality
No evidenceNo study could be found

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Selection and inclusion of studies.

After removing duplicate references, 2,695 unique references were identified for screening (Figure 1). Detailed reviews of the abstracts revealed 17 relevant full-text articles for selection (all in English) (3, 4, 21–35). Of these 17 articles, 3 were excluded, since they were almost similar publications of the same study (25, 27, 28). Three studies by Buckland-Wright et al (25–27) are regarded as 1 study, and 2 studies authored by Macfarlane et al and Buckland-Wright et al (28, 32) are regarded as 1 study from this point forward. In total, 14 articles were included for further analyses. No nested case–control studies were retrieved.

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Figure 1. Results of the literature search.

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Methodologic quality of articles.

The 2 reviewers scored a total of 224 items and agreed on 207 items (92%) (Table 2), with an intraclass correlation coefficient for interobserver agreement of 0.92 (95% confidence interval [95% CI] 0.67–0.98). The 17 disagreements were resolved after a discussion, whereupon consensus was reached. The most common reasons for the disagreement were whether the selection of the study subjects was clear and the studied risk factors were presented correctly. Eight of the 14 articles were of high quality (quality score ≥69%). The mean quality score of all articles was 72% (median 69% [range 31%–100%]).

Table 2. Results of the study quality assessment scores in chronological order*
Author, year (ref.)CriteriaQuality score, no./total (%)
123567891012131416171819
  • *

    1 = present and 0 = absent or no information. Criteria 4, 11, and 15 were not applicable, since no nested case–control studies were selected for this systematic review. The intraclass correlation coefficient for interobserver agreement was 0.92 (95% confidence interval 0.67–0.98), based on 224 items.

  • Scores resolved by discussion.

  • High-quality study.

Hutton et al, 1986 (30)00011000100011005/16 (31)
Kallman et al, 1990 (31)001110011111011111/16 (69)
Buckland-Wright et al, 1990–1992 (25–27)01111001010111009/16 (56)
Macfarlane et al, 1991 (32) and Buckland-Wright et al, 1995 (28)01111000010111008/16 (50)
Harris et al, 1994 (29)10011001010101007/16 (44)
Balblanc et al, 1995 (22)111110001011110010/16 (63)
Olejárová et al, 2000 (33)111111000110110010/16 (63)
Allen et al, 2006 (21)011110011100111111/16 (69)
Botha-Scheepers et al, 2009 (4)111111011111111115/16 (94)
Botha-Scheepers et al, 2007 (24)111111111111111116/16 (100)
Bijsterbosch et al, 2011 (3)111111011111111115/16 (94)
Bijsterbosch et al, 2011 (23)111110011111111114/16 (88)
Yusuf et al, 2011 (35)111110111111111115/16 (94)
Güler-Yüksel et al, 2011 (34)111111110111111115/16 (94)

The source population in some studies was not clearly described (25–28, 30, 32). The participation rates in 4 articles were not available (22, 30–32). Information on withdrawals and completers was seldom given (24). No or inappropriate reporting of outcome measures was the case in some studies, leading to lower quality scores of articles (25–30, 32).

Study characteristics.

The characteristics of the included articles are shown in Table 3. One study included only men (31); all other studies contained more women than men. Most study patients were middle-aged (>50 years), except for 1 population-based study (31). Hand OA was determined by radiographic criteria in 13 studies (3, 4, 21–23, 25–35). The most frequently used radiographic criteria were the Kellgren/Lawrence (K/L) criteria (36). One study used only clinical criteria (the American College of Rheumatology [ACR] criteria for hand OA) (24, 37), and 6 articles combined clinical and radiographic criteria for the definition of hand OA (3, 4, 22, 23, 30, 33). Five studies used the ACR criteria for hand OA as the clinical definition for hand OA at baseline (3, 4, 22–24).

Table 3. Study characteristics of the reviewed manuscripts in chronological order*
Author, year (ref.)Source population; no. of patients at followup (% women); mean followup, years; mean age, yearsDefinition of hand OA for inclusionDefinition of hand OA progressionDeterminantOutcome/results
  • *

    OA = osteoarthritis; BLSA = Baltimore Longitudinal Study of Aging; K/L = Kellgren/Lawrence; RR = relative risk/ratio; 95% CI = 95% confidence interval; OST = osteophytes; JSN = joint space narrowing; BMI = body mass index; PIP = proximal interphalangeal; DIP = distal interphalangeal; ACR = American College of Rheumatology; GOGO = Genetics of Generalized Osteoarthritis study; AUSCAN = Australian/Canadian Hand Osteoarthritis Index; GARP = Genetics Osteoarthritis and Progression study; OARSI = Osteoarthritis Research Society International; OR = odds ratio; BMD = bone mineral density.

  • Adjusted for age, number of joints with OA, and time between assessments.

  • Adjusted for age, sex, and time between assessments.

  • §

    Adjusted for age, sex, and familial effects.

  • Adjusted for age, sex, and BMI.

  • #

    Adjusted for age, sex, clinical outcome measure, followup time, and family effects.

  • **

    Adjusted for age, sex, baseline OST and JSN scores, followup time, and family effects.

  • ††

    Adjusted for family effects and anatomic phase at baseline.

  • ‡‡

    Adjusted for age, sex, postmenopausal status, BMI, family effect, smoking status, use of hormone replacement therapy, bisphosphonates, calcium and vitamin D supplements, and BMD scores at baseline.

Hutton et al, 1986 (30)Unclear; 14 (86); 3–5; 62“Typical clinical and radiographic features of generalized nodal OA”Radiographic (method not reported)Scintigraphic scan“44% of scan positive joints showed progression compared with 10% of scan negative joints (P < 0.001)”
Kallman et al, 1990 (31)General population (BLSA); 177 (0); 21.8; 49.3Radiographic (K/L grade ≥1)Radiographic (K/L or Kallman score)Age
  • Progression per grade increase, RR (95% CI)

    • K/L: 1.04 (1.02–1.07)

    • OST: 1.06 (0.96–1.15)

    • JSN: 1.01 (0.97–1.05)

    • JSN/OST: 1.05 (1.03–1.07)

Buckland-Wright et al, 1990–1992 (25–27)Unclear; 32 (91); 1.5; 62Radiographic (≥2 features: OST, JSN, subchondral sclerosis)Radiographic (change in JSN or subchondral cortical thickness) on quantitative microfocal radiographyAge, subchondral cortical thicknessNo difference
Macfarlane et al, 1991 (32) and Buckland-Wright et al, 1995 (28)Unclear; 32 (91); 1; 62Radiographic (≥2 features: OST, JSN, subchondral sclerosis)Radiographic (change in OST length or area [mm2] or OST [no.]) on quantitative microfocal radiographyChange in scintigraphic scan over 12 monthsIncreased or positive bone scan (mean ± SD change in area 0.51 ± 2.91) versus decreased or negative bone scan (mean ± SD change 0.08 ± 1.32; P < 0.005)
Harris et al, 1994 (29)Secondary care; 59 (76); 10; 69Radiographic (unclear)Radiographic (K/L or Kallman score)Age, sex, BMI, knee OA, knee OA progression, joints affected by OA in PIP/DIP joint sitesNo difference, except weak correlation (P = 0.059) for joints affected by OA in PIP/DIP joint sites
Balblanc et al, 1995 (22)Unclear; 15 (93); 4; 59Clinical, radiographic (ACR criteria)RadiographicScintigraphic scan“The mean increase in the radiographic progression was 2.81 times greater in positive than in negative joints (P < 0.002)”
Olejárová et al, 2000 (33)Secondary care; 45 (88); 2; 67.0Radiographic and clinical (K/L grade ≥2, symptoms on most days during past month)Radiographic (Kallman score), clinical (sum of joint tenderness scores)Scintigraphic scanRadiographic/clinical progression in positive joints 21.0%/21.2% versus radiographic/clinical progression in negative joints 6.6%/13.7% (P < 0.001 for both)
Allen et al, 2006 (21)Familial hand OA (GOGO); 426 (80); 4.1; 67.7Structural and radiographic (bony enlargements, K/L grade ≥2)Clinical (change in AUSCAN, pinch and grip strength)Global assessment of changeAdjusted β
 AUSCAN, right/left hand: 0.29 (P < 0.001)/0.24 (P < 0.001)
Adjusted β
 Grip strength, right/left hand: −0.16 (P = 0.003)/−0.13 (P = 0.015)
 Pinch grip, right/left hand: −0.13 (P = 0.022)/−0.11 (P = 0.060)
Botha-Scheepers et al, 2009 (4)Familial OA recruited from primary and secondary care (GARP); 172 (79); 2; 59.7Clinical, structural, and radiographic (ACR criteria, bony swellings, K/L grade ≥2)Radiographic (OARSI)Postmenopausal stage, age, sex, self-reported pain and functionAdjusted RR (95% CI)§
  • JSN progression

    • Early postmenopausal stage: 3.2 (1.1–6.6)

  • OST progression

    • Younger age: 1.9 (1.0–3.2)

    • Female sex: 2.9 (1.0–6.4)

    • Early postmenopausal stage: 2.6 (1.0–4.6)

  • Self-reported pain/function not associated

Botha-Scheepers et al, 2007 (24)GARP; 154 (80); 2; 60.4Clinical (ACR criteria)Radiographic (OARSI)Concordance between siblingsAdjusted OR (95% CI)
  • JSN progression: 1.3 (0.4–4.0)

  • OST progression: 1.2 (0.4–3.8)

Bijsterbosch et al, 2011 (3)GARP; 289 (83); 6.1; 59.5Clinical, radiographic (K/L grade ≥2, ACR criteria)Radiographic and clinical (OARSI, AUSCAN pain and function)Self-reported pain and function, no. of painful joints, pain intensity, no. of nodes, OST, JSN, erosive OA, nodal OA, thumb base OAAdjusted RR (95% CI) for clinical progression in pain/function in highest tertile#
Self-reported pain: 5.74 (4.38–6.65)/3.56 (1.63–5.83)
Self-reported function: 2.57 (1.26–4.13)/6.88 (5.30–7.90)
No. of painful joints: 2.11 (1.25–3.08)/2.39 (1.47–3.37)
Adjusted RR (95% CI) for radiographic progression in highest tertile**
  • Self-reported pain: 1.62 (1.14–2.02)

  • Pain intensity: 1.70 (1.18–2.19)

  • No. of nodes: 1.84 (1.19–2.48)

  • OST: 1.86 (1.38–2.21)

  • JSN: 1.24 (0.82–1.63)

  • Erosive OA: 1.55 (1.04–1.8)

  • Nodal OA: 1.94 (1.37–2.48)

  • Thumb base OA: 1.16 (0.91–1.36)

Bijsterbosch et al, 2011 (23)GARP; 236 (83); 6.1; 58.9Clinical, radiographic (K/L grade ≥2, ACR criteria)Radiographic (Verbruggen-Veys)Concordance between siblings, erosive joints, self-reported pain/stiffness, pain on pressure, nodes, limited motion, JSN, OST, AUSCANAdjusted OR (95% CI) for erosive evolution
Concordance between siblings: 6.2 (1.4–27.5)
Adjusted OR (95% CI) for erosive evolution††
  • Self-reported pain: 2.8 (1.7–4.7)

  • Self-reported stiffness: 2.3 (1.3–4.0)

  • Pain on pressure: 2.2 (1.4–3.4)

  • Nodes: 2.7 (1.7–4.5)

  • Limited motion: 2.6 (1.2–5.4)

  • JSN: 9.8 (5.7–16.6)

  • OST: 0.7 (0.3–2.0)

  • AUSCAN: 1.07 (1.02–1.12)

Yusuf et al, 2011 (35)GARP; 164 (81); 6; 60Radiographic (K/L grade ≥2)Radiographic (OARSI)Adiponectin, leptin, resistinAdjusted RR (95% CI) for hand OA progression
  • Adiponectin level 16.6–28.4 μg/ml: 0.3 (0.2–0.7)

  • Adiponectin level >28.4 μg/ml: 0.3 (0.2–0.7)

Güler-Yüksel et al, 2011 (34)GARP; 181 (80); 2; 60Radiographic (K/L grade ≥2)Radiographic (OARSI)Accelerated metacarpal BMDAdjusted RR (95% CI) for progressive hand OA‡‡
  • Accelerated BMD loss (>3 mg/cm2/year): 2.1 (1.1–4.3)

In almost all studies, progression was defined as radiographic progression (e.g., following the K/L or Osteoarthritis Research Society International [OARSI] scoring [38]), whereas clinical progression was also investigated in 2 studies (3, 33). Radiographic progression of erosive OA (EOA) specifically was investigated in 1 study (23). A definition of only clinical progression as the outcome was used in 1 study (21). The median followup time of the included studies was 4 years (range 1–21.8 years).

Association between risk factors and progression.

An overview of the investigated determinants and their relationship to radiographic and/or clinical progression of hand OA is shown in Table 3 and summarized below. If negative and positive findings were available in 1 article, only positive findings were reported in Table 3. Of the 14 included articles, 8 were of good/high quality (3, 4, 21, 23, 24, 31, 34, 35). Table 4 shows the overall level of evidence stratified for determinant and outcome.

Table 4. Overall levels of evidence, stratified for determinant and outcome*
Determinant (ref.)Total no. of studiesOutcome (no. of studies)No. of all positive studies/no. of high-quality positive studiesOverall evidence, radiographic OAOverall evidence, clinical OA
  • *

    References3,4,23, and24 are regarded as 1 study in this table, since the patients originated from the same study population. OA = osteoarthritis; Rad = radiographic; Clin = clinical; limited pos = limited evidence for a positive association with hand OA progression; inconclusive = inconclusive evidence for an association with hand OA progression; EOA = erosive OA; limited no = limited evidence for no association with hand OA progression; JSN = joint space narrowing; BMI = body mass index; BMD = bone mineral density.

Scintigraphy (22, 28, 30, 32, 33)4Rad (4)/Clin (1)4/0, 1/0Limited posLimited pos
Age (4, 25–27, 29, 31)4Rad (4)1/1Inconclusive
Sex (4, 21, 29)3Rad (2)/Clin (1)1/1, 1/1InconclusiveLimited pos
Affected OA group (21, 29)2Rad (1)/Clin (1)1/0, 1/1Limited posLimited pos
No. of OA joints (21)1Clin (1)1/1Limited pos
Painful joints, intensity and no. (3, 23)1Rad (1)/Rad EOA (1)/Clin (1)1/1, 1/1, 1/1Limited pos/limited posLimited pos
Self-reported pain (3, 4, 23)1Rad (1)/Clin (1)1/1, 1/1Limited posLimited pos
Self-reported function (3, 4, 23)1Rad (1)/Clin (1)0/0, 1/1Limited noLimited pos
Self-reported stiffness (23)1Rad (1)0/0Limited no
Limited motion of joint (23)1Rad (1)0/0Limited pos
Erosive OA (3, 23)1Rad (1)/Clin (1)1/1, 0/0Limited posLimited no
Nodal OA (3)1Rad (1)/Clin (1)1/1, 0/0Limited posLimited no
Nodes, no. and presence (3, 23)1Rad (1)/Rad EOA (1)/Clin (1)1/1, 1/1, 0/0Limited pos/limited noLimited no
Thumb OA (3)1Rad (1)/Clin (1)0/0, 0/0Limited noLimited no
Osteophytes (3, 23)1Rad (1)/Rad EOA (1)/Clin (1)1/1, 0/0, 0/0Limited pos/limited noLimited no
JSN (3, 23)1Rad (1)/Rad EOA (1)/Clin (1)0/0, 1/1, 0/0Limited no/limited posLimited no
Subchondral cortical thickness (25–27)1Rad (1)0/0Limited no
Knee OA presence/knee OA progression (29)1Rad (1)/Rad (1)0/0, 0/0Limited no/limited no
Family effect (23, 24)1Rad (1)/Rad EOA (1)0/0, 1/1Limited no/limited pos
Early menopause (4)1Rad (1)1/1Limited pos
BMI (29)1Rad (1)0/0Limited no
Adiponectin (35)1Rad (1)1/1Limited pos
Accelerated BMD loss (34)1Rad (1)1/1Limited pos
Scintigraphy.

All 4 studies investigating a positive (abnormal) scintigraphic scan (all using 99mTc) as the determinant for radiographic progression (22, 28, 30, 32, 33) (Table 3) reported a positive association. One study also reported a positive association with clinical progression (33). Limited evidence, based on consistent associations found in 4 low-quality studies, was present for the positive association of an abnormal scintigraphic scan with radiographic progression (22, 28, 30, 32, 33) (Table 4). The reported effect sizes varied from 21–44% progression in positive joints versus 6.6–10% progression in negative joints (30, 33), to a 2.8 times progression in positive joints compared to negative joints (22).

Age.

Age was investigated as a risk factor for radiographic progression in 4 studies (4, 25–27, 29, 31). The determinant was analyzed by different methods, from a continuous measurement (25–27, 29) to several age categories (31) or dichotomized into 2 age groups (4). One study showed a positive association for older age (RR 1.05 [95% CI 1.03–1.07]) with joint space narrowing (JSN) and osteophyte progression combined (31), whereas 1 study showed a negative association for older age (patients between ages 40 and 59 years versus patients ages ≥60 years for osteophyte progression [adjusted RR 1.9 (95% CI 1.0–3.2)]) (4). In 2 studies (25–27, 29), age showed no association. The level of evidence of age as a risk factor for hand OA progression was inconclusive (4, 25–27, 29, 31).

Female sex.

One high-quality study showed a positive association for female sex with radiographic progression (adjusted RR 2.9 [95% CI 1.0–6.4]) (4), whereas a low-quality study showed no association (29). One study suggested that women were more likely than men to report worsening of symptoms over time (clinical progression) (21). Hence, there was inconclusive evidence for an association between female sex and radiographic progression (4, 29), while there was limited evidence for a positive association with clinical progression (21).

Affected OA group.

One high-quality study reported on the association of lower global assessment scores with Australian/Canadian Hand Osteoarthritis Index (AUSCAN) (39) changes in proximal interphalangeal (PIP) and carpometacarpal (CMC) joint OA (P < 0.05), meaning that clinical progression of hand OA in PIP joints or first CMC joints was associated with an increase of AUSCAN scores (21). However, this study did not report the association of clinical progression and AUSCAN changes in distal interphalangeal (DIP) joint OA.

One low-quality study reported on an increase of radiographic hand OA (defined as a K/L score ≥2) in 188 DIP joints and 85 PIP joints with OA at baseline to 282 DIP joints and 168 PIP joints with OA after 10 years of followup (29). The evidence of an affected OA group with radiographic or clinical progression was limited.

Number of joints with OA.

The number of joints affected by OA (K/L grade ≥2) at baseline was associated with lower grip and pinch grip strength after 4 years (21) in 1 high-quality study, demonstrating limited evidence for a positive association between the number of joints with OA and clinical progression (21).

Painful joints.

One article showed a positive association between the number of painful joints (patient level, in tertiles, by the Doyle Index [40]) and radiographic and clinical progression (adjusted RR 1.63 [95% CI 1.19–2.00] and adjusted RR 2.39 [95% CI 1.47–3.37], respectively) (3). Pain intensity (joint level, in tertiles, by the Doyle Index) was also positively associated with radiographic progression (adjusted RR 1.7 [95% CI 1.18–2.19]), whereas it had no effect on clinical progression (3). Pain on pressure (joint level, yes versus no) was associated with erosive evolution (adjusted OR 2.2 [95% CI 1.4–3.4]) (23). The level of evidence for a positive association of painful joints (presence, intensity, and number) with radiographic and clinical progression was limited, since these patients were part of 1 high-quality study (3, 23).

Hand OA subsets.

EOA, as defined by the Verbruggen-Veys scoring method (41), was investigated as a risk factor for radiographic and clinical progression over 6 years (3). EOA was positively associated with radiographic progression (adjusted RR 1.55 [95% CI 1.04–1.88]) and not with clinical progression (3). If a proband had ≥3 erosive joints, the sibling had a higher risk of having radiographic erosive progression (adjusted OR 6.2 [95% CI 1.4–27.5]) (23). The evidence for the positive association between presence of EOA and radiographic progression was limited.

The presence of nodal OA (presence of Heberden's/Bouchard's nodes affecting ≥2 rays of either hand) was associated with radiographic progression (adjusted RR 1.94 [95% CI 1.37–2.48]) (3). A positive association was found between the number of nodes and radiographic progression (adjusted RR 1.84 [95% CI 1.19–2.48]) (3). A positive association between the presence of nodes and erosive evolution of hand OA was reported (adjusted OR 2.7 [95% CI 1.7–4.5]) (23). There was limited evidence that symptomatic thumb base OA (pain/stiffness in the first CMC joint on most days) was not associated with radiographic or clinical progression (23).

Self-reported pain, function, and stiffness and limited motion of the joint.

Three high-quality articles (with patients originating from the same study) investigated self-reported pain. Self-reported pain was positively associated with radiographic progression after 6 years in 1 study (3, 23); 1 article reported no association for radiographic progression after 2 years (4). Also, a positive association was found for clinical progression in 1 article (adjusted RR 3.56 [95% CI 1.63–5.83]) (3). There was limited evidence for the association between self-reported pain and radiographic/clinical progression.

In the same 3 high-quality articles, self-reported function was investigated. There was limited evidence for a positive effect for clinical progression after 6 years (adjusted RR 6.88 [95% CI 5.30–7.90]) (3) and limited evidence for no association for radiographic progression after 2 and 6 years (3, 4, 23).

Self-reported stiffness was not associated with radiographic progression (23). There was limited evidence for a positive association between limited motion of the joint with erosive evolution (23).

Radiographic OA features and scores.

The presence of osteophytes (highest tertile, by OARSI grade) was positively associated with radiographic progression (adjusted RR 1.86 [95% CI 1.38–2.21]), but not with clinical progression after 6 years (3). No association was seen between an OARSI grade 2–3 osteophyte with erosive evolution at the joint level (23). For an OARSI grade 2–3 JSN, a positive association was found with erosive evolution (adjusted OR 9.8 [95% CI 5.7–16.6]) (23). There was limited evidence for the inverse association between the highest tertile of JSN with radiographic and clinical progression (3). Knee OA at baseline, knee OA progression, and subchondral cortical thickness of the hand joints were not associated with radiographic hand OA progression (25–27, 29).

Family effect.

Two articles (with patients originating from the same study) investigated the familial effect as a determinant, of which 1 showed no association between the familial effect and radiographic progression after 2 years (adjusted OR 1.3 [95% CI 0.4–4.0]) (24). A positive association was reported for the concordance between probands and siblings for erosive evolution in IP joints after 6 years (adjusted OR 4.7 [95% CI 1.4–15.8]) (23). There was limited evidence that familial effect does not contribute to radiographic hand OA progression (24) and limited evidence for a positive association with erosive evolution (23).

Hormonal factors (menopause, adiponectin, leptin, and resistin) and body mass index (BMI).

Menopause was investigated in 1 study, showing a positive association for women in an early postmenopausal stage (≤10 years) with radiographic progression (adjusted RR 3.2 [95% CI 1.1–6.6] for JSN progression) (4).

One high-quality study showed that higher levels of adiponectin in serum were associated with a lower risk of hand OA progression after 6 years (35), whereas no association was found for leptin and resistin in the same study (35). BMI (as a continuous measurement) showed no association with radiographic progression (29). The evidence was limited for these factors, since these findings were reported in a single study (4, 29, 35).

Bone mineral density (BMD) loss.

One high-quality article reported that accelerated metacarpal BMD loss, defined as >3 mg/cm2/year, was positively associated with radiographic hand OA progression after 2 years (adjusted RR 2.1 [95% CI 1.1–4.3]) (34).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

To our knowledge, this is the first systematic review that summarizes determinants for radiographic and clinical progression in hand OA. Limited evidence from 4 studies is available for scintigraphy as a risk factor for radiographic progression of hand OA. Other baseline factors (e.g., the number of painful joints, EOA) show limited evidence for a positive association. Factors such as age and sex show conflicting evidence in their association with hand OA progression. This study suggests that a positive scintigraphic test could be used to study the progression of pain and function as well as structural progression in hand OA.

A strength of this systematic review is that predefined qualitative levels of evidence were used to summarize the data by using a set of criteria as proposed in prognostic studies (16, 18). Another strength is that the set of criteria was scored by 2 independent readers. However, only statistical significances were included in the judgment for a positive or negative association, and the sample size of the study was not taken into account. If a small study showed a positive but statistically not significant association, this information was not incorporated. Most risk factors were only investigated in 1 or 2 single studies. Since the studies were heterogeneous and often no effect sizes were given, a formal pooling and subsequent meta-analysis were not possible. This could be one of the explanations why some factors (e.g., age and sex) showed inconclusive evidence. Another reason why limited associations with hand OA progression were found is that very few studies investigated the same determinants of interest.

Because of the strict a priori selection, a relatively large proportion of articles was not considered in the systematic review, even though these articles reported on risk factors for the disease course in hand OA. The most common reason for exclusion was that incident development and progression of hand OA were investigated at the same time during followup (8–14, 42, 43), resulting in a heterogeneous case mix of the study population of interest. The risk factors investigated in these types of studies cannot be exclusively associated with the progression of hand OA. A 10-year followup study showed that radiographic changes over time in incident hand OA (patients who started without OA at baseline and progress to new OA) and progressive hand OA (patients with established OA at baseline who progress in their OA over time) occurred most frequently in the DIP joints (8). The article was excluded for this review since subjects were selected based on prior meniscectomy and not on having hand OA at baseline. Another study showed that the rate of degeneration in PIP joints was much lower than in DIP joints; unfortunately, this article also included healthy subjects without OA at baseline (9). If these studies had reported analyses separately for incident and progressive hand OA, additional evidence could possibly be provided for the risk factor affected hand OA group. Other risk factors such as running, blood pressure, and carotid intima-media thickness were also investigated in relation to hand OA progression, but these study populations also contained mixed non-OA and established hand OA cases at baseline (11, 13, 42).

The limited evidence for a positive association of an abnormal scintigram with radiographic progression was based on 4 low-quality studies from the 1980s and 1990s (22, 30, 32, 33). In a technetium scintigram, labeling with diphosphonates is used. Uptake of diphosphonates in bone can indicate an increased blood flow representing inflammation, with high sensitivity but low specificity. Higher bone uptake can also indicate new bone formation (44). In clinical practice for hand OA patients, performance of a scintigram is not an easy method because radiation is used. More recently, imaging modalities such as magnetic resonance imaging (MRI) in hand OA have been introduced. MRI is able to visualize features such as bone marrow lesions and synovitis. Comparative studies of scintigraphy and MRI in rheumatoid arthritis showed good correlation between these methods with respect to visualization of inflammatory signs in subchondral bone (45, 46). Studies in sacroiliitis showed that MRI could even be more sensitive for detecting subcortical bone marrow edema than scintigraphy (47). Future studies should investigate whether the meaning of MRI is similar to the meaning of scintigraphy in hand OA and if this could be of value as a biomarker for hand OA progression.

Whether age is a risk factor for OA progression is unclear (4, 25–27, 29, 31). The discrepancies in results between studies can be explained by the differences in parameters for age that were used and by the duration of followup between studies. Further studies are needed to elucidate a possible age effect. A female predominance in the development of clinical and radiographic hand OA has previously been reported (48); however, female sex was not a conclusive risk factor for radiographic hand OA progression (4, 29). The difference in study results could be explained by the difference in the followup duration and the mean age of the study participants; in relatively young women, an association with progression was found when compared to men (4), but in relatively older women, such an association was not seen. This suggests an interaction between sex and age, and this interaction must be investigated further. For clinical progression, a positive association was found with female sex, which could be explained by the notion that women may report more often than men about their worsening of symptoms over time (21).

For all other risk factors that were summarized in this review, the conclusion was based on a single study. This study gives insight into what has been investigated already, but further research is needed to confirm these associations.

Most studies in this review focused on radiographic progression and not clinical progression, although at the moment no consensus is available on how clinical or radiographic hand OA progression should be defined. Our results suggest that structural determinants, such as nodes, nodal OA, osteophytes, and erosions are especially risk factors for radiographic progression, whereas clinical symptoms, including self-reported function, are risk factors for clinical progression. Another remarkable finding is the difference in risk factors for radiographic progression and erosive evolution. These results could reflect differences in underlying processes that play a role in different types of progression. However, since the number of studies that investigated these determinants is small, more studies are warranted.

Several limitations to this systematic review can be addressed. Unfortunately, it was not possible to pool the data into a meta-analysis to provide a more precise estimate of the association with the outcome due to heterogeneity of the studied populations and progression. However, the heterogeneity of studies and lack of appropriate effect sizes in this review are a strong argument against a meta-analysis (49). The results cannot be generalized for the general population, since most studies were hospital based. Furthermore, studies used different kinds of definitions for hand OA progression, since no consensus is available on how hand OA progression should be defined. Publication bias could not be assessed with, for example, a funnel plot (50), since only a few studies reported ORs or RRs. No judgment can be made whether only positive findings have been published.

In conclusion, this systematic review revealed that there is limited evidence present for scintigraphy at baseline as a risk factor for hand OA progression, based on 4 studies. All other factors showed limited (mostly based on 1 article) or conflicting evidence. Future high-quality studies examining risk factors for hand OA progression, especially clinical progression, are needed to replicate these findings and determine modifiable factors in symptomatic patients.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kwok had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Kwok, Rosendaal, Huizinga, Kloppenburg.

Acquisition of data. Kwok, Plevier, Kloppenburg.

Analysis and interpretation of data. Kwok, Kloppenburg.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
ACR_21851_sm_AppendixA.doc24KSupplementary Appendix A
ACR_21851_sm_AppendixB.doc33KSupplementary Appendix B

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