Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms

in European Journal of Endocrinology

Objective

Adults with X-linked hypophosphatemia (XLH) may suffer from skeletal symptoms leading to functional disability. No data on their quality of life (QoL) have been reported so far. Our objectives were to evaluate the QoL and its determinants in XLH adults.

Patients and methods

We conducted a prospective study in XLH adults, who consulted for musculoskeletal symptoms between 2013 and 2014. We assessed their QoL using HAQ, RAPID3 and SF36, and analysed the variables associated with low QoL. We compared their QoL to that of patients affected with axial spondyloarthritis (ax-SpA) (paired on age and gender), a rheumatologic disorder with a known low QoL.

Results

Fifty-two XLH adults (37 women (71.1%); mean age 41.8±13.3 years) were included; 44 (84.6%) patients had an altered QoL. Increased age and presence of structural lesions were significantly associated with worse QoL (HAQ, RAPID3) (P<0.05). Presence of enthesopathies was significantly associated with worse RAPID3 (OR=4.45 (1.09–18.29), P=0.038). Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with a better SF36-mental component score (OR=0.14 (0.03–0.57), P=0.007 and OR=0.26 (0.07–0.98), P=0.047 respectively). QoL was significantly worse in XLH than in ax-SpA adults (VAS pain, SF36-PCS, RAPID3) (P<0.05).

Conclusion

Our study showed i) QoL of XLH adults is altered and significantly worse than that of ax-SpA patients (VAS pain, SF36-PCS and RAPID3), ii) structural lesions and especially enthesopathies are associated with a worse QoL and iii) treatment using phosphate supplements and/or vitamin D is associated with a better mental health score.

Abstract

Objective

Adults with X-linked hypophosphatemia (XLH) may suffer from skeletal symptoms leading to functional disability. No data on their quality of life (QoL) have been reported so far. Our objectives were to evaluate the QoL and its determinants in XLH adults.

Patients and methods

We conducted a prospective study in XLH adults, who consulted for musculoskeletal symptoms between 2013 and 2014. We assessed their QoL using HAQ, RAPID3 and SF36, and analysed the variables associated with low QoL. We compared their QoL to that of patients affected with axial spondyloarthritis (ax-SpA) (paired on age and gender), a rheumatologic disorder with a known low QoL.

Results

Fifty-two XLH adults (37 women (71.1%); mean age 41.8±13.3 years) were included; 44 (84.6%) patients had an altered QoL. Increased age and presence of structural lesions were significantly associated with worse QoL (HAQ, RAPID3) (P<0.05). Presence of enthesopathies was significantly associated with worse RAPID3 (OR=4.45 (1.09–18.29), P=0.038). Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with a better SF36-mental component score (OR=0.14 (0.03–0.57), P=0.007 and OR=0.26 (0.07–0.98), P=0.047 respectively). QoL was significantly worse in XLH than in ax-SpA adults (VAS pain, SF36-PCS, RAPID3) (P<0.05).

Conclusion

Our study showed i) QoL of XLH adults is altered and significantly worse than that of ax-SpA patients (VAS pain, SF36-PCS and RAPID3), ii) structural lesions and especially enthesopathies are associated with a worse QoL and iii) treatment using phosphate supplements and/or vitamin D is associated with a better mental health score.

Introduction

X-linked hypophosphatemia (XLH), the most common heritable form of rickets or osteomalacia, is due to loss-of-function mutations in the phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX), which results in elevated blood levels of fibroblast growth factor 23 (FGF23), phosphate wasting, hypophosphatemia and decreased vitamin D hydroxylation in the kidney. XLH has an incidence of 3.9/100 000 live births and a prevalence of 4.8/100 000 (1).

In children, phenotypic expression includes variable degrees of growth retardation, bone pain and deformities, impaired dental mineralisation, delayed walking, craniostenosis, waddling gait, leg bowing and rickets. Therapy with phosphate salts and vitamin D analogs aim at reducing bone pain, improving dentition, correcting leg deformities, improving adult height and decreasing the number of surgeries (2, 3). Initiation at early ages is recommended as the early initiation of treatment optimises final body height results (2, 3).

Adult patients with XLH (XLH adults) can be affected not only by skeletal complications related to spontaneous fractures because of persistent osteomalacia but also early osteoarthritis and enthesopathies, for which the severity of symptoms and of structural involvement is variable (3, 4, 5, 6). The disease outcome in adults remains inadequately described. Most adults are treated with phosphate supplements and vitamin D analogs to reduce extent of osteomalacia and to improve fractures healing or surgery recovery; however, there is no consensus on the indications and duration of treatment in adults. Serum alkaline phosphatase activity is measured to quantify the extent of osteomalacia; some biological tests (25 OH vitamin D, calcaemia, phosphatemia, calciuria, phosphaturia, parathyroid hormone serum level) are performed for the monitoring of XLH, in order to avoid some complications such as hypercalciuria or hyperparathyroidism (2, 3).

On the other hand, other long-term skeletal complications (osteoarthritis and enthesopathies) are also responsible for musculoskeletal pain and fatigue likely leading to disability and altered quality of life (QoL) (2). Visual analogic pain scales may help to quantify the degree of pain and disability but are not appropriate to assess the disease burden.

The objectives of our study were to evaluate the QoL of XLH adults with skeletal symptoms and to identify which variables were associated with an altered QoL. To evaluate the severity of the functional disability and its impact on the QoL, we compared the QoL of XLH adults to that of adults affected with axial spondyloarthritis (ax-SpA). Ax-SpA is a chronic rheumatic disease affecting young patients with similar radiological phenotype of enthesopathies and for which the low scores of QoL due to function disability are already known. Our ultimate goal is to provide QoL and its determinants as novel outcomes for the monitoring of therapeutic interventions in XLH.

Patients and methods

Study design

Descriptive prospective study in a tertiary centre.

Participants

This study was conducted in XLH adults carrying a PHEX mutation; all of them were referred for musculoskeletal symptoms in our Rheumatology department, between December 2013 and December 2014. All participants received written information and gave oral consent for use of their data, which were obtained as part of routine assessment in such patients. No extra blood samples or X-rays exams were performed for this study.

Clinical, biological and radiological parameters

The following variables were assessed using interviews and physical exams for each patient by the rheumatologist: age at visit, age at diagnosis, family history of XLH, history of orthopaedic surgery of lower limbs, vitamin D analogs and phosphate supplements during childhood, pain related to musculoskeletal location at time of assessment, pain intensity using Visual Analogic Scale (VAS), fatigue, lower limbs deformations, reported dental defects, current treatment with vitamin D, vitamin D analogs and/or phosphate supplements, biological data (calcaemia, phosphatemia, serum alkaline phosphatase, parathyroid hormone (PTH), 25OH vitamin D).

Imaging of the whole skeleton was performed using the EOS biplane X-ray imaging, in an upright weight-bearing position providing a high quality image with less radiation than standard imaging techniques. The quality of the image is similar to computed radiography and digital radiography (7). EOS can image the full length of the body, removing the need for digital stitching (7). Presence of osteoarthritis of spine, hip and knee (defined as formation of osteophytes on joint margins or narrowing of joint cartilage associated with sclerosis of subchondral bone or small pseudocystic areas with sclerotic walls in subchondral bone or altered shape of the bone ends) (8), enthesopathies (defined as bone proliferation at site of ligament attachments or calcification of ligaments) (9, 10) and sequelae of insufficiency fractures (defined by incomplete cortical break sometimes associated with a periosteal reaction without history of trauma (11) were evaluated, on the whole skeleton except the skull (Fig. 1), by two experienced rheumatologists blinded to each other who adjudicated any discrepancy. A training session was done before the start of the study (12, 13, 14, 15).

Figure 1

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Figure 1

X-ray features in XLH adults. (a) Osteoarthritis. (b) Enthesopathies: 1/lumbar spine, 2/pelvis. (c) Fractures.

Citation: European Journal of Endocrinology 174, 3; 10.1530/EJE-15-0661

Forty-three patients (82.7%) had full body EOS imaging, the others had X-rays of the region of interest. Nine patients (17.3%) had X-rays recently performed at the time of referral, and EOS imaging was not performed for them.

Health Related QoL measurements

Pain was quantified at the time of evaluation on a VAS from 0 (no pain) to 100 (worst pain).

Health Related QoL (HRQoL) was assessed using three validated questionnaires, completed by the patient at the time of visit: health assessment questionnaire (HAQ), Routine Assessment of Patient Index 3 (RAPID3) and short form 36 (SF36). None of them have been tested in XLH adults. We excluded patients unable to read and understand the questionnaires.

HAQ

The HAQ concerns functional disability and pain in rheumatic diseases (16). Physical function is assessed with 20 questions about daily activities grouped in eight categories: dressing and grooming, arising, eating, walking, hygiene, reach and grip. The final score, ranging from 0 (no difficulty in performing the task) to 3 (failure to achieve the task), corresponds to the mean of the sum of these eight category scores (each category score obtained by using the highest sub-category score) and takes into account the use of aids or devices (16). HAQ has been used in rheumatic diseases (rheumatoid arthritis, spondyloarthritis) and compared with healthy controls (17). HAQ is considered low when score is higher than 0.5 (18).

RAPID3

RAPID3 is a composite index assessing three domains: physical function, pain and disease activity. Each domain is scored from 0 to 10 and the final score is the sum of the three domains. High scores represent the worse altered health state (19, 20, 21). RAPID 3 was first used in rheumatoid arthritis (RA); comparison of RAPID 3 with RA activity score (DAS28) shows that they determine outcomes in similar categories, such as remission and low, moderate and high disease activity. A score >12 indicates high severity, 6–12 indicates moderate severity and 3–6 indicates low severity. A score of <3 indicates remission. We chose the threshold >6 (moderate severity) for low QoL in our population as done in other studies (20, 21).

SF36

The SF36 is a generic questionnaire of QoL with 36 questions divided into eight domains, scored from 0 (worst QoL) to 100 (best QoL): physical function (PF), bodily pain (BP), vitality (VT), social function (SF), mental health (MH), general health (GH), role physical (RP), role emotional (RE). The SF36 can be presented as the physical component score (PCS=PF+RP+BP+GH) and mental component score (MCS=MH+RE+SF+VT). The final score is the mean of the sum scores for the domains (22).

There is no threshold value delimiting low and normal QoL (22).

Axial spondyloarthritis control group

The control group was constituted of ax-SpA adults followed in the same department during the same period and matched for age and gender (23, 24). These patients gave their oral consent for the participation in this study. The HAQ, RAPID3 and SF36 scores have been validated in ax-SpA (25, 26).

Statistical analysis

First, we described the characteristics of the XLH adult patients and results of QoL (mean values (±s.d.)). In our study, altered QoL was defined for each index: HAQ >0.5 (17, 18), RAPID3 >6 (19, 20, 21), SF 36 values <median values (in absence of consensual threshold value, in the literature). We also defined a composite criterion of altered QoL as having an HAQ >0.5, or an RAPID3 >6, or one of the SF36 component scores <median value. A logistic regression was used to assess the variables significantly associated with altered QoL. The variables tested were: age, gender, family history of XLH, history of orthopaedic lower limb surgery, history of treatment in childhood (combination of phosphate supplements and vitamin D analogs), duration of disease (time since diagnosis), clinical symptoms (musculoskeletal pain, fractures, musculoskeletal fatigue, reported dental defects, deformation of lower limbs), radiological lesions (osteoarthritis, enthesopathies, sequelae of insufficiency fractures), current treatment with phosphate supplements, vitamin D, vitamin D analogs, analgesics, non-steroidal anti-inflammatory drugs and/or physiotherapy.

We compared the QoL of XLH adults to that of the ax-SpA adults using a Student test.

P value <0.05 was considered as statistically significant. The statistical analysis was performed using the SAS Software SAS (version 9.3; SAS Institute, Cary, NC, USA).

Results

Characteristics of the XLH adult patients

In total, 52 XLH adults (71.1% female, mean age of 41.8±13.3 years), with a mean (±s.d.) disease duration of 34.6±16.5 years, were referred to our department for skeletal symptoms, and all of them were included in the study. Their characteristics are described in Table 1. At the time of evaluation, musculoskeletal pain and fatigue were reported in 90.4 and 86.0% of patients respectively. Radiological abnormalities were present in 32 patients (61.5%): osteoarthritis in 85.4%, enthesopathies in 64.0% and sequelae of femoral insufficiency fractures in 36.0%. At the time of QoL evaluation, 64.6, 59.2 and 66.7% patients were receiving phosphate supplements, vitamin D or vitamin D analogs respectively. Only 31.2 and 23.9% were receiving analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) respectively.

Table 1

Characteristics of XLH adults included in the study.

VariablesXLH adults
Patients (n)52
Age (years), mean (±s.d.)41.8 (±13.3)
Gender (n) (% female)37 (71.1)
Family history of XLH (n) (%)26 (72.2)
History of orthopaedic lower limbs surgery (n) (%)33 (63.5)
Treatment during childhood (n) (%)31 (73.8)
Time since diagnosis (years), mean y (±s.d.)34.6 (±16.5)
History of fractures (n) (%)16 (40.0)
Deformations of lower limbs (n) (%)44 (95.6)
Self reported dental defects (n) (%)20 (62.5)
Phosphorous (mmol/l), mean (±s.d.) (normal range 0.8–1.5)0.56 (±0.08)
Calcium (mmol/l), mean (±s.d.) (normal range 2.2–2.6)2.31 (±0.09)
PTH (pg/ml), mean (±s.d.) (normal range 10–60)62.8 (±28.7)
25OH vitamin D (ng/ml) mean (±s.d.) (normal range 10–45)32.5 (±15.2)
Alkaline phosphatase (IU/l), mean (±s.d.) (normal range 40–100)80.0 (±26.9)
Structural lesions, n/n of patients with data available (%)32/52 (61.5)
Radiological osteoarthritis41/48 (85.4)
n/n of patients with data available (%)
 Spine29/46 (63.0)
 Hip37/47 (78.7)
 Knee22/47 (46.8)
Enthesopathies, n/n of patients with data available (%)32/50 (64.0)
Radiological fractures, n/n of patients with data available (%)18/50 (36.0)
Current treatment (n) (%)
 Phosphate supplements31 (64.6)
 Vitamin D29 (59.2)
 Vitamin D analogs32 (66.7)
 Analgesics15 (31.2)
 NSAIDs11 (23.9)
Physiotherapy27 (57.4)

XLH, X-linked hypophosphatemia; n, number; NSAIDs, non steroidal anti-inflammatory drugs.

QoL results in XLH patients

Mean (±s.d.) values of VAS pain, HAQ, RAPID 3, SF36 PCS and SF36 MCS are reported in Table 2.

Table 2

Comparison of quality of life of XLH and ax-SpA populations. Means (±s.d.) are reported in the table.

VariablesXLHAx-SpAP value
HAQ (0–3)0.69 (0.56)0.66 (0.62)0.523
RAPID3 (0–30)12.1 (6.4)8.9 (6.0)0.017
SF36 PCS (0–100)49.5 (20.5)58.3 (21.2)0.029
SF36 PF60.6 (23.7)71.6 (21.7)0.023
SF36 RP40.4 (37.7)45.7 (37.9)0.534
SF36 BP54.3 (23.6)66.8 (23.8)0.010
SF36 GH42.9 (18.4)49.0 (19.7)0.060
SF36 MCS (0–100)57.9 (21.3)63.1 (23.0)0.207
SF36 VT42.5 (19.9)47.8 (20.7)0.204
SF36 SF70.4 (20.3)76.9 (23.7)0.077
SF36 RE59.0 (45.1)62.2 (46.7)0.670
SF36 MH59.7 (17.7)65.6 (20.6)0.217
VAS pain (0–100)50.0 (26.0)36.0 (26.0)0.008

XLH, X-linked hypophosphatemia; Ax-SpA, axial spondyloarthritis; HAQ, health assessment questionnaire; RAPID3, routine assessment of patient index data 3; SF36, short form 36; PCS, physical component score; MCS, mental component score; BP, bodily pain; PF, physical function; RP, role physical; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; VAS, visual analogic scale.

Twenty-nine (55.8%), 40 (76.9%), 26 (50%) and 26 (50%) XLH adults had a low QoL defined by either an HAQ (>0.5), an RAPID3 (>6), an SF36-PCS (<42.71, median value) or an SF36-MCS (<57.71, median value) respectively. Forty-four (84.6%) XLH adults had a low QoL defined by the composite score: HAQ (>0.5) or RAPID3 (>6) or SF36-PCS (<42.71) or SF36-MCS (<57.71).

Variables associated with a low QoL

For each questionnaire of QoL, age was significantly associated with HAQ >0.5 and RAPID3 >6. Women described worse QoL than males in terms of RAPID3 and SF36-PCS. Dental defects were significantly associated with worse QoL reported by HAQ and RAPID3. Structural lesions (all lesions as a whole) were significantly associated with worse scores of HAQ and RAPID3. Enthesopathies were significantly associated with worse scores of RAPID3. Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with better SF36-MCS scores (Table 3).

Table 3

Variables associated with worse QoL in XLH adults using logistic regression.

Assessment of an altered quality of lifeVariables significantly associatedOdds ratioP value
HAQ >0.5Age1.06 (1.00–1.12)0.036
Dental defects7.00 (1.19–41.36)0.032
Structural lesions6.75 (1.19–38.40)0.031
RAPID3 >6Age1.07 (1.00–1.14)0.048
Female gender5.60 (1.40–22.36)0.015
Dental defects13.57 (1.34–137.45)0.027
Structural lesions6.43 (1.37–30.11)0.018
Enthesopathies4.45 (1.09–18.29)0.038
SF36-PCS <42.71Female gender4.03 (1.08–15.09)0.038
SF36-MCS <57.71Vitamin D treatment0.26 (0.07–0.98)0.047
Phosphate supplements treatment0.14 (0.03–0.57)0.007
Composite criterionaAge1.11 (1.01–1.22)0.031
Female gender5.67 (1.15–27.94)0.033
Musculoskeletal fatigue8.25 (1.23–55.57)0.030
Enthesopathies7.50 (1.32–42.50)0.023

QoL, quality of life; XLH, X-linked hypophosphatemia; HAQ, health assessment questionnaire; RAPID3, routine assessment of patient index data 3; SF36, short form 36; PCS, physical component score; MCS, mental component score.

Composite criterion defined as HAQ >0.5 or RAPID3 >6 or SF36-PCS <median value or SF36-MCS <median value.

Age, female gender, musculoskeletal fatigue and enthesopathies were significantly associated with a reduced QoL defined by the composite score (HAQ >0.5 or RAPID3 >6 or SF36 <median value) (Table 3).

Comparison of QoL in XLH and ax-SpA populations

Ax-SpA population

A total of 52 patients (63.6% female, mean age of 45.3±12.7 years) with ax-SpA matched for age and gender, were included in the study as a control group. The mean duration of their disease was 13.3±9.5 years. The disease activity of the ax-SpA patients was reasonably well controlled as judged by the mean (±s.d.) values of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores of 32.3±20.0 and 28.4±23.8 respectively, and by the C-reactive protein mean (±s.d.) value of 4.61 (±7.10) mg/l. Thirty-eight (73.1%) patients were receiving TNFα-blockers; 15 (28.8%) and 22 (42.3%) patients were treated with analgesics and NSAIDs respectively. Forty-eight (92.3%) patients had structural lesions: 28.0, 75.0 and 77.1% presented with syndesmophytes, radiological sacro-iliitis and MRI sacroiliitis respectively. The prevalence of the spinal enthesopathies was lower in the ax-SpA adults than that of XLH adults (28% vs 64% respectively, P=0.0001).

QoL of XLH and comparison with ax-SpA

Average HAQ scores were similar in the two groups of patients (Table 2). However, VAS pain was higher in XLH than in ax-SpA adults (50.0 vs 36.0, P=0.008). Although there was no difference in the percentage of patients receiving analgesics and NSAIDs between the two groups, QoL was significantly worse in XLH than in ax-SpA patients, with a higher RAPID3 (12.1 vs 8.9, P=0.017) and a lower SF36 PCS (49.5 vs 58.3, P=0.029).

Discussion

This is the first study of QoL impairment conducted in adult patients with XLH. Our study, performed in one centre on 52 consecutive patients over one year shows that young XLH adults with musculoskeletal symptoms display a severely impaired QoL, confirming that XLH can be a physically disabling condition. Age, female gender and presence of enthesopathies were significantly associated with impaired QoL.

Comparison with general population and other chronic rheumatic diseases

We compared QoL of XLH patients with available data on the general population and populations of patients with chronic musculoskeletal diseases. These indirect comparisons show that XLH adults have a lower QoL than the general population (26, 27) and their QoL is close to that of patients with chronic diseases (Table 4). Indeed, the mean values of QoL of XLH adults are similar to those reported in patients with rheumatoid arthritis, another severe disabling condition, assessed by SF36 (28), HAQ (29) and RAPID3 (18, 30). Patients with osteoarthritis presented similar (medical stage of osteoarthritis) or worse (surgical stage of osteoarthritis) QoL than that of XLH adults, in terms of RAPID3 (30), HAQ (31) and SF36 (32). Patients with juvenile idiopathic arthritis have, on average, better QoL than XLH adults (29, 32).

Table 4

Health related quality of life scores for our X-linked hypophosphatemia (XLH) patients, French population and rheumatologic disease populations.

Health related quality of life scores, mean (s.d.)
Osteoarthritis
XLHFrench populationRheumatoid arthritisJuvenile idiopathic arthritisMSSS
HAQ (0–3)
 n59a99c9c44c
 Mean (s.d.)0.69 (0.56)0.1520.843 (0.639)0.232 (0.561)0.561 (0.518)
RAPID3 (0–30)NANA
 n174d113d
 Mean (s.d.)12.1 (6.4)12.2 (8.0)12.1 (6.2)
SF36 (0–100)
 n391b137e32f139g97g
 PF60.6 (23.7)83.7 (21)35.0 (50.0)77.548.8 (23.5)35.8 (21.4)
 RP40.4 (37.7)80.3 (31)0.0 (50.0)5041.2 (40.1)22.0 (31.9)
 BP54.3 (23.6)69.6 (14)33.3 (33.3)4042.3 (20.8)34.0 (16.7)
 GH42.9 (18.4)66.4 (19)47.0 (37.0)4551.2 (19.8)54.3 (16.5)
 VT42.5 (19.9)57.6 (19)45.0 (25.0)6543.8 (19.8)37.1 (15.0)
 SF70.4 (20.3)79.0 (31)66.7 (44.5)5048.8 (23.5)35.8 (21.4)
 RE59.0 (45.1)81.6 (32)66.7 (100.0)4049.6 (43.7)26.9 (38.6)
 MH59.7 (17.7)66.5 (16)68.0 (28.0)7059.0 (21.1)52.3 (19.0)

MS, medical stage; SS, surgical stage; BP, bodily pain; PF, physical function; RP, role physical; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; NA, not available.

(17)

(29)

(30)

(27)

(28)

(32)

(31)

We compared the XLH adults to ax-SpA patients because structural damages are comparable in both diseases including ossifications and enthesopathies (Table 2). As expected, VAS global pain was lower in ax-SpA as 73.1% of them were treated with TNF-blockers. Only a minority of XLH patients were taking analgesics or NSAIDs at the time of referral, as most of them considered them as ineffective if in their chronic pain. However, XLH adults had lower physical function and abilities. Interestingly, we did not observe any difference between XLH and ax-SpA patients on SF36-mental component score, suggesting that XLH adults were coping with their physical limitations. Although they had a poor chronic physical condition, XLH adults seemed to maintain appropriate emotional and behavioural mental health.

We have also found, in our study, that the treatment with phosphate supplements and/or vitamin D during adulthood was associated with a better mental health in XLH adults. However, it is not possible to determine if the therapy allowed patients to feel better or if patients with better mental health are more susceptible to take these treatments. The link between phosphate homeostasis and functional symptoms such as fatigue has been suggested but there is no evidence of causality (33).

Prevalence of structural lesions and mechanisms of formation

In our cohort of young XLH adults, 85.4% of the patients displayed early features of osteoarthritis of the lumbar spine, the hip or the knees. Enthesopathies were significantly more frequent in XLH than in ax-SpA patients (64% vs 28%). In a Danish study conducted on 35 adult patients (68.6% females), enthesopathies and calcifications of the collateral ligaments of the spine were observed in 84% of the patients aged 40 years or more (6).

It has been shown that the early initiation of treatment with a combination of phosphate supplements and vitamin D analogs during childhood progressively corrects the leg deformities (34). However, the effect of treatment in adults on skeletal complications (osteoarthritis, enthesopathies) is still unknown (2, 35).

Different mechanisms can explain the new bone formation in XLH. In ax-SpA, there is some evidence that inflammation precedes radiographic progression in the skeleton (36, 37) or that new bone formation can be considered as a repair mechanism associated with the transformation of new inflammatory lesions to fatty degenerative changes (38, 39). However, formation of enthesophytes can occur in absence of inflammation and may be due to excess of mechanical stress and composition of the bone matrix. This feature has already been described in a mouse model of XLH, where a histological analysis of affected enthesis was performed. The mineralisation of enthesis was not due to osteoblastic formation but to an increased expression of FGFR3 and Klotho in the fibrocartilage leading to new bone formation and hence enthesophytes (35).

Limitations and strengths

As a tertiary referral centre, we deal with patients with more severe disease and our group of patients may have more disability than the average adult population affected with XLH. Our data cannot be generalised to all XLH patients. We compared XLH adults to ax-SpA patients because of the similarities of skeletal lesions, but we recognise that this does not explore the difference of QoL with age and sex-matched healthy controls.

QoL completion by a patient is inevitably impacted by external factors (disability due to comorbidities, psychological impact of a chronic disease) and may also be fluctuating with evaluation time. As our study was initially designed to assess QoL of XLH patients whatever the context of the patients, we did not adjust on comorbidities and psychological diagnoses as confounding factors. Data on QoL outcomes were obtained 15–20 years ago without any recent normative values and thus may not be still valid.

We recruited a large sample of patients who were referred through the network of the National Reference Centre for Rare Disorders of the Mineral Metabolism as soon as a disabling condition was detected. Another major strength of our study is the systematic use of questionnaires validated in chronic musculoskeletal diseases. We chose the questionnaires that are the most frequently used in rheumatic diseases. SF36 and RAPID3 are general questionnaires whereas HAQ is a specific one, assessing physical function. We recognise that none of these questionnaires have been validated in XLH. However, we circumvented this issue by comparing the XLH adult group to the ax-SpA adult group, for which these questionnaires have been previously validated. In our study, the difference between patients and ax-SpA was the largest with RAPID3. The RAPID3 score, computable in 5 s, has been well correlated with disease activity in rheumatoid arthritis and might be able to distinguish adequate and non-adequate response to treatment with disease modifying anti-rheumatic drugs (40, 41). Its sensitivity to change in other diseases, such as XLH, needs further prospective studies.

Novel therapies are under development in XLH such as anti-FGF23 which showed promising results, in mice, in improving mineralisation and cartilage development, promoting growth, improving muscle strength and motor activity (42) and, in humans, in improving serum phosphate (43). Although it is obvious that XLH children would benefit from this new treatment, the questions remains unanswered if there is an indication of treating XLH adults and if so which outcomes are relevant in adults. Our study shows that enthesopathies are a major determinant of the QoL and of the physical function in XLH adults. Therefore, it is relevant to assess the worst domains of QoL in order to manage appropriately; moreover, QoL could be a surrogate outcome to evaluate efficacy of new treatments.

Our study conducted in symptomatic adults with XLH shows that QoL is severely impaired, even more than that of young adults affected with axial spondyloarthritis. Structural lesions (osteoarthritis, enthesopathies and insufficiency bone fractures) are frequent in young XLH adults and are associated with the altered QoL, especially for enthesopathies. Phosphate supplements and/or vitamin D are associated with a better mental health score. QoL assessment is clinically relevant for the assessment of treatment outcomes in this adult population.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

H Che participated in study conception and design, acquisition of data, analysis and interpretation of data; was also involved in drafting the manuscript; gave final approval of the version to be published and agreed to be accountable for all aspects of the work. C Roux participated in study conception and design, analysis and interpretation of data; was involved in revising the manuscript critically; gave final approval of the version to be published and agreed to be accountable for all aspects of the work. A Etcheto participated in acquisition of data, analysis and interpretation of data; was involved in drafting the manuscript; gave final approval of the version to be published and agreed to be accountable for all aspects of the work. A Rothenbuhler participated in acquisition of data, analysis and interpretation of data; was involved in revising the manuscript critically; gave final approval of the version to be published and agreed to be accountable for all aspects of the work. P Kamenicky participated in acquisition of data, analysis and interpretation of data; was involved in revising the manuscript critically; gave final approval of the version to be published and agreed to be accountable for all aspects of the work. A Linglart participated in acquisition of data, analysis and interpretation of data; was involved in revising the manuscript critically; gave final approval of the version to be published and agreed to be accountable for all aspects of the work. K Briot participated in study conception and design, acquisition of data, analysis and interpretation of data; was involved in drafting the manuscript and in revising the manuscript critically; gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

References

  • 1

    Beck-NielsenSSBrock-JacobsenBGramJBrixenKJensenTK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. European Journal of Endocrinology2009160491497. (doi:10.1530/EJE-08-0818).

  • 2

    CarpenterTOImelEAHolmIAJan de BeurSMInsognaKL. A clinician's guide to X-linked hypophosphatemia. Journal of Bone and Mineral Research20112613811388. (doi:10.1002/jbmr.340).

  • 3

    LinglartABiosse-DuplanMBriotKChaussainCEsterleLGuillaume-CzitromSKamenickyPNevouxJPriéDRothenbuhlerA. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocrine Connections20143R13R30. (doi:10.1530/EC-13-0103).

  • 4

    PettiforJM. What's new in hypophosphataemic rickets?European Journal of Pediatrics2008167493499. (doi:10.1007/s00431-007-0662-1).

  • 5

    Chaussain-MillerCSindingCWolikowMLasfarguesJ-JGodeauGGarabédianM. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. Journal of Pediatrics2003142324331. (doi:10.1067/mpd.2003.119).

  • 6

    Beck-NielsenSSBrusgaardKRasmussenLMBrixenKBrock-JacobsenBPoulsenMRVestergaardPRalstonSHAlbaghaOMEPoulsenS. Phenotype presentation of hypophosphatemic rickets in adults. Calcified Tissue International201087108119. (doi:10.1007/s00223-010-9373-0).

  • 7

    McKennaCWadeRFariaRYangHStirkLGummersonNSculpherMWoolacottN. EOS 2D/3D X-ray imaging system: a systematic review and economic evaluation. Health Technology Assessment2012161188. (doi:10.3310/hta16140).

  • 8

    KellgrenJHLawrenceJS. Radiological assessment of osteo-arthrosis. Annals of the Rheumatic Diseases195716494502. (doi:10.1136/ard.16.4.494).

  • 9

    ShaibaniAWorkmanRRothschildBM. The significance of enthesopathy as a skeletal phenomenon. Clinical and Experimental Rheumatology199311399403.

  • 10

    ResnickDNiwayamaG. Entheses and enthesopathy. Anatomical, pathological, and radiological correlation. Radiology198314619. (doi:10.1148/radiology.146.1.6849029).

  • 11

    PentecostRLMurrayRABrindleyHH. Fatigue, insufficiency, and pathologic fractures. Journal of the American Medical Association196418710011004.

  • 12

    MoltóAFreireVFeydyAPaternotteSMaksymowychWPBenhamouMRannouFDougadosMGossecL. Assessing structural changes in axial spondyloarthritis using a low-dose biplanar imaging system. Rheumatology20145316691675. (doi:10.1093/rheumatology/keu143).

  • 13

    DeschênesSCharronGBeaudoinGLabelleHDuboisJMironMCParentS. Diagnostic imaging of spinal deformities: reducing patients radiation dose with a new slot-scanning X-ray imager. Spine201035989994. (doi:10.1097/BRS.0b013e3181bdcaa4).

  • 14

    BendayaSLazennecJYAnglinCAllenaRSellamNThoumiePSkalliW. Healthy vs. osteoarthritic hips: a comparison of hip, pelvis and femoral parameters and relationships using the EOS® system. Clinical Biomechanics201530195204. (doi:10.1016/j.clinbiomech.2014.11.010).

  • 15

    BriotKFechtenbaumJEtchetoAKoltaSFeydyARouxC. Diagnosis of vertebral fractures using a low-dose biplanar imaging system. Osteoporosis International20152626492655. (doi:10.1007/s00198-015-3190-2).

  • 16

    FriesJFSpitzPWYoungDY. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. Journal of Rheumatology19829789793.

  • 17

    GuilleminFBriançonSPourelJ. Validity and discriminant ability of the HAQ Functional Index in early rheumatoid arthritis. Disability and Rehabilitation1992147177. (doi:10.3109/09638289209167073).

  • 18

    WellsGABoersMSheaBBrooksPMSimonLSStrandCVAletahaDAndersonJJBombardierCDougadosM. Minimal disease activity for rheumatoid arthritis: a preliminary definition. Journal of Rheumatology20053220162024.

  • 19

    PincusTBergmanMJYaziciYHinesPRaghupathiKMacleanR. An index of only patient-reported outcome measures, routine assessment of patient index data 3 (RAPID3), in two abatacept clinical trials: similar results to disease activity score (DAS28) and other RAPID indices that include physician-reported measures. Rheumatology200847345349. (doi:10.1093/rheumatology/kem364).

  • 20

    PincusTSwearingenCJBergmanMJColglazierCLKaellATKunathAMSiegelELYaziciY. RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in five versus more than ninety seconds. Arthritis Care & Research201062181189. (doi:10.1002/acr.20066).

  • 21

    PincusTYaziciYBergmanMJ. RAPID3, an index to assess and monitor patients with rheumatoid arthritis, without formal joint counts: similar results to DAS28 and CDAI in clinical trials and clinical care. Rheumatic Diseases Clinics of North America200935773778. (doi:10.1016/j.rdc.2009.10.008).

  • 22

    WareJESherbourneCDTheMOS36-item. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care199230473483. (doi:10.1097/00005650-199206000-00002).

  • 23

    SieperJRudwaleitMBaraliakosXBrandtJBraunJBurgos-VargasRDougadosMHermannK-GLandewéRMaksymowychW. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Annals of the Rheumatic Diseases200968 (Suppl 2) 144. (doi:10.1136/ard.2008.104018).

  • 24

    CheungPPPaternotteSBurkiVDurnezAElhaiMFabreguetIKoumakisEMeyerMPayetJRoureF. Performance of the assessment in Spondyloarthritis International Society classification for axial and peripheral spondyloarthritis in an established clinical cohort: comparison with criteria sets of Amor and the European Spondylarthropathy Study Group. Journal of Rheumatology201239816821. (doi:10.3899/jrheum.111088).

  • 25

    TuranYDuruözMTCerrahogluL. Quality of life in patients with ankylosing spondylitis: a pilot study. Rheumatology International200727895899. (doi:10.1007/s00296-007-0315-8).

  • 26

    DanveAReddyAVakil-GilaniKGargNDinnoADeodharA. Routine assessment of patient index data 3 score (RAPID3) correlates well with Bath Ankylosing Spondylitis Disease Activity index (BASDAI) in the assessment of disease activity and monitoring progression of axial spondyloarthritis. Clinical Rheumatology201534117124. (doi:10.1007/s10067-014-2827-4).

  • 27

    Le PenCLevyELoosFBanzetMNBasdevantA. “Specific” scale compared with “generic” scale: a double measurement of the quality of life in a French community sample of obese subjects. Journal of Epidemiology and Community Health199852445450. (doi:10.1136/jech.52.7.445).

  • 28

    TalamoJFraterAGallivanSYoungA. Use of the short form 36 (SF36) for health status measurement in rheumatoid arthritis. British Journal of Rheumatology199736463469. (doi:10.1093/rheumatology/36.4.463).

  • 29

    LaasKRoineRRäsänenPSintonenHLeirisalo-RepoMHUS QoL Study Group. Health-related quality of life in patients with common rheumatic diseases referred to a university clinic. Rheumatology International200929267273. (doi:10.1007/s00296-008-0673-x).

  • 30

    CastrejónIBergmanMJPincusT. MDHAQ/RAPID3 to recognize improvement over 2 months in usual care of patients with osteoarthritis, systemic lupus erythematosus, spondyloarthropathy, and gout, as well as rheumatoid arthritis. Journal of Clinical Rheumatology201319169174. (doi:10.1097/RHU.0b013e3182936b98).

  • 31

    RatA-CCosteJPouchotJBaumannMSpitzERetel-RudeNLe QuintrecJ-SDumont-FischerDGuilleminF. OAKHQOL: a new instrument to measure quality of life in knee and hip osteoarthritis. Journal of Clinical Epidemiology2005584755. (doi:10.1016/j.jclinepi.2004.04.011).

  • 32

    Duarte-SalazarCGuzmán-VázquezSSoto-MolinaHCháidez-RosalesPIlizaliturri-SánchezVNieves-SilvaJValero-GonzálezFAguilera-ZepedaJM. Disability impact on quality of life in Mexican adults with juvenile idiopathic arthritis and juvenile ankylosing spondylitis. Clinical and Experimental Rheumatology200725922927.

  • 33

    De LorenzoFHargreavesJKakkarVV. Phosphate diabetes in patients with chronic fatigue syndrome. Postgraduate Medical Journal199874229232. (doi:10.1136/pgmj.74.870.229).

  • 34

    MäkitieODoriaAKoohSWColeWGDanemanASochettE. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. Journal of Clinical Endocrinology and Metabolism20038835913597. (doi:10.1210/jc.2003-030036).

  • 35

    LiangGKatzLDInsognaKLCarpenterTOMacicaCM. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcified Tissue International200985235246. (doi:10.1007/s00223-009-9270-6).

  • 36

    BaraliakosXListingJRudwaleitMSieperJBraunJ. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Research & Therapy200810R104. (doi:10.1186/ar2496).

  • 37

    MaksymowychWPChiowchanwisawakitPClareTPedersenSJØstergaardMLambertRG. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis and Rheumatism20096093102. (doi:10.1002/art.24132).

  • 38

    SieperJAppelHBraunJRudwaleitM. Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis and Rheumatism200858649656. (doi:10.1002/art.23260).

  • 39

    BaraliakosXListingJBuschmannJvon der ReckeABraunJ. A comparison of new bone formation in patients with ankylosing spondylitis and patients with diffuse idiopathic skeletal hyperostosis: a retrospective cohort study over six years. Arthritis and Rheumatism20126411271133. (doi:10.1002/art.33447).

  • 40

    PincusT. RAPID3, an index of only 3 patient self-report core data set measures, but not ESR, recognizes incomplete responses to methotrexate in usual care of patients with rheumatoid arthritis. Bulletin of the Hospital for Joint Diseases201371117120.

  • 41

    CastrejónIDougadosMCombeBGuilleminFFautrelBPincusT. Can remission in rheumatoid arthritis be assessed without laboratory tests or a formal joint count? possible remission criteria based on a self-report RAPID3 score and careful joint examination in the ESPOIR cohort. Journal of Rheumatology201340386393. (doi:10.3899/jrheum.121059).

  • 42

    AonoYHasegawaHYamazakiYShimadaTFujitaTYamashitaTFukumotoS. Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. Journal of Bone and Mineral Research201126803810. (doi:10.1002/jbmr.275).

  • 43

    CarpenterTOImelEARuppeMDWeberTJKlausnerMAWooddellMMKawakamiTItoTZhangXHumphreyJ. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. Journal of Clinical Investigation201412415871597. (doi:10.1172/JCI72829).

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Official journal of

European Society of Endocrinology

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Figures

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    X-ray features in XLH adults. (a) Osteoarthritis. (b) Enthesopathies: 1/lumbar spine, 2/pelvis. (c) Fractures.

References

1

Beck-NielsenSSBrock-JacobsenBGramJBrixenKJensenTK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. European Journal of Endocrinology2009160491497. (doi:10.1530/EJE-08-0818).

2

CarpenterTOImelEAHolmIAJan de BeurSMInsognaKL. A clinician's guide to X-linked hypophosphatemia. Journal of Bone and Mineral Research20112613811388. (doi:10.1002/jbmr.340).

3

LinglartABiosse-DuplanMBriotKChaussainCEsterleLGuillaume-CzitromSKamenickyPNevouxJPriéDRothenbuhlerA. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocrine Connections20143R13R30. (doi:10.1530/EC-13-0103).

4

PettiforJM. What's new in hypophosphataemic rickets?European Journal of Pediatrics2008167493499. (doi:10.1007/s00431-007-0662-1).

5

Chaussain-MillerCSindingCWolikowMLasfarguesJ-JGodeauGGarabédianM. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. Journal of Pediatrics2003142324331. (doi:10.1067/mpd.2003.119).

6

Beck-NielsenSSBrusgaardKRasmussenLMBrixenKBrock-JacobsenBPoulsenMRVestergaardPRalstonSHAlbaghaOMEPoulsenS. Phenotype presentation of hypophosphatemic rickets in adults. Calcified Tissue International201087108119. (doi:10.1007/s00223-010-9373-0).

7

McKennaCWadeRFariaRYangHStirkLGummersonNSculpherMWoolacottN. EOS 2D/3D X-ray imaging system: a systematic review and economic evaluation. Health Technology Assessment2012161188. (doi:10.3310/hta16140).

8

KellgrenJHLawrenceJS. Radiological assessment of osteo-arthrosis. Annals of the Rheumatic Diseases195716494502. (doi:10.1136/ard.16.4.494).

9

ShaibaniAWorkmanRRothschildBM. The significance of enthesopathy as a skeletal phenomenon. Clinical and Experimental Rheumatology199311399403.

10

ResnickDNiwayamaG. Entheses and enthesopathy. Anatomical, pathological, and radiological correlation. Radiology198314619. (doi:10.1148/radiology.146.1.6849029).

11

PentecostRLMurrayRABrindleyHH. Fatigue, insufficiency, and pathologic fractures. Journal of the American Medical Association196418710011004.

12

MoltóAFreireVFeydyAPaternotteSMaksymowychWPBenhamouMRannouFDougadosMGossecL. Assessing structural changes in axial spondyloarthritis using a low-dose biplanar imaging system. Rheumatology20145316691675. (doi:10.1093/rheumatology/keu143).

13

DeschênesSCharronGBeaudoinGLabelleHDuboisJMironMCParentS. Diagnostic imaging of spinal deformities: reducing patients radiation dose with a new slot-scanning X-ray imager. Spine201035989994. (doi:10.1097/BRS.0b013e3181bdcaa4).

14

BendayaSLazennecJYAnglinCAllenaRSellamNThoumiePSkalliW. Healthy vs. osteoarthritic hips: a comparison of hip, pelvis and femoral parameters and relationships using the EOS® system. Clinical Biomechanics201530195204. (doi:10.1016/j.clinbiomech.2014.11.010).

15

BriotKFechtenbaumJEtchetoAKoltaSFeydyARouxC. Diagnosis of vertebral fractures using a low-dose biplanar imaging system. Osteoporosis International20152626492655. (doi:10.1007/s00198-015-3190-2).

16

FriesJFSpitzPWYoungDY. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. Journal of Rheumatology19829789793.

17

GuilleminFBriançonSPourelJ. Validity and discriminant ability of the HAQ Functional Index in early rheumatoid arthritis. Disability and Rehabilitation1992147177. (doi:10.3109/09638289209167073).

18

WellsGABoersMSheaBBrooksPMSimonLSStrandCVAletahaDAndersonJJBombardierCDougadosM. Minimal disease activity for rheumatoid arthritis: a preliminary definition. Journal of Rheumatology20053220162024.

19

PincusTBergmanMJYaziciYHinesPRaghupathiKMacleanR. An index of only patient-reported outcome measures, routine assessment of patient index data 3 (RAPID3), in two abatacept clinical trials: similar results to disease activity score (DAS28) and other RAPID indices that include physician-reported measures. Rheumatology200847345349. (doi:10.1093/rheumatology/kem364).

20

PincusTSwearingenCJBergmanMJColglazierCLKaellATKunathAMSiegelELYaziciY. RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in five versus more than ninety seconds. Arthritis Care & Research201062181189. (doi:10.1002/acr.20066).

21

PincusTYaziciYBergmanMJ. RAPID3, an index to assess and monitor patients with rheumatoid arthritis, without formal joint counts: similar results to DAS28 and CDAI in clinical trials and clinical care. Rheumatic Diseases Clinics of North America200935773778. (doi:10.1016/j.rdc.2009.10.008).

22

WareJESherbourneCDTheMOS36-item. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Medical Care199230473483. (doi:10.1097/00005650-199206000-00002).

23

SieperJRudwaleitMBaraliakosXBrandtJBraunJBurgos-VargasRDougadosMHermannK-GLandewéRMaksymowychW. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Annals of the Rheumatic Diseases200968 (Suppl 2) 144. (doi:10.1136/ard.2008.104018).

24

CheungPPPaternotteSBurkiVDurnezAElhaiMFabreguetIKoumakisEMeyerMPayetJRoureF. Performance of the assessment in Spondyloarthritis International Society classification for axial and peripheral spondyloarthritis in an established clinical cohort: comparison with criteria sets of Amor and the European Spondylarthropathy Study Group. Journal of Rheumatology201239816821. (doi:10.3899/jrheum.111088).

25

TuranYDuruözMTCerrahogluL. Quality of life in patients with ankylosing spondylitis: a pilot study. Rheumatology International200727895899. (doi:10.1007/s00296-007-0315-8).

26

DanveAReddyAVakil-GilaniKGargNDinnoADeodharA. Routine assessment of patient index data 3 score (RAPID3) correlates well with Bath Ankylosing Spondylitis Disease Activity index (BASDAI) in the assessment of disease activity and monitoring progression of axial spondyloarthritis. Clinical Rheumatology201534117124. (doi:10.1007/s10067-014-2827-4).

27

Le PenCLevyELoosFBanzetMNBasdevantA. “Specific” scale compared with “generic” scale: a double measurement of the quality of life in a French community sample of obese subjects. Journal of Epidemiology and Community Health199852445450. (doi:10.1136/jech.52.7.445).

28

TalamoJFraterAGallivanSYoungA. Use of the short form 36 (SF36) for health status measurement in rheumatoid arthritis. British Journal of Rheumatology199736463469. (doi:10.1093/rheumatology/36.4.463).

29

LaasKRoineRRäsänenPSintonenHLeirisalo-RepoMHUS QoL Study Group. Health-related quality of life in patients with common rheumatic diseases referred to a university clinic. Rheumatology International200929267273. (doi:10.1007/s00296-008-0673-x).

30

CastrejónIBergmanMJPincusT. MDHAQ/RAPID3 to recognize improvement over 2 months in usual care of patients with osteoarthritis, systemic lupus erythematosus, spondyloarthropathy, and gout, as well as rheumatoid arthritis. Journal of Clinical Rheumatology201319169174. (doi:10.1097/RHU.0b013e3182936b98).

31

RatA-CCosteJPouchotJBaumannMSpitzERetel-RudeNLe QuintrecJ-SDumont-FischerDGuilleminF. OAKHQOL: a new instrument to measure quality of life in knee and hip osteoarthritis. Journal of Clinical Epidemiology2005584755. (doi:10.1016/j.jclinepi.2004.04.011).

32

Duarte-SalazarCGuzmán-VázquezSSoto-MolinaHCháidez-RosalesPIlizaliturri-SánchezVNieves-SilvaJValero-GonzálezFAguilera-ZepedaJM. Disability impact on quality of life in Mexican adults with juvenile idiopathic arthritis and juvenile ankylosing spondylitis. Clinical and Experimental Rheumatology200725922927.

33

De LorenzoFHargreavesJKakkarVV. Phosphate diabetes in patients with chronic fatigue syndrome. Postgraduate Medical Journal199874229232. (doi:10.1136/pgmj.74.870.229).

34

MäkitieODoriaAKoohSWColeWGDanemanASochettE. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. Journal of Clinical Endocrinology and Metabolism20038835913597. (doi:10.1210/jc.2003-030036).

35

LiangGKatzLDInsognaKLCarpenterTOMacicaCM. Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcified Tissue International200985235246. (doi:10.1007/s00223-009-9270-6).

36

BaraliakosXListingJRudwaleitMSieperJBraunJ. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Research & Therapy200810R104. (doi:10.1186/ar2496).

37

MaksymowychWPChiowchanwisawakitPClareTPedersenSJØstergaardMLambertRG. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis and Rheumatism20096093102. (doi:10.1002/art.24132).

38

SieperJAppelHBraunJRudwaleitM. Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis and Rheumatism200858649656. (doi:10.1002/art.23260).

39

BaraliakosXListingJBuschmannJvon der ReckeABraunJ. A comparison of new bone formation in patients with ankylosing spondylitis and patients with diffuse idiopathic skeletal hyperostosis: a retrospective cohort study over six years. Arthritis and Rheumatism20126411271133. (doi:10.1002/art.33447).

40

PincusT. RAPID3, an index of only 3 patient self-report core data set measures, but not ESR, recognizes incomplete responses to methotrexate in usual care of patients with rheumatoid arthritis. Bulletin of the Hospital for Joint Diseases201371117120.

41

CastrejónIDougadosMCombeBGuilleminFFautrelBPincusT. Can remission in rheumatoid arthritis be assessed without laboratory tests or a formal joint count? possible remission criteria based on a self-report RAPID3 score and careful joint examination in the ESPOIR cohort. Journal of Rheumatology201340386393. (doi:10.3899/jrheum.121059).

42

AonoYHasegawaHYamazakiYShimadaTFujitaTYamashitaTFukumotoS. Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. Journal of Bone and Mineral Research201126803810. (doi:10.1002/jbmr.275).

43

CarpenterTOImelEARuppeMDWeberTJKlausnerMAWooddellMMKawakamiTItoTZhangXHumphreyJ. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. Journal of Clinical Investigation201412415871597. (doi:10.1172/JCI72829).

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