Royal National Hospital for Rheumatic Diseases

OBJECTIVE: Disease status, in terms of disease activity, disease progression and prognosis is difficult to define in ankylosing spondylitis (AS). No gold standard exists. Therefore, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a self-administered instrument, has been developed as a new approach to defining disease activity in patients with AS. METHODS: The index, designed by a multidisciplinary team with input from patients, consists of six 10 cm horizontal visual analog scales to measure severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness (both qualitative and quantitative). The final BASDAI score has a range of 0 to 10. The index was distributed to a cross section of patients, including inpatients receiving 3 weeks of intensive physiotherapy treatment and hospital outpatients. BASDAI was completed by a total of 154 patients. Validation of the new instrument was achieved through analysis of user friendliness, reliability (consistency), score distribution and sensitivity to change. Comparisons were made with a previous Bath disease activity index (DAI) and the Newcastle Enthesis Index. RESULTS: The BASDAI was found by patients to be quick and simple to complete (mean: 67 s). Test-retest reliability was good (r = 0.93; p < 0.001), as was the distribution of scores across the scale (score range: 0.5-10; mean: 4.31). BASDAI was sensitive to change, reflecting a 16% (mean) improvement in inpatient scores after 3 weeks of treatment. It is superior to the DAI in terms of construct and content validity and to the Enthesis Index in all aspects. CONCLUSION: In summary, BASDAI is user friendly, reliability, sensitive to change and reflects the entire spectrum of disease. It is a comprehensive self-administered instrument for assessing disease activity in AS.

OBJECTIVE: To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE). METHODS: A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status. RESULTS: Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients. CONCLUSION: This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.

Classification criteria for most of the disorders belonging to the spondylarthropathy group already exist. However, the spectrum of spondylarthropathy is wider than the sum of these disorders suggests. Seronegative oligoarthritis, dactylitis or polyarthritis of the lower extremities, heel pain due to enthesitis, and other undifferentiated cases of spondylarthropathy have been ignored in epidemiologic studies because of the inadequacy of existing criteria. In order to define classification criteria that also encompass patients with undifferentiated spondylarthropathy, we studied 403 patients with all forms of spondylarthropathy and 674 control patients with other rheumatic diseases. The diagnoses were based on the local clinical expert's opinion. The 403 patients included 168 with ankylosing spondylitis, 68 with psoriatic arthritis, 41 with reactive arthritis, 17 with inflammatory bowel disease and arthritis, and 109 with unclassified spondylarthropathy. Based on statistical analysis and clinical reasoning, we propose the following classification criteria for spondylarthropathy: inflammatory spinal pain or synovitis (asymmetric or predominantly in the lower limbs), together with at least 1 of the following: positive family history, psoriasis, inflammatory bowel disease, urethritis, or acute diarrhea, alternating buttock pain, enthesopathy, or sacroiliitis as determined from radiography of the pelvic region. These criteria resulted in a sensitivity of 87% and a specificity of 87%. The proposed classification criteria are easy to apply in clinical practice and performed well in all 7 participating centers. However, we regard them as preliminary until they have been further evaluated in other settings.

OBJECTIVE: After pain and stiffness, one of the most important complaints of patients with ankylosing spondylitis (AS) is disability. The main aims of treatment are to control pain but also to improve function. Various methods of assessing function exist but are either not specific for the disease or have not been adequately validated. As a result of this deficiency we developed the Bath Ankylosing Spondylitis Functional Index (BASFI) as a new approach to defining and monitoring functional ability in patients with AS. METHODS: This self-assessment instrument was designed by a team of medical professionals in conjunction with patients, and consists of 8 specific questions regarding function in AS and 2 questions reflecting the patient's ability to cope with everyday life. Each question is answered on a 10 cm horizontal visual analog scale, the mean of which gives the BASFI score (0-10). The questionnaire was completed 257 times in total: once by 116 outpatients and by 47 inpatients on 3 occasions over a 3-week intensive physiotherapy course. In addition, the instrument was compared with the Dougados functional index. RESULTS: Patients scores covered 95% of the BASFI range, giving a normal distribution of results. In contrast only 65% of the Dougados functional index scale was used. Furthermore, over the 3 week period of inpatient treatment, the BASFI revealed a significant improvement in function (20%, p = 0.004) while there was a less impressive change in the Dougados functional index (6%, p = 0.03). This demonstrates the superior sensitivity of the BASFI: Consistency was good for both indices (p < 0.001), as was the relationship between patient perception of function and function as assessed by an external observer (p < 0.001). CONCLUSION: The BASFI satisfies the criteria required of a functional index: it is quick and easy to complete, is reliable and is sensitive to change across the whole spectrum of disease.

OBJECTIVE: Different sets of diagnostic criteria have been proposed for Sjögren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community. METHODS: The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study included 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II. RESULTS: The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined. CONCLUSION: Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.

Acceptance of chronic pain entails that an individual reduce unsuccessful attempts to avoid or control pain and focus instead on participation in valued activities and the pursuit of personally relevant goals. Recent research suggests that pain-related acceptance leads to enhanced emotional and physical functioning in chronic pain patients above and beyond the influence of depression, pain intensity, and coping. In these studies, acceptance was measured using the Chronic Pain Acceptance Questionnaire (CPAQ). Preliminary analyses of the CPAQ have supported its psychometric properties. The present study sought to further refine the CPAQ by examining its factor structure and evaluating the relations of these factors to other indices of pain-related distress and disability. Although a previously demonstrated factor structure of the CPAQ was generally supported, only factors assessing (a) the degree to which one engaged in life activities regardless of the pain and (b) willingness to experience pain had adequate reliability and validity and were significantly related to the other measures of patient functioning. A revised version of the CPAQ is suggested.

The idiopathic inflammatory myopathies are characterized by muscle weakness, skin disease and internal organ involvement. Autoimmunity is known to have a role in myositis pathogenesis, and myositis-specific autoantibodies, targeting important intracellular proteins, are regarded as key biomarkers aiding in the diagnosis of patients. In recent years, a number of novel myositis autoantibodies including anti-TIF1, anti-NXP2, anti-MDA5, anti-SAE, anti-HMGCR and anti-cN1A have been identified in both adult and juvenile patients. These autoantibodies correlate with distinct clinical manifestations and importantly are found in inclusion body, statin-induced, clinically amyopathic and juvenile groups of myositis patients, previously believed to be mainly autoantibody negative. In this review, we will describe the main myositis-specific and myositis-associated autoantibodies and their frequencies and clinical associations across different ages and ethnic groups. We will also discuss preliminary studies investigating correlations between specific myositis autoantibody titres and clinical markers of disease course, collectively demonstrating the utility of myositis autoantibodies as both diagnostic and prognostic markers of disease.

OBJECTIVE: To determine the most appropriate clinical measurements for the assessment of ankylosing spondylitis (AS) to develop the new metrology index. METHODS: One hundred and ninety-three individuals with AS were studied. The patients reflected the entire spectrum of cases of AS. Metrology was performed on 327 occasions. First the metrology (20 measurements) of 43 patients was analyzed. From this, 5 simple clinical measurements were defined which most accurately reflect axial status: cervical rotation, tragus to wall distance, lateral flexion, modified Schober's, and intermalleolar distance. These measurements were assessed for reliability, speed and both inter and intraobserver variability in another 40 patients. RESULTS: Analysis of the first group of 43 patients and a subsequent group of 54 patients, using the 5 measurements that constitute this new Bath AS Metrology Index (BASMI), demonstrated that they accurately and reliably mirror the 20 clinical measurements assessed previously (r = 0.92, p < 0.001). In a new group of 40 patients the measurements were demonstrated to be accurate and reproducible for both intraobserver variability (r = 0.99, p < 0.001) and interobserver variability (r = 0.97, p < 0.001). In a further 56 patients, admitted for inpatient therapy, an improvement in the BASMI from 3.34 (SD 2.71) to 2.16 (SD 2.42) was noted over a period of 3 weeks (regardless of disease severity) which indicates a sensitivity to change (chi 2 = 6.55, p < 0.01). The mean improvement over baseline was about 30%. CONCLUSION: Five clinical measurements provide a composite index (BASMI) and define disease status in AS. The BASMI is quick (7 min), reproducible and sensitive to change across the disease spectrum.

OBJECTIVE: To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA). METHODS: GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA, based on consensus achieved at face-to-face meetings and via online surveys. We conducted literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, using an online questionnaire. RESULTS: Six overarching principles had ≥80% agreement among both health care professionals (n = 135) and patient research partners (n = 10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin disease, nail disease, and comorbidities in the setting of PsA, using the Grading of Recommendations, Assessment, Development and Evaluation process. Agreement of >80% was reached for approval of the individual recommendations and the overall schema. CONCLUSION: We present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other health care providers, and patient research partners). Further updates are anticipated as the therapeutic landscape in PsA evolves.

OBJECTIVE: A 2-year randomized controlled trial was performed to test the hypothesis that long-term, continuous treatment with nonsteroidal antiinflammatory drugs (NSAIDs), in comparison with NSAID treatment on demand only, influences radiographic progression in patients with ankylosing spondylitis (AS). METHODS: Patients with AS (n = 215), who had previously participated in a 6-week, randomized, double-blind clinical trial that compared celecoxib, ketoprofen, and placebo, were randomly allocated to receive either continuous treatment with NSAIDs or on-demand treatment with NSAIDs for a period of 2 years. All patients began treatment with celecoxib, at a starting dosage of 100 mg twice daily; patients could increase this dosage to 200 mg twice daily or could switch to another NSAID while maintaining the same treatment strategy. Structural changes were assessed by radiographs of the lumbar and cervical spine and scored according to the modified Stoke Ankylosing Spondylitis Spine Score by one observer who was blinded to the treatment strategy and temporal order of the radiographs. Statistical analyses included a between-group comparison of 1) radiographic progression scores (by Mann-Whitney U test), 2) time-averaged values of variables reflecting signs and symptoms of AS (by linear regression analysis), and 3) the frequency of reported site-specific adverse events (by chi-square test or Fisher's exact test, as appropriate). RESULTS: Complete sets of radiographs were available for 76 of the 111 patients in the continuous-treatment group and for 74 of the 104 patients in the on-demand group. The mean +/- SD scores for radiographic progression were 0.4 +/- 1.7 in the continuous-treatment group and 1.5 +/- 2.5 in the on-demand treatment group (P = 0.002). Parameters reflecting signs and symptoms were not statistically significantly different between groups. The between-group difference in radiographic progression did not disappear after adjusting for baseline values of radiographic damage or disease activity variables and for time-averaged values of disease activity variables, nor after input of missing data. Relevant adverse events tended to occur more frequently in the continuous-treatment group than in the on-demand group (for hypertension, 9% versus 3%; for abdominal pain, 11% versus 6%; for dyspepsia, 41% versus 38%), but the differences were not statistically significant. CONCLUSION: A strategy of continuous use of NSAIDs reduces radiographic progression in symptomatic patients with AS, without increasing toxicity substantially.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

OBJECTIVE: To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). METHODS: Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence-specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. RESULTS: Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co-twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. CONCLUSION: Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

Research and treatment of chronic pain over the past 20 or more years have tended to focus on patient coping as the primary behavioral contribution to adjustment. The purpose of the present study was to compare a coping approach to chronic pain with a different behavioral approach referred to as acceptance of chronic pain. These approaches were compared in terms of their ability to predict distress and disability in a sample of patients seeking treatment for chronic pain. Subjects were 230 adults assessed at a university pain management center. All patients completed the coping strategies questionnaire and the chronic pain acceptance questionnaire among other standard measures. Results showed that coping variables were relatively weakly related to acceptance of pain and relatively unreliably related to pain adjustment variables. On the other hand, acceptance of chronic pain was associated with less pain, disability, depression and pain-related anxiety, higher daily uptime, and better work status. Regression analyses examined the independent contributions of coping and acceptance to key adjustment indicators in relation to chronic pain. Results from these analyses demonstrated that acceptance of pain repeatedly accounted for more variance than coping variables.

OBJECTIVE: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. METHODS: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. RESULTS: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. CONCLUSIONS: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

BACKGROUND: We assessed mirror visual feedback (MVF) to test the hypothesis that incongruence between motor output and sensory input produces complex regional pain syndrome (CRPS) (type 1) pain. METHODS: Eight subjects (disease duration > or =3 weeks to < or =3 yr) were studied over 6 weeks with assessments including two controls (no device and viewing a non-reflective surface) and the intervention (MVF). Pain severity and vasomotor changes were recorded. RESULTS: The control stages had no analgesic effect. MVF in early CRPS (< or =8 weeks) had an immediate analgesic effect and in intermediate disease (< or =1 yr) led to a reduction in stiffness. At 6 weeks, normalization of function and thermal differences had occurred (early and intermediate disease). No change was found in chronic CRPS. CONCLUSIONS: In early CRPS (type 1), visual input from a moving, unaffected limb re-establishes the pain-free relationship between sensory feedback and motor execution. Trophic changes and a less plastic neural pathway preclude this in chronic disease.

STUDY DESIGN: A literature review was conducted. OBJECTIVE: To examine the outcome of behavioral (BT) and cognitive-behavioral treatment (CBT), collectively referred to as BT-CBT, for chronic pain, to identify the predictors of treatment outcome, and to investigate the change processes associated with these treatments. SUMMARY OF BACKGROUND DATA: Numerous controlled clinical trials of BT-CBT for chronic pain, alone or more commonly in multidisciplinary treatment contexts, suggest that these treatments are effective. However, further study is needed to examine which outcome variables change, when, for whom, and how. METHODS: Published literature was gathered from Medline, PsychLit, and searches of relevant journals. RESULTS: Overall, BT-CBT for chronic pain reduces patients' pain, distress, and pain behavior, and improves their daily functioning. Differences across studies in sample characteristics, treatment features, and assessment methods seem to produce varied treatment results. Also, some patients benefit more than others. Highly distressed patients who see their pain as an uncontrollable and highly negative life event derive less benefit than other patients. Decreased negative emotional responses to pain, decreased perceptions of disability, and increased orientation toward self-management during the course of treatment predict favorable treatment outcome. CONCLUSIONS: Current BT-CBT helps many patients with chronic pain. Continuing clinical research should improve the matching of treatments with patient characteristics and refine the focus of treatments on behavior changes most associated with positive outcome. Further study of fear, attention, readiness to adopt self-management strategies, acceptance of pain, and new combinations of interdisciplinary treatments may lead to improved interventions.

OBJECTIVES: To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). METHODS: We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. RESULTS: Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. CONCLUSIONS: In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.

Adolescents with chronic pain also report severe disability and emotional distress. A clinical sample of 80 adolescents and accompanying parents were investigated to first measure the extent of distress, and second to investigate the relationships between adolescent distress, parental distress and adolescent coping. Measures of pain intensity, anxiety, depression, disability and coping were obtained from adolescents. Parents completed measures including their own anxiety, depression and parenting stress. Overall, adolescents reported high levels of disability, depression and anxiety, and parents reported high levels of depression, anxiety and parenting stress. Multiple regression analyses revealed that the best predictors of adolescent emotional distress were the extent to which the adolescents catastrophize and seek social support to cope with the pain. There were no clear predictors of parental anxiety or depression but the specific pattern of parenting stress was best predicted by the younger age of the adolescent, the greater the chronicity of the problem, and the greater the extent of adolescent depression. These findings suggest that emotional coping is a critical variable in the distress associated with adolescent chronic pain. It is argued that adolescent emotional coping may best be understood within a relational context of seeking emotional support.

Peak bone mass is an important determinant of the risk of osteoporotic fracture, and preventive strategies against osteoporosis require a clear understanding of the factors influencing bone gain in early life. We report a longitudinal study aiming to identify the relationships between childhood growth, lifestyle, and peak bone mass in women. One hundred and fifty-three women born in a British city during 1968-1969 were traced and studied in 1990. Data on their growth in childhood was obtained from linked birth and school health records; current bone mineral measurements were made by dual X-ray absorptiometry. There were statistically significant associations between weight at 1 year and BMC (but not BMD) at the lumbar spine (r = 0.32, p < 0.01) and femoral neck (r = 0.26, p < 0.01). These remained significant after adjusting for current weight. There were also strong relationships between childhood height measurements and adult BMC at the two skeletal sites. Physical activity was the major lifestyle determinant of BMD after allowing for body build. We conclude that infant growth and physical activity in childhood are important determinants of peak bone mass in women. Growth primarily determines the size of the skeletal envelope, and its trajectory is established by age 1 year. Activity, in contrast, modulates the mineral density within the skeletal envelope and may contribute to the consolidation of bone following the end of linear growth.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. METHODS: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. RESULTS: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3⁻5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. CONCLUSIONS: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.