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McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3′, 5′-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS, but not in humans with fibrous dysplasia. Positron emission tomography (PET) imaging of PDE4 with 11C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods:11C-(R)-rolipram whole-body and brain PET scans were performed in six individuals with MAS (three for brain scans and six for whole-body scans) and nine healthy controls (seven for brain scans and six for whole-body scans). Results:11C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in 11C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected, which could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with 11C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.

In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and "brain fog." Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL are unclear. Thirty-one patients with hypoparathyroidism were treated in an open-label study with full replacement subcutaneous PTH 1-34 twice daily for up to 5.3 years, with individualized fine-dosing titration. Prior to initiation of PTH 1-34, conventional therapy was optimized. The 36-Item Short Form (SF-36) Health Survey, Fatigue Symptom Inventory (FSI), and 6-minute walk test (6MWT) were assessed at PTH start (baseline), every 6 months on PTH, and after PTH discontinuation. The SF-36 assesses physical function (PF), physical role limitations (RP), bodily pain (BP), general health (GH), vitality (VT), emotional role limitations (RE), social function (SF), and mental health (MH). Compared to population norms, patients at baseline had lower scores in RP, GH, VT, and MH (p

Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro-osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, FGF23, and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and FGF23 demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age-dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age-dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age-dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.

Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic tumoral calcinosis. Luciferase immunoprecipitation systems revealed markedly elevated FGF23 autoantibodies without detectable FGFR1 or Klotho autoantibodies. Using an in vitro FGF23 functional assay, we found that the FGF23 autoantibodies in the patient’s plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case, to our knowledge, of autoimmune hyperphosphatemic tumoral calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic tumoral calcinosis and suggests that immunomodulatory therapy may be an effective treatment.

OBJECTIVE: To compare the severity of illness of patients with systemic lupus erythematosus (SLE) between those hospitalized at academic medical centers and those hospitalized at community hospitals. METHODS: In this population based cross-sectional survey, data on all hospitalizations of patients with SLE in California, New York, and Pennsylvania in 2000 were obtained from discharge abstracts submitted by acute care hospitals to state health planning agencies. Patients hospitalized at one of 36 academic medical centers in these states (N = 2072) were compared to patients hospitalized at community hospitals (N = 9373). The primary measures of severity of illness were the SLE Comorbidity Index, a weighted index of SLE manifestations and comorbid medical conditions based on discharge diagnoses, and long lengths of stay, defined as stays that exceeded the 90th percentile of hospital stays in the same diagnosis-related group in the United States. RESULTS: Compared to patients at community hospitals, patients at academic medical centers had substantially higher scores on the SLE Comorbidity Index (odds ratio for each 1-point increase 1.27, 95% confidence interval 1.15-1.40, p or = 300 beds) community hospitals in the same metropolitan areas. Results for the SLE Comorbidity Index were similar in the subset of patients with SLE as the primary discharge diagnosis. CONCLUSION: Patients with SLE hospitalized at academic medical centers are generally more severely ill than those hospitalized at community hospitals, including large community hospitals in the same area.

ContextMcCune-Albright syndrome (MAS) is a rare disorder characterized by fibrous dysplasia of bone, café-au-lait macules, and hyperfunctioning endocrinopathies. It arises from somatic gain-of-function mutations in GNAS, which encodes the cAMP-regulating protein Gαs. Somatic GNAS mutations have been reported in intraductal papillary mucinous neoplasms (IPMNs) and various gastrointestinal (GI) tumors. The clinical spectrum and prevalence of MAS-associated GI disease is not well established.ObjectiveDefine the spectrum and prevalence of MAS-associated GI pathology in a large cohort of patients with MAS.DesignCross-sectional study.SettingNational Institutes of Health Clinical Center and The Johns Hopkins Hospital.MethodsFifty-four consecutive subjects with MAS (28 males; age range, 7 to 67 years) were screened with magnetic resonance cholangiopancreatography (MRCP).ResultsThirty of 54 subjects (56%) had radiographic GI abnormalities. Twenty-five (46%) of the screened subjects had IPMNs (mean age of 35.1 years). Fourteen of the 25 had IPMNs alone, and 11 had IPMNs and abnormal hepatobiliary imaging. The 30 patients with MAS-associated GI pathology had a higher prevalence of acute pancreatitis, diabetes mellitus, and skeletal disease burden of fibrous dysplasia than patients without GI disease.ConclusionsA broad spectrum of GI pathology is associated with MAS. IPMNs are common and occur at a younger age than in the general population. Patients with MAS should be considered for screening with a focused GI history and baseline MRCP. Further determination of the natural history and malignant potential of IPMNs in MAS is needed.

Subcutaneous human parathyroid hormone (hPTH) therapy can effectively manage hypocalcemia in hypoparathyroidism, with varying effects on hypercalciuria. However, little is known about its ability to decrease the renal comorbidities of hypoparathyroidism: nephrocalcinosis (NC), nephrolithiasis (NL), and renal insufficiency. Urinary citrate (Ucit) promotes the solubility of urinary calcium (UCa); hypocitraturia is a risk factor for NC/NL. Twenty-four-hour UCa, Ucit, and UCa/Ucit were determined in 31 hypoparathyroid subjects receiving hPTH 1-34 therapy for up to 5 years. Before hPTH 1-34, the geometric least squares mean UCa was 346 mg/day (normal

Scoliosis is a complication of fibrous dysplasia/McCune-Albright syndrome (FD/MAS); however, risk factors and long-term outcomes are unknown. Bisphosphonates are commonly used; however, it is unknown whether their use decrease the risk of progressive scoliosis. Clinical data from the National Institutes of Health (NIH) cohort study was reviewed. Cobb angles were measured, and variables associated with scoliosis progression were identified. Of 138 subjects with available radiographs, 84 (61%) had scoliosis, including 55 (65%) classified as mild (Cobb angle >10 to ≤30 degrees), 11 (13%) as moderate (>30 to ≤45 degrees), and 18 (22%) as severe (>45 degrees). Total skeletal disease burden was highly associated with scoliosis severity (p < 0.0001). Endocrinopathies associated with scoliosis included fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (p < 0.001) and hyperthyroidism (p < 0.001). Bone turnover markers, including osteocalcin and NTX-telopeptides, were associated with severe scoliosis (p < 0.01). Associations were identified between Cobb angle and functional metrics, including leg length discrepancy (p < 0.01), hip range of motion (p < 0.05), and strength of the gluteus medius and maximus (p < 0.01). Longitudinal analyses were conducted in 69 subjects who had serial radiographs over a median 4.9-year period (range, 0.9 to 14.7 years). Twenty-two subjects were treated with bisphosphonates; there was no difference in Cobb angle progression compared to untreated subjects (0.10 versus 0.53 degrees/year, p = 0.36). Longitudinal data was available for 10 of 12 subjects treated with spinal fusion; one had instrumentation failure, but in nine subjects Cobb angles were stable with 6.1 years of follow-up (range, 0.9 to 14.7 years). Two fatalities from scoliosis-associated restrictive lung disease occurred in subjects managed non-operatively. Scoliosis occurs frequently in patients with polyostotic FD, and may be potentially fatal. The primary risk factor for progressive scoliosis is total skeletal disease burden. Treatable features that contribute to scoliosis progression include leg length discrepancy, FGF23-mediated hypophosphatemia, and hyperthyroidism. Current data do not support routine use of bisphosphonates to prevent progression of spinal curvature. Spinal fusion is frequently effective in providing long-term stability, and may be lifesaving. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Objective.We examined agreement between the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) response criteria in rheumatoid arthritis (RA) and tested whether discordant responses were associated with patients’ baseline characteristics or changes in RA activity encapsulated by the different criteria.Methods.In a prospective longitudinal study, we examined responses of 243 patients with active RA to escalation of antirheumatic treatment. We computed agreement between pairs of response criteria using κ coefficients and identified patient characteristics associated with unique responses to individual criteria.Results.We found that 110 patients (45.3%) had an ACR 20% improvement (ACR20) response, 135 (55.5%) had a EULAR moderate/good response, and 83 (34.1%) had an SDAI50 response. Agreement was moderate to good (ACR20/EULAR κ 0.57; ACR20/SDAI50 κ 0.64; EULAR/SDAI50 κ 0.59). All who had SDAI50 response also had a EULAR response. Patient characteristics at baseline generally did not distinguish those who responded to both, 1, or neither criterion. Discordance was most often because of improvements in the erythrocyte sedimentation rate or C-reactive protein level among EULAR and SDAI50 responders, which were not as common among ACR20 responders. Based on receiver-operating characteristic curves, SDAI35 response had a better balance of sensitivity and specificity relative to ACR20 and EULAR moderate/good responses than SDAI50.Conclusion.Discordant responses to RA improvement criteria are most often because of differences in responses of acute-phase reactants. SDAI35 response had higher sensitivity for improvement, as reflected by other response criteria, than SDAI50 response.

Tumor-induced osteomalacia (TIO) is a debilitating paraneoplastic condition caused by small phosphaturic mesenchymal tumors (PMTs) that secrete large amounts of the phosphate-regulating and vitamin D-regulating hormone, FGF23. Tumor removal results in cure. However, because of high perioperative comorbidity, either from tumor location or host factors, surgery is sometimes not an option. Tumor destruction via cryoablation may be an effective option for inoperable PMTs. Three subjects with a confirmed diagnosis of TIO were studied. All three underwent cryoablation of suspected PMTs rather than surgery due to significant medical comorbidities or challenging anatomical location. Subject 3 had tumor embolization 24 hours prior to cryoablation because of the size and hypervascularity of the tumor. The success of the tumor cryoablation was defined by normalization of serum phosphate and FGF23. Cryoablation resulted in a rapid decrease in plasma intact FGF23 by 24 hours postprocedure in all three subjects (0, 2, and 9 pg/mL, respectively) with normalization of blood phosphate by postprocedure day 3. Three-day renal tubular reabsorption of phosphate increased to 76%, 94%, and 95.2%, respectively; 1, 25(OH)2 vitamin D increased to 84, 138, and 196 pg/ml, respectively. All three had dramatic clinical improvement in pain and weakness. Two subjects tolerated the procedure well with no complications; one had significant prolonged procedure-related localized pain. Although surgery remains the treatment of choice, cryoablation may be an effective, less invasive, and safe treatment for patients with difficult to remove tumors or who are poor surgical candidates. © 2017 American Society for Bone and Mineral Research.

OBJECTIVE In rheumatoid arthritis (RA), the patient global assessment (PGA) has been strongly associated with pain severity, but less often with other measures, including disease activity measures. We tested whether RA activity and psychological measures had direct associations with the PGA or indirect associations that were mediated by pain. We also tested whether the correlates of the PGA differed with the degree of RA activity. METHODS We studied 260 patients with active RA on 2 visits in a prospective longitudinal study. We used path analysis to test direct and indirect associations of Disease Activity Score in 28 joints (DAS28), morning stiffness, Health Assessment Questionnaire (HAQ), fatigue, physical role limitations, social functioning, depressive symptoms, and health distress with the PGA. RESULTS Among the 509 visits, the median PGA score was 50 (25th-75th percentile: 24-66). Pain severity had the strongest association with the PGA, but direct associations were also found for morning stiffness severity, health distress, fatigue, and DAS28. Morning stiffness severity, DAS28, health distress, and HAQ were also indirectly associated with the PGA through pain. Among visits with DAS28 ≥5.4, pain, morning stiffness severity, and HAQ were the only determinants of the PGA. Among visits with DAS28

OBJECTIVE The aim was to determine whether the time trade-off (TTO) and standard gamble utilities can detect treatment-related improvement in overall quality of life in patients with active RA. METHODS We measured TTO and standard gamble utilities in 192 patients before and after escalation of anti-rheumatic treatment in a prospective longitudinal study. We also examined associations between changes in utilities and patient-reported improvement during the study, and with EULAR responses. RESULTS Mean TTO at baseline was 0.68 (median 0.82) and mean standard gamble 0.80 (median 0.93). Both utilities improved significantly with treatment. Standardized response means, a measure of responsiveness, were 0.37 for the TTO and 0.20 for the standard gamble, and comparable to those of two mental health measures and the CRP, but lower than other RA activity measures. Changes in utilities were not significantly associated with patient-reported improvement. The standard gamble, but not the TTO, had a graded association with EULAR responses. CONCLUSION Utilities by the TTO and standard gamble were able to detect improvement in overall quality of life with anti-rheumatic treatment in patients with active RA, suggesting applicability in clinical trials. The standard gamble was associated with reference measures of improvement, although not as strongly as measures of RA activity, as expected with its generic orientation.

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.

SUMMARY: Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. PURPOSE: CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. METHODS: Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. RESULTS: Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. CONCLUSION: An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.

McCune–Albright syndrome (MAS) is a rare, non-hereditable genetic disorder classically defined by a clinical presentation of bone (fibrous dysplasia), skin (cafe-au-lait macules), and/or endocrine abnormalities. Sporadic occurrence of an activating mutation in the GNAS gene creates a mosaic tissue environment marked with normal and mutated cells. Mutation effect is variable with ability to cause significant disruption to various organs. Bone abnormalities include deformities and fractures, which may lead to pain, disability, and immobility. Visible irregularly shaped skin markings may be large and pronounced. Hyper-functioning endocrinopathies pose challenges to normal growth, development, and function. Individual presentation is unique in extent and severity with a range from mild, barely recognizable symptoms to severe, disfiguring disease. MAS commonly presents in childhood with a fracture or endocrine abnormality, which leads to a diagnosis. Individual variation drives the need for medical and nursing care that is centered on an accurate diagnosis. Management and treatment of bone and endocrine disease enhances and promotes patient well-being and optimal physical functioning. Despite the complexity and challenges, the majority of individuals affected appear to be psychologically well adjusted and live productive lives (Kelly et al., Bone 37(3):388–394; 2005).

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain-of-function mutations of the calcium-sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to 4 distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca(2+)(i)), and ERK and p38(MAPK) phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p=0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol and little calcium supplementation. NPSP795 was generally safe and well-tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half-maximally activated (EC(50)) at lower concentrations of extracellular calcium (Ca(2+)(o)) compared to wild type (WT) CaR; NPSP795 exposure increased the EC(50) for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype, or the response to calcilytics, suggesting that other parameters impact the response to the drug.

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

Objectives Estimates of minimal clinically important differences in health measures may be affected by the anchor used. We examined if domain-specific transition questions had higher construct validity than global health transition questions as anchors for measures in a given domain. Study Design and Setting In a prospective study of 249 patients with rheumatoid arthritis, we examined changes in pain, physical function, joint swelling, stiffness, fatigue, and depression with treatment. We related these changes to a domain-specific transition question, global arthritis transition question, and the Short Form-36 (SF-36) health transition item. Results Changes in all six clinical measures were more highly correlated with the domain-specific transition questions than with the global arthritis question and SF-36 transition question. Discrimination between patients who improved or not was also better using domain-specific questions. Estimates of minimal clinically important improvement (MCII) differed with the anchor when these were based on mean changes. MCII estimates from receiver operating characteristic curve analysis were not influenced by the choice of anchor when anchors had high agreement. Conclusion Domain-specific transition questions had higher construct validity as anchors for determining clinically important differences in health measures focused on a single domain than either global disease or general health transition questions.

The patient global assessment (PGA) occupies a central place among measures of rheumatoid arthritis (RA). Not only is the PGA one of the core measures in the American College of Rheumatology (ACR) response criteria, but it is the only patient-reported measure included in composite RA activity measures and in new criteria for remission. The PGA is an attractive measure because it is intended to capture, in a single item, an overall summary of the impact of RA on a patient's well-being. .However, its loosely-defined nature may contribute to wide variation among patients in the aspects of RA that are emphasized in marking the PGA, and which may be influenced by mood or other psychological factors. In several cross-sectional analyses, pain severity was the dominant influence on the PGA, accounting for up to 75% of inter-patient variation in ratings (1–7). Physical functioning, fatigue, depression, and in some studies, joint counts, were also important. The relative contribution of these features is difficult to assess because not all studies included measures of depression, fatigue, stiffness, or joint counts. A study that reported a major contribution of depression to the PGA did not include a measure of pain (8). To understand which aspects of RA influence patients’ assessments of change in their status, it is important to perform longitudinal comparisons, rather than rely on indirect between-patient comparisons of cross-sectional studies. Few longitudinal studies have investigated which RA activity measures are associated with changes in the PGA (5, 9–11). One study examined only pain and physical functioning, another only the Disease Activity Score (DAS), and the single study that examined fatigue and depression did not include joint counts. In clinical practice, informal appraisals of patients’ overall status are more common than formal measures such as the PGA. Universal questions to patients include how they feel now and if they feel better. These appraisals are retrospective judgments that, like the PGA, are intended to integrate diverse aspects of disease into a single assessment. However, because they depend on recall, changes reported retrospectively may differ from those measured prospectively on measures such as the PGA, and the validity of retrospective judgments of improvement has been questioned (12). Our first goal was to identify the RA-related measures associated with prospectively measured changes in the PGA. If changes in clinical factors other than pain were associated with changes in PGA, it would validate the PGA as a summary measure of multiple aspects of RA. We were also interested in whether depression and fatigue were independently associated with changes in the PGA. Our second goal was to identify if changes in RA activity measures were associated with patients’ retrospective judgments of improvement in overall arthritis status as a way to validate this outcome measure. Our third goal was to compare the RA activity measures that were associated with patients' retrospective judgments with those associated with the PGA. The former directly reflects the assessments provided by patients in clinical practice, and the comparison would provide insight into how patients form their appraisals of improvement.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic condition in which phosphaturic mesenchymal tumors (PMTs) secrete high levels of fibroblast growth factor 23 (FGF23) into the circulation. This results in renal phosphate wasting, hypophosphatemia, muscle weakness, bone pain, and pathological fractures. Recent studies suggest that fibronectin-fibroblast growth factor receptor 1 (FN1-FGFR1) translocations may be a driver of tumorigenesis. We present a patient with TIO who also exhibited clinical findings suggestive of Cowden syndrome (CS), a rare autosomal dominant disorder characterized by numerous benign hamartomas, as well as an increased risk for multiple malignancies, such as thyroid cancer. While CS is a clinical diagnosis, most, but not all, harbor a mutation in the tumor suppressor gene PTEN. Genetic testing revealed a somatic FN1-FGFR1 translocation in the FGF23-producing tumor causing TIO; however, a germline PTEN mutation was not identified. To our knowledge, this is the first reported case of concurrent TIO and CS.

Subcutaneous human parathyroid hormone (hPTH) therapy can effectively manage hypocalcemia in hypoparathyroidism, with varying effects on hypercalciuria. However, little is known about its ability to decrease the renal comorbidities of hypoparathyroidism: nephrocalcinosis (NC), nephrolithiasis (NL), and renal insufficiency. Urinary citrate (Ucit) promotes the solubility of urinary calcium (UCa); hypocitraturia is a risk factor for NC/NL. Twenty-four-hour UCa, Ucit, and UCa/Ucit were determined in 31 hypoparathyroid subjects receiving hPTH 1-34 therapy for up to 5 years. Before hPTH 1-34, the geometric least squares mean UCa was 346 mg/day (normal250) and Ucit was 500 mg/day (normal 250-1190); UCa/Ucit was 0.67 mg/mg. After 6 months of hPTH 1-34, UCa decreased (238, p 0.001), but with a greater decrease in Ucit (268, p 0.001), increasing UCa/Ucit, which became significant over time (p 0.001). After stopping hPTH 1-34 and resuming conventional therapy (follow-up; FU), compared to the last measures on hPTH 1-34, Ucit rose to 626 (p 0.001), reducing UCa/Ucit to 0.44, (p 0.05); UCa also rose (273), but was still lower than baseline (p 0.05). Daily hPTH 1-34 dose did not correlate with UCa, but was inversely related to Ucit, and directly related to UCa/Ucit (p 0.01). Mean blood bicarbonate decreased significantly on hPTH 1-34 and remained lower than baseline at FU (p 0.01). Mean eGFR increased on hPTH 1-34 (86 to 96 mL/min/1.73 m

Scoliosis is a complication of fibrous dysplasia/McCune-Albright syndrome (FD/MAS); however, risk factors and long-term outcomes are unknown. Bisphosphonates are commonly used; however, it is unknown whether their use decrease the risk of progressive scoliosis. Clinical data from the National Institutes of Health (NIH) cohort study was reviewed. Cobb angles were measured, and variables associated with scoliosis progression were identified. Of 138 subjects with available radiographs, 84 (61%) had scoliosis, including 55 (65%) classified as mild (Cobb angle10 to ≤30 degrees), 11 (13%) as moderate (30 to ≤45 degrees), and 18 (22%) as severe (45 degrees). Total skeletal disease burden was highly associated with scoliosis severity (p 0.0001). Endocrinopathies associated with scoliosis included fibroblast growth factor 23 (FGF23)-mediated hypophosphatemia (p 0.001) and hyperthyroidism (p 0.001). Bone turnover markers, including osteocalcin and NTX-telopeptides, were associated with severe scoliosis (p 0.01). Associations were identified between Cobb angle and functional metrics, including leg length discrepancy (p 0.01), hip range of motion (p 0.05), and strength of the gluteus medius and maximus (p 0.01). Longitudinal analyses were conducted in 69 subjects who had serial radiographs over a median 4.9-year period (range, 0.9 to 14.7 years). Twenty-two subjects were treated with bisphosphonates; there was no difference in Cobb angle progression compared to untreated subjects (0.10 versus 0.53 degrees/year, p = 0.36). Longitudinal data was available for 10 of 12 subjects treated with spinal fusion; one had instrumentation failure, but in nine subjects Cobb angles were stable with 6.1 years of follow-up (range, 0.9 to 14.7 years). Two fatalities from scoliosis-associated restrictive lung disease occurred in subjects managed non-operatively. Scoliosis occurs frequently in patients with polyostotic FD, and may be potentially fatal. The primary risk factor for progressive scoliosis is total skeletal disease burden. Treatable features that contribute to scoliosis progression include leg length discrepancy, FGF23-mediated hypophosphatemia, and hyperthyroidism. Current data do not support routine use of bisphosphonates to prevent progression of spinal curvature. Spinal fusion is frequently effective in providing long-term stability, and may be lifesaving. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Tumor-induced osteomalacia (TIO) is a debilitating paraneoplastic condition caused by small phosphaturic mesenchymal tumors (PMTs) that secrete large amounts of the phosphate- and vitamin D-regulating hormone, FGF23. Tumor removal results in cure. However, due to high perioperative comorbidity, either from tumor location or host factors, surgery is sometimes not an option. Tumor destruction via cryoablation may be an effective option for inoperable PMTs. Three subjects with a confirmed diagnosis of TIO were studied. All three underwent cryoablation of suspected PMTs rather than surgery due to significant medical comorbidities or challenging anatomical location. subject #3 had tumor embolization 24-hours prior to cryoablation due to the size and hypervascularity of the tumor. The success of the tumor cryoablation was defined by normalization of serum phosphate and FGF23. Cryoablation resulted in a rapid decrease in plasma intact FGF23 by 24-hours post-procedure in all three subjects (0, 2, and 9 pg/mL, respectively) with normalization of blood phosphate by post-procedure day #3. Day #3 renal tubular reabsorption of phosphate increased to 76%, 94% and 95.2%, respectively; 1, 25 (OH2) vitamin D increased to 84, 138 and 196, respectively. All three had dramatic clinical improvement in pain and weakness. Two subjects tolerated the procedure well with no complications; one had significant prolonged procedure-related localized pain. Although surgery remains the treatment of choice, cryoablation may be an effective, less invasive, and safe treatment for patients with difficult to remove tumors or who are poor surgical candidates.

Background No single “gold standard” measure is available to assess patients with rheumatoid arthritis (RA) in clinical trials and routine care, as in hypertension, diabetes, and other diseases. Therefore, an index of several measures, such as a DAS28 (Disease Activity Score-28) and CDAI (Clinical Disease Activity Index), based on 7 RA core data set measures; is needed. However, the only quantitative data in many (most) patients in routine rheumatology care are laboratory test results. RAPID3 (routine assessment of patient index data), which includes only patient self-report scores, is considerably more feasible than DAS28 or CDAI for routine care, distinguishes active from control treatments in RA clinical trials similarly and is correlated significantly with these indices. A minimal clinically important improvement (MCII) to interpret changes in clinical trials and clinical care has not been established for RAPID3 Objectives To estimate MCII of RAPID3, and compare results to MCIIs of DAS28 and CDAI. Methods Post hoc analyses were performed of a reported longitudinal study of 250 patients with active RA (1). All 7 RA core data set measures were collected at baseline and after treatment escalation with prednisone 1 month later or with disease modifying medications or biologic agents 4 months later (1). Patient judgment of improvement in arthritis status was obtained as “improved”, “the same” or “worsened”, and analyzed in relation to changes in RAPID3, DAS28 and CDAI. RAPID3 is the sum of 3 0–10 measures: physical function on a HAQ recalculated from 0–3 to 0–10, pain and patient global estimate on 0–10 VAS (visual analog scales), total=0–30. DAS28-ESR (erythrocyte sedimentation rate) and CDAI were computed as described in the literature. Changes in all indices, standardized response means (SRM), MCIIs as changes that had a specificity of 0.80 for improvement based on receiver-operating characteristic curves, and MCII as a proportion of the maximum score were computed. Results Among 250 patients, 167 (66.8%) reported improvement. RA activity and SRMs improved similarly per the 3 indices (Table). ROC curve areas were ≥0.77 (Table). MCIIs with specificity for improvement of 0.80 were -3.5 for RAPID3, -1.17 for DAS28-ESR, and -12.5 for CDAI. MCIIs were in a similar range of 11.6% to 16.8% of maximum score (Table). Conclusions MCIIs for RAPID3, DAS28, and CDAI were in a similar range. Knowledge concerning MCII thresholds can improve interpretation of data from clinical trials and routine clinical care. References Ward, M et al, Ann Rheum Dis 2015, 74:1691–1696. Disclosure of Interest I. Castrejon: None declared, M. Ward: None declared, M. Bergman: None declared, L. Guthrie: None declared, M. Alba: None declared, T. Pincus Shareholder of: Health Report Services, Inc

Measures of health status and health-related quality of life have been recognized as essential components of clinical evaluations because they provide patients’ perspectives on how they are affected by a disease (1,2). Consequently, patient-reported outcomes have been included as endpoints in many clinical trials, allowing treatment effects to be assessed more comprehensively. In rheumatoid arthritis (RA), measures such as pain scales and the Health Assessment Questionnaire Disability Index have been used for decades, and clinical trials have also increasingly included generic health status measures, particularly the Short-Form 36 (SF-36) (3–9). The SF-36 includes eight scales that assess pain, physical functioning, general health, fatigue/vitality, mental health, social functioning, and role limitations due to either physical or emotional problems. Two summary scores, the physical component summary (PCS) and mental component summary (MCS) can also be computed. The SF-36 therefore assesses a broader range of health concerns than RA-specific measures, and because it is a generic measure, comparisons are possible across diseases. The SF-36 is the most commonly used patient-reported measure worldwide, and has had extensive testing of reliability and validity (10–12). Interpretation of SF-36 scores has been aided by development of population-based normative values, and by rescaling methods that allow patients’ scores to be directly compared to general population means. However, interpretation of changes in SF-36 scores is not intuitive, and requires knowledge of the degree of change that corresponds to improvement (or deterioration) in health that is recognized as important or meaningful to patients (13). Scores may improve significantly with treatment, but the magnitude of the change may not be clinically important. Determination of thresholds for clinically important improvement, and reporting the proportion of patients who had changes exceeding this threshold, were highlighted by the U.S. Food and Drug Administration as important considerations in using patient-reported outcomes in clinical trials (14). Despite its wide use, estimates of minimal clinically important improvement (MCII) for SF-36 scales are not well-established (15). Thresholds of 3, 5, or 10 points on the individual scales, and 2.5, 3, or 5 points on the physical and mental component summaries, have been cited as MCIIs in studies of RA (5–8,16). A uniform threshold has commonly been applied to all scales, even though the interpretation of changes in individual scales may differ. The single study that served as the source of these estimates in RA used the original version of the SF-36, which has a one week recall period rather than the 4 week recall version more commonly used in RA clinical trials, and examined normalized scores for the PCS and MCS but not for the individual scales (17). In this study, MCIIs varied from 2.4 to 16.4 for individual scale scores, and were 4.4 and 3.1 for the PCS and MCS, respectively. The investigators noted that a single best estimate of MCII could not be established, and that estimates for the scales related to mental health had limited validity because they did not vary much with RA severity (17). They did not use these estimates in a subsequent study (18). Complicating matters further, it is difficult to generalize estimates of MCIIs across diseases and treatments, because different diseases impact different aspects of health, and different aspects of health are responsive to different treatments (19). In this study, we sought to estimate MCIIs for the SF-36 for patients with active RA who are receiving treatment with disease-modifying medications, biologics, or prednisone, so that these may be applied in clinical trials that use the SF-36. We examined population-normalized scores for the SF-36-version 2 with 4 week recall, as this is the version most commonly used in clinical trials currently.

Objective To examine the association of the American College of Rheumatology (ACR) response criteria (20% improvement [ACR20], ACR50, and ACR70) and the European League Against Rheumatism (EULAR) response criteria with patient-reported improvement in rheumatoid arthritis (RA) activity. Methods Two hundred fifty patients with active RA were studied prospectively, before and after escalation of antirheumatic treatment. Patients were asked to report if they subjectively judged that they had experienced important improvement with treatment, and the proportion of patients who reported improvement was compared with the proportion who met the ACR20, ACR50, ACR70, and EULAR response criteria. Results Improvement in overall arthritis status was reported by 167 patients (66.8%), while 107 patients (42.8%) had an ACR20 response, 52 (20.8%) had an ACR50 response, 24 (9.6%) had an ACR70 response, and 136 (54.4%) had a EULAR moderate/good response. ACR20 response had a sensitivity of 0.57 and a specificity of 0.85 for clinically important improvement as judged by patients. Sensitivities of the ACR50, ACR70, and EULAR moderate/good responses were 0.30, 0.14, and 0.68, respectively, while their specificities were 0.97, 0.99, and 0.73, respectively. The ACR hybrid score with the highest sensitivity and specificity for important improvement was 19.99. Conclusion Among patients with active RA, ACR20 responses are highly specific measures of improvement as judged by patients, but exclude a substantial proportion of patients who consider themselves improved. Response criteria are associated with, but not equivalent to, patient-perceived improvement.

Objective Thresholds of minimal clinically important improvement (MCII) are needed to plan and interpret clinical trials. We estimated MCIIs for the rheumatoid arthritis (RA) activity measures of patient global assessment, pain score, Health Assessment Questionnaire Disability Index (HAQ), Disease Activity Score-28 (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Methods In this prospective longitudinal study, we studied 250 patients who had active RA. Disease activity measures were collected before and either 1 month (for patients treated with prednisone) or 4 months (for patients treated with disease modifying medications or biologics) after treatment escalation. Patient judgments of improvement in arthritis status were related to prospectively assessed changes in the measures. MCIIs were changes that had a specificity of 0.80 for improvement based on receiver operating characteristic curve analysis. We used bootstrapping to provide estimates with predictive validity. Results At baseline, the mean (±SD) DAS28-ESR (erythrocyte sedimentation rate) was 6.16±1.2 and mean SDAI was 38.6±14.8. Improvement in overall arthritis status was reported by 167 patients (66.8%). Patients were consistent in their ratings of improvement versus no change or worsening, with receiver operating characteristic curve areas ≥0.74. MCIIs with a specificity for improvement of 0.80 were: patient global assessment −18, pain score −20, HAQ −0.375, DAS28-ESR −1.2, DAS28-CRP (C-reactive protein) −1.0, SDAI −13, and CDAI −12. Conclusions MCIIs for individual core set measures were larger than previous estimates. Reporting the proportion of patients who meet these MCII thresholds can improve the interpretation of clinical trials in RA.

Objective The study determined if time perspective was associated with medication adherence among people with hypertension and diabetes. Methods Using the Health Beliefs Model, we used path analysis to test direct and indirect effects of time perspective and health beliefs on adherence among 178 people who participated in a community-based survey near Washington, D.C. We measured three time perspectives (future, present fatalistic, and present hedonistic) with the Zimbardo Time Perspective Inventory and medication adherence by self-report. Results The total model demonstrated a good fit (RMSEA=0.17, 90% CI [0.10, 0.28], p =0.003; comparative fit index=0.91). Future time perspective and age showed direct effects on increased medication adherence; an increase by a single unit in future time perspective was associated with a 0.32 standard deviation increase in reported adherence. There were no significant indirect effects of time perspective with reported medication adherence through health beliefs. Conclusion The findings provide the first evidence that time perspective plays an under-recognized role as a psychological motivator in medication adherence. Practice implications Patient counseling for medication adherence may be enhanced if clinicians incorporate consideration of the patient's time perspective.

A 20-month-old female presented with bloody discharge in her diaper. Significant findings on her physical examination included length greater than the 95th percentile, Tanner stage 2 breasts, and a large, light brown macule on her lower back near the crease of her buttocks with jagged edges that did not cross the midline. Pelvic ultrasound showed a large unilateral ovarian cyst. Skeletal maturity (bone age) was advanced. A 5-year-old male presented with leg pain and limp following a minor fall during a pillow fight with his brother. Radiographs showed a fracture at the site of a fibrous dysplastic lesion in the femoral neck with “ground glass” appearance. He had two light brown birthmarks with irregular borders on his posterior neck and chest. Neither crossed the midline of his body nor had changed much in size. These children had different clinical presentations, but they share the diagnosis of McCune–Albright syndrome. An overview of the clinical features of McCune–Albright syndrome follows.

Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with 111Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and 18fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo-SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.

Objective McCune–Albright syndrome (MAS) is a rare disorder with a broad spectrum including precocious puberty (PP) due to recurrent estrogen-secreting ovarian cysts. This study evaluates the long-term safety and efficacy of letrozole treatment in large cohort of girls with MAS-associated PP. Design Retrospective cohort analysis. Methods Clinical data, including history and physical examination, bone age, and pelvic ultrasounds, were reviewed on 28 letrozole-treated girls. Adult height was reviewed for 42 historical controls. Outcomes included rate of skeletal maturation, growth velocity, predicted adult height and adult height. Results Twenty-eight girls received letrozole treatment. Treatment duration was 4.1 ± 2.6 years (mean ± 1 s.d.) (range: 0.5–10.9) and mean follow-up was 6.0 ± 3.3 years (range: 0.5–15.0), for a total of 135.9 person-years of follow-up. Letrozole treatment was highly effective at decreasing the rate of skeletal maturation, with a decline in change in bone age over change in chronological age (ΔBA/ΔCA) from 1.7 (IQR: 2.3) to 0.5 (IQR: 0.4) (P Z-scores, which declined from 2.2 ± 2.3 to −0.6 ± 1.6 (P = 0.0004). Predicted adult height Z-scores increased significantly from −2.9 ± 3.2 to −0.8 ± 1.5 for subjects on treatment (P = 0.004). Four subjects who completed treatment reached adult height Z-scores ranging from −1.5 to 1.7 (median: −0.6), which were increased in comparison with untreated historical controls (P = 0.02). There was no change in uterine size or ovarian volumes, and no adverse events over the treatment period. Conclusions In this study with the longest follow-up to date, letrozole treatment resulted in sustained beneficial effects on skeletal maturation, growth velocity and predicted adult height.

Context: Phosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors. Objective: Our objective was to evaluate the use of 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO). Design: This was a single-center prospective study of patients with TIO. Setting: The study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015. Subjects: Eleven subjects (six females, five males) with TIO were included. Intervention: Subjects underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxy...

Objective: Patient-physician discordance in health status ratings may arise because patients use temporal comparisons (comparing their current status with their previous status), while clinicians use social comparisons (comparing this patient's status to that of other patients, or to the full range of disease severity possible) to guide their assessments. We compared discordance between patients with rheumatoid arthritis (RA) and clinicians using either the conventional patient global assessment (PGA) or a rating scale with five anchors describing different health states. We hypothesized that discordance would be smaller with the rating scale because clinicians likely used similar social comparisons when making global assessments. Methods: We prospectively studied 206 patients with active RA, and assessed the PGA (0 – 100), rating scale (0 – 100), and evaluator global assessment (EGA; 0 – 100)) on each of two visits (total 401 visits). We compared the PGA/EGA discordance and the rating scale/EGA discordance at each visit. Results: The mean (± standard deviation) PGA/EGA discordance was 8.5 ± 22.4, and the mean rating scale/EGA discordance was 2.3 ± 24.0. The intraclass correlation, measuring agreement, was higher between the rating scale and EGA than between the PGA and EGA (0.39 versus 0.31). Agreement was larger at low levels of RA activity on both pairs of measures. Conclusion: Discordance between patients' global assessments and evaluators' global assessments was smaller when patients used a social standard of comparison than when they marked the PGA, suggesting that differences in standards of comparison contribute to patient-clinician discordance when the PGA is used. This article is protected by copyright. All rights reserved.

Objective.Patient global assessment (PGA) is commonly measured using a visual analog scale (VAS). The VAS asks patients to integrate many dimensions of rheumatoid arthritis (RA) activity, yet its scope is poorly defined and its endpoints are vague. We investigated whether a modified Rating Scale that used marker states and more defined endpoints would provide a more valid measure of PGA.Methods.In our prospective longitudinal study, 164 patients with active RA rated their global arthritis activity using the VAS and Rating Scale before and after treatment. To compare construct validity, we correlated each score with 2 reference measures of RA activity, the 28-joint count Disease Activity Score (DAS28) and the physician global assessment, and examined how each measure was associated with different aspects of RA activity, including pain, functioning, and depressive symptoms, in multivariate regression analyses. We also examined sensitivity to change.Results.Both measures were correlated with the DAS28 (r = 0.39 for VAS; r = 0.35 for Rating Scale) and physician global assessment (r = 0.41 for VAS; r = 0.26 for Rating Scale) at the baseline visit. Pain and depressive symptoms had the strongest association with the VAS, while functional limitations and depressive symptoms had the strongest association with the Rating Scale. Residual analysis showed no differences in heterogeneity of patients’ ratings. VAS was more sensitive to change than the Rating Scale (standardized response means of 0.55 and 0.45).Conclusion.As measures of PGA, the VAS and Rating Scale had comparable construct validity, but differed in which aspects of arthritis activity influenced scores. VAS was more sensitive to change.

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated while iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in 7 subjects; no causative mutation was found in the eighth. Biopsies from 4 subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in 1 subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the 2 subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and peri-lesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation.

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

McCune-Albright syndrome (MAS) is defined by the triad of cafe ´ -au-lait skin pigmentation, polyostotic fibrous dysplasia, and hyperfunctioning endocrinopathies, such as precocious puberty, hyperthyroidism, GH excess, and Cushing’s syndrome. This disorder is caused by sporadic, postzygotic activating mutations in the GNAS1 gene, which codes for the Gs protein in the cAMP signaling cascade. Nodular and diffuse goiters (with and without hyperthyroidism), as well as benign thyroid nodules, have been reported in association with MAS. Herein we report two cases of thyroid carcinoma in patients with MAS. The first is a case of papillary thyroid cancer detected incidentally during a hemithyroidectomy for hyperthyroidism in a 14-yr-old girl. The second is one of a 41-yr-old woman with long-standing MAS and an enlarging thyroid nodule, which was diagnosed as a clear cell thyroid carcinoma, a rare variant of thyroid cancer. Molecular analysis revealed that foci of malignancy and adjacent areas of hyperplasia and some areas of normal thyroid harbored activating mutations of Arg 201 in the GNAS1 gene. These findings suggest that the infrequent development of thyroid carcinoma in MAS patients involves additional mutational or epigenetic events. (J Clin Endocrinol Metab 88: 4413– 4417, 2003)

Purpose The utility of In-111 DTPA octreotide scintigraphy (SRS) for disease detection in patients with metastatic thyroid carcinoma (TCA) remains controversial. The authors compared the sensitivity of In-111-based SRS, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and extensive conventional radiographic imaging (CRI) in this type of cancer. Methods SRS, FDG PET, and CRI were performed concurrently in 21 patients (age, 56.4 +/- 12.9 years) who had aggressive TCA. Concordance rates % of lesion positivity among pairs of different techniques (A and B) were calculated as the ratio of the number of lesions positive with both techniques divided by the sum of the total number of lesions positive with technique A + total number of lesions positive with technique B, which was then multiplied by 200. Results The combined use of CRI, FDG PET, and SRS resulted in the detection of 105 lesions, presumed to be due to metastatic deposits. Sensitivities for SRS and FDG-PET imaging were 49.5% and 67.6%, respectively. The lesion detection concordance rates were as follows: CRI versus FDG PET, 80.8%; CRI versus SRS, 74.2%; and FDG-PET versus SRS, 58.6%. Importantly, SRS detected five unexpected lesions, which were negative by both CRI and FDG-PET imaging. In two representative patients, a positive correlation (Spearman's rank = 0.71; = 0.0576) existed between the percentage of lesional In-111 DTPA octreotide uptake and the standard uptake value in eight concordant lesions. Conclusion Although SRS has only moderate sensitivity for disease detection in metastatic TCA, sometimes it can reveal lesions that otherwise would be undetectable by either CRI or FDG-PET imaging.

Long-term thyroid hormone (TH) therapy aiming at the suppression of serum thyrotropin (TSH) has been traditionally used in the management of well differentiated thyroid cancer (ThyrCa). However, formal validation of the effects of thyroid hormone suppression therapy (THST) through randomized controlled trials is lacking. Additionally, the role - if any - of TSH effect at low ambient concentrations upon human thyroid tumorigenesis remains unclear.Evaluation of the effect of THST on the clinical outcomes of papillary and/or follicular ThyrCa.By using a quantitative research synthesis approach in a cumulative ThyrCa cohort, we evaluated the effect of THST on the likelihood of major adverse clinical events (disease progression/recurrence and death). A total of 28 clinical trials published during the period 1934-2001 were identified; only 10 were amenable to meta-analysis. Causality was assessed by Hill criteria.Out of 4, 174 patients with ThyrCa, 2, 880 (69%) were reported as being on THST. Meta-analysis showed that the group of patients who received THST had a decreased risk of major adverse clinical events (RR = 0.73; Cl = 0.60-0.88; P0.05). Further, by applying a Likert scale, 15/17 interpretable studies showed either a 'likely' or 'questionable' beneficial effect of THST. Assessment of causality between TSHT and reduction of major adverse clinical events suggested a probable association.THST appears justified in ThyrCa patients following initial therapy. As most primary studies were imperfect, future research will better define the effect of THST upon ThyrCa clinical outcomes.

Objective Estimates of minimal clinically important improvements (MCIIs) are larger among patients with higher values at baseline, suggesting that these patients require larger changes to appreciate improvements. We examined if baseline dependency of MCIIs was associated with specific patients across three measures, or was owing to floor and ceiling effects. Study Design and Setting We prospectively examined 250 outpatients with active rheumatoid arthritis (RA). We used an anchor-based approach to estimate MCIIs for three measures of RA activity (patient global assessment, swollen joint count, and walking time). We examined if the same patients constituted the baseline subgroups with high MCIIs across measures. Results The MCIIs were greater for those with higher baseline values of all three measures. At the ceiling, there was little opportunity to improve, and judgments were unrelated to measured changes. At midrange, improvements were balanced by worsenings, including some judged as improvements. At the floor, improvements were not similarly balanced. Patients in subgroups with high MCII for patient global assessment were not also predominantly in subgroups with high MCII for the swollen joint count or walking time, and vice versa. Conclusion Variation in MCII by baseline values is because of floor and ceiling effects rather than expectations of particular patients.

Purpose. Time perspective, a psychological construct denoting subjective orientation to either present or future concerns, has been inconsistently associated with healthy behaviors in adults. We hypothesized that associations would be stronger in young adults, who are first developing independent attitudes, than in older adults. Design. Cross-sectional survey. Setting. The study was conducted in three cities in the Mid-Atlantic region. Subjects. Subjects were 790 patrons of barber and beauty shops. Measures. Measures used were the Zimbardo Time Perspective Inventory future, present-fatalistic, and present-hedonistic subscales and current smoking, days per week of recreational exercise, and height and weight, by self-report. Analysis. We tested if associations between time perspective and exercise, obesity, and current smoking differed by age group (18–24 years, 25–34 years, and 35 years and older) using analysis of variance and logistic regression. Results. Higher future time perspective scores, indicating greater focus on future events, was associated with more frequent exercise, whereas higher present-fatalistic time perspective scores, indicating more hopelessness, was associated with less frequent exercise in 18- to 24-year-olds, but not in older individuals. Lower future time perspective scores, and higher present-hedonistic time perspective scores, indicating interest in pleasure-seeking, were also associated with obesity only in 18- to 24-year-olds. Current smoking was not related to time perspective in any age group. Conclusion. Time perspective has age-specific associations with exercise and obesity, suggesting stages when time perspective may influence health behavior decision making.

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Whether a person engages in a particular behavior depends in part on the anticipated consequences of the behavior. Outcome expectancies are a major component of social learning theories of behavior, and are shaped by appraisals of both the likelihood of the outcome and of how rewarding or beneficial the outcome is expected to be1,2. For many health behaviors, such as exercising or eating a healthy diet, some benefits may occur only far in the future, with lower likelihoods of heart disease and cancer. At the same time, these behaviors may involve short-term sacrifices, inconveniences, or disappointments. How a person values future benefits versus present enjoyment (or disengagement from health-promoting behaviors) may influence their outcome expectancies3,4. Some individuals may have a long time horizon and highly value their future health, engaging in whatever behaviors possible to safeguard it. Others may discount the value of future health, believing they are either not susceptible to or can escape any harmful consequences of present behaviors, or that they have time to remediate before consequences develop. Expectancies may differ for near compared to far-off outcomes. Because much of health education involves motivating people to engage in behaviors that provide future health benefits, understanding peoples’ perspectives on time may be important for shaping, delivering, or targeting health promotion interventions. Psychological time perspective is a construct that represents a person’s orientation of the past, present, and future and how it shapes their decision-making5,6. Time perspective is theorized as a subconscious cognitive framework used when making decisions about short-term and long-term goals. In some circumstances, the primary orientation favors consideration of the future, while in other circumstances, the primary orientation may favor the present or the past. Time perspective may be conceived as multidimensional, with different time frames influencing motivations for different decisions and in different domains simultaneously, or as unidimensional, with people having a time perspective that is predominantly future-, present-, or past-oriented6. Time perspective affects the perception and resonance of health-promoting messages, suggesting this construct is actively accessed when decisions regarding health are considered7. Psychological time perspective has been associated with the likelihood of engagement in several risky health behaviors, including substance abuse8–15, gambling16, risky driving11,16,17, and unsafe sexual practices11,14,18–20. However, whether time perspective is associated with more common health behaviors, such as smoking, diet, and recreational exercise, is less clear. Greater future orientation on the Consideration of Future Consequences (CFC) scale was associated with lower body mass indexes (N.B. with obesity considered a result of several different health behaviors), but was not associated with current smoking, in a large community sample in England21. Among volunteers who responded to an online survey in the United States, greater future orientation on the CFC scale was associated with lower body mass indexes and a lower likelihood of current smoking, but was not associated with regular exercise22. Among adolescents, future orientation has been associated with more physical activity and eating a healthy diet23. However, among a small sample of patients undergoing cardiac rehabilitation, scores on the future subscale of the Zimbardo Time Perspective Inventory (ZTPI) were not associated with either exercise or diet, while higher scores on the present-fatalistic subscale were associated with more (rather than less) exercise24. Lastly, in a national sample in Great Britain, associations were found between future orientation and both not smoking and eating more vegetables, but not with recreational activity25. In a previous study, we found no associations between the future and present subscales of the ZTPI and smoking, obesity, or exercise in a community sample26. Although the sample was representative of the local population, participants were highly-educated and had low prevalences of smoking and physical inactivity. Both of these factors may have limited our ability to detect associations between time perspective and health behaviors. More highly-educated individuals tend to be more future-oriented than less well-educated persons and those of lower socioeconomic status21,25–28. Therefore, the association between time perspective and health behaviors may have been affected by the socioeconomic composition of the sample. The purpose of the current study was to examine associations between time perspective and smoking, obesity, and recreational exercise in a diverse community-based sample of lower socioeconomic status than our previous study. We hypothesized that persons with higher future-orientation would be less likely to be smokers or to be obese, and more likely to exercise. In addition, we hypothesized that those with higher present-orientation would be more likely to be smokers or obese, and less likely to exercise. Also, future time perspective and health share similar socioeconomic gradients. Because time perspective provides a scheme for motivations of investments in future health, time perspective has been theorized to be a mediator of socioeconomic disparities in health21,25,26,29–31. An additional aim of this study was to test if time perspective mediated the association between socioeconomic status and health behaviors.

Time perspective is a measure of the degree to which one’s thinking is motivated by considerations of the future, present, or past. Time perspective has been proposed as a potential mediator of socioeconomic disparities in health because it has been associated with health behaviors and is presumed to vary with socioeconomic status. In this cross-sectional community-based survey of respondents recruited from hair salons and barber shops in a suburb of Washington DC, we examined the association between time perspective and both education level and occupation. We asked participants (N = 525) to complete a questionnaire that included three subscales (future, present-fatalistic, and present-hedonistic) of the Zimbardo Time Perspective Inventory. Participants with more formal education and those with professional occupations had higher scores on the future time perspective subscale, and lower scores on the present-fatalistic subscale, than participants with less formal education or a non-professional occupation. Present-fatalistic scores were also higher among participants whose parents had less formal education. Present-hedonistic scores were not associated with either education level or professional occupation. Time perspective scores were not independently associated with the likelihood of obesity, smoking, or exercise. In this community sample, future time perspective was associated with current socioeconomic status, and past-fatalistic time perspective was associated with both current and childhood socioeconomic status.