P053 Interstitial Nephritis from IBD: Complicated Conclusions.

CASE: BACKGROUND: Kidney injury in IBD is challenging. Tubulointerstitial nephritis (TIN) is linked to aminosalicylates, but also described in drug-naïve patients, suggesting that TIN may be a direct manifestation of IBD. We describe three cases of TIN in IBD to illustrate the challenges in determining the etiology of the injury. CASES: Case #1: 58-year-old male with a horseshoe kidney deformity, uncontrolled hypertension, GERD and small bowel stricturing Crohn's disease (CD), previously on mercaptopurine and allopurinol, subsequently transitioned to adalimumab, maintaining clinical and radiologic remission. Two years later, he developed acute kidney injury in setting of high fevers and sweats, with negative infectious evaluation. Medications included adalimumab, PPI, valacyclovir and torsemide. Renal biopsy revealed TIN with dense, zonal and focal granulomatous features suggestive of drug-induced hypersensitivity, chronic infection, sarcoidosis or an extra-intestinal manifestation of CD. Case #2: 45-year-old female with SLE, nephrolithiasis, GERD, hypertension and ulcerative colitis (UC), initially on mesalamine, then vedolizumab, with clinical and endoscopic remission. Her SCr increased at the time of her UC diagnosis, and worsened over 6 months while on mesalamine, vedolizumab, PPI and losartan. Renal biopsy demonstrated acute and chronic TIN with eosinophils raising concern for an allergic/drug-induced injury. Nephrology concluded that her TIN was secondary to either UC or one of her medications. Case #3: 33-year-old male with UC transitioned to vedolizumab, having failed budesonide and mesalamine. He had latent TB and received 9 months of isoniazid. While on mesalamine, vedolizumab and PPI, he developed fever, chills and night sweats, with an acute rise in SCr, prompting discontinuation of meds. Three months later, still in remission and with improved SCr, he restarted vedolizumab. A year later he developed low-grade fever with elevated SCr, prompting discontinuation. Renal biopsy revealed acute and chronic TIN with severe interstitial fibrosis, tubular atrophy and focal global glomerulosclerosis. He started prednisone and remained off other IBD therapy for 6 months, but repeat colonoscopy revealed mild colitis. He restarted mesalamine, but again developed elevated SCr 2 months later. Repeat renal biopsy revealed TIN with less interstitial fibrosis and focal global glomerulosclerosis, and nephrology suggested his interstitial nephritis was likely secondary to UC over his medications. He started azathioprine with significant improvement in SCr and clinical remission of UC. DISCUSSION: In all three cases, neither nephrology consultation nor renal biopsy helped distinguish the etiology of renal injury, defaulting to either the IBD meds or an extra-intestinal manifestation of IBD, and not accounting for the acute inflammatory symptoms in two of the cases. While literature review reveals several cases that allege kidney injury as an extra-intestinal target of IBD serious doubts remain. TIN secondary to aminosalicylates is well-documented, but there are few reports of adalimumab-induced granulomatous TIN and only one report of vedolizumab-induced TIN. Each of our patients had well-controlled IBD and multiple confounding variables that could impact kidney function or cause TIN, including hypertension and multiple potential culprit medications, illustrating the dilemma of determining the etiology of renal injury in IBD patients.

A safety review of recent advancements in the treatment of psoriasis: analysis of clinical trial safety data.

INTRODUCTION: The management of psoriasis can include oral medications and injectable biologics. Safety data of these various treatment options are important to consider when choosing the right treatment for the patient. AREAS COVERED: This review evaluates the safety of newer treatments approved for psoriasis, including interleukin-(IL)-17 inhibitors, IL-23/p19 inhibitors, ustekinumab, certolizumab pegol and apremilast, using phases III and IV clinical trial data. EXPERT OPINION: Even as treatment of psoriasis becomes safer, it is important to recognize both common and uncommon adverse effects of treatment. Common adverse effects are similar across treatment options, including upper respiratory infection and injection-site reaction. Serious adverse effects occur less frequently and specific to the psoriasis treatment option, such as inflammatory bowel disease and candida infections with IL-17 inhibitors, tuberculosis with certolizumab pegol, and psychiatric events with apremilast. While IL-23/p19 inhibitors may have a slightly better safety profile than other biologics, long-term data are limited. The conclusions that can be drawn from clinical trial safety data are limited given that many clinical trials are not large enough to detect rare safety events. Data from registries provide important complementary information on long-term safety but there are limitations including a lack of randomized assignment between drug treatments.

Adults with cystic fibrosis have deficits in bone structure and strength at the distal tibia despite similar size and measuring standard and relative sites.

Individuals with cystic fibrosis (CF) have lower bone mineral density (BMD) by DXA and are at higher risk of fracture than healthy controls. However, the 2-dimensional measurement of areal BMD (aBMD) provided by DXA is influenced by bone size and the true extent of the bone deficit is unclear. Our objective was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) and individual trabecula segmentation (ITS) analysis to compare volumetric BMD (vBMD), microarchitecture and estimated strength at the distal radius and tibia in 26 young adults with CF and 26 controls matched for age, gender, and race. To assess the effect of limb length and minimize the confounding effects of size on HR-pQCT outcomes, we scanned participants at both the standard fixed HR-pQCT measurement sites and at a subject-specific relative site that varied according to limb length. CF participants did not differ significantly in age, height, weight, or BMI from controls. Ulnar and tibial lengths were 9mm shorter in CF patients, though differences were not significant. CF patients had significantly lower BMI-adjusted aBMD by DXA at the lumbar spine (8.9%, p<0.01), total hip (11.5%, p<0.01) and femoral neck (14.5%, p<0.01), but not at the forearm. At the fixed radius site, thickness of trabecular plates and torsional stiffness were significantly lower in CF participants than controls. At the relative radius site, only torsional stiffness was significantly lower in CF participants. At the tibia, total, trabecular and cortical vBMD were significantly lower at both fixed and relative sites in CF participants, with fewer, more widely-spaced trabecular plates, lower trabecular connectivity, and lower axial and torsional stiffness. Our results confirm that aBMD is lower at the spine and hip in young adults with CF, independent of BMI and body size. We also conclude that vBMD and stiffness are lower at the weight-bearing tibia. The pathogenesis of these differences in bone density and strength at the tibia appear to be related to trabecular drop-out and reduced trabecular connectivity and to be independent of differences in limb length, as assessed by scanning participants at both standard and relative sites. We concluded that significant deficits in bone structure and strength persist in young adults with CF, despite advances in care that permit them to attain relatively normal height and weight.

Effect of Low Vitamin D on Volumetric Bone Mineral Density, Bone Microarchitecture, and Stiffness in Primary Hyperparathyroidism.

CONTEXT: Patients with 25-hydroxyvitamin D deficiency (25OHD <20 ng/ml) and primary hyperparathyroidism (PHPT) have more severe disease reflected by higher serum PTH levels compared to those with vitamin D levels in the insufficient (20-29 ng/ml) or replete range (≥ 30 ng/ml). OBJECTIVE: To study the effect of low vitamin D in PHPT on volumetric bone mineral density (vBMD), bone microarchitecture, and bone strength. DESIGN, SETTING, AND PARTICIPANTS: This is a cross-sectional analysis of 99 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital. OUTCOME MEASURES: Bone microarchitecture and strength were assessed with high-resolution peripheral quantitative computed tomography (HRpQCT), microfinite element analysis, and individual trabecula segmentation. RESULTS: In this cohort, 25OHD levels were deficient in 18.1%, insufficient in 35.4% and replete in 46.5%. Those with lower 25OHD levels had higher PTH (P < .0001), were younger (P = .001) and tended to weigh more (P = .053). There were no age-, weight- and sex-adjusted between-group differences (<20 vs 20-29 vs ≥ 30 ng/ml) in any HRpQCT, microfinite element analysis, or individual trabecula segmentation indices. Because few participants had 25OHD below 20 ng/ml, we also compared those with 25OHD below 30 vs at least 30 ng/ml and found only a trend toward lower adjusted cortical vBMD (3.1%, P = .08) and higher cortical porosity (least squares mean ± SEM 7.5 ± 0.3 vs 6.6 ± 0.3%, P = .07) at the tibia but not the radius. Stiffness did not differ at either site. In multiple regression analysis, 25OHD accounted for only three of the 49.2% known variance in cortical vBMD; 25OHD was not significant in the model for cortical porosity at the tibia. CONCLUSION: Low 25OHD levels are associated with higher PTH levels in PHPT, but contrary to our hypothesis, these differences did not significantly affect vBMD or microarchitecture, nor did they result in lower stiffness. Low vitamin D in PHPT using current 25OHD thresholds for insufficiency and deficiency did not significantly affect skeletal integrity as assessed by HRpQCT.

Seasonal Variability in Vitamin D Levels No Longer Detectable in Primary Hyperparathyroidism.

CONTEXT: Seasonal variability in 25-hydroxyvitamin D [25(OH)D] and PTH levels in the general population has been associated with differences in bone turnover markers, bone density, and fracture risk. Seasonal variability in 25(OH)D and PTH levels has also been reported in primary hyperparathyroidism (PHPT). OBJECTIVE: Given the widespread use of vitamin D supplements, we sought to determine whether patients with PHPT still demonstrated seasonal variation in 25(OH)D levels. DESIGN AND SETTING: This cross-sectional study was conducted at a university medical center at a Northeastern U.S. latitude (New York, NY). PATIENTS: One hundred patients with PHPT participated in the study. OUTCOME MEASURES: We assessed vitamin D supplement use and seasonal variation in serum 25(OH)D. RESULTS: Patients had PHPT ([mean ± SD] calcium, 10.8 ± 1.0 mg/dL; PTH, 85 ± 48 pg/mL) with a mean 25(OH)D level of 29 ± 10 ng/mL. Although only one fifth of participants had vitamin D deficiency (19% < 20 ng/mL), more than half were either deficient or insufficient (54% < 30 ng/mL). Sun exposure varied by season, but there were no seasonal differences in levels of 25(OH)D, PTH, bone markers, or bone mineral density, or in the prevalence of 25(OH)D less than 20 or less than 30 ng/mL. Most of the participants (65%) took supplemental vitamin D (dose among users: mean, 1643 ± 1496 IU; median, 1000 IU daily), and supplement users had markedly better vitamin D status than nonusers (25(OH)D < 20 ng/mL: 8 vs 40%; P < .0001; < 30 ng/mL: 40 vs 80%; P = .0001; ≥ 30 ng/mL: 60 vs 20%; P = .0001). CONCLUSIONS: We found no evidence of seasonal variation in 25(OH)D levels or PHPT disease severity in the Northeastern United States. This change is likely due to widespread high vitamin D supplement intake, which has resulted in better vitamin D status among supplement users and can mask the effect of season on serum 25(OH)D levels.

Vitamin D in Primary Hyperparathyroidism: Effects on Clinical, Biochemical, and Densitometric Presentation.

CONTEXT: Vitamin D (25-hydroxyvitamin D [25OHD]) deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common in primary hyperparathyroidism (PHPT), but data regarding their skeletal effects in PHPT are limited. OBJECTIVE: The objective was to evaluate the association between 25OHD levels and PHPT severity. DESIGN, SETTINGS, AND PARTICIPANTS: This is a cross-sectional analysis of 100 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital setting. OUTCOME MEASURES: We measured calciotropic hormones, bone turnover markers, and bone mineral density (BMD) by dual x-ray absorptiometry. RESULTS: Lower 25OHD was associated with some (PTH: r = -0.42; P < .0001; 1,25-dihydroxyvitamin D: r = -0.27; P = .008; serum PO4: r = 0.31; P = .002) but not all (serum/urine calcium) indicators of PHPT severity. Lower 25OHD was also associated with younger age, higher body mass index, male gender, better renal function, and lower vitamin D intake. Comparison of those with deficient (<20 ng/mL; 19%) vs insufficient (20-29 ng/mL; 35%) vs replete (≥30 ng/mL; 46%) 25OHD demonstrated more severe PHPT as reflected by higher PTH (mean ± SEM, 126 ± 10 vs 81 ± 7 vs 72 ± 7 pg/mL; P < .0001) but no difference in nephrolithiasis, osteoporosis, fractures, serum or urinary calcium, bone turnover markers, or BMD after adjustment for age and weight. In women, T-scores at the 1/3 radius were lower in those with 25OHD of 20-29 ng/mL, compared to those who were vitamin D replete (P = .048). In multiple regression modeling, 25OHD (but not PTH) was an independent predictor of 1/3 radius BMD. CONCLUSION: Vitamin D deficiency is associated with more severe PHPT as reflected by PTH levels, but effects on BMD are limited to the cortical 1/3 radius and are quite modest. These data support international guidelines that consider PHPT patients with 25OHD <20 ng/mL to be deficient. However, in this cohort with few profoundly vitamin D-deficient patients, vitamin D status did not appear to significantly impact clinical presentation or bone density.

Abnormalities in cortical bone, trabecular plates, and stiffness in postmenopausal women treated with glucocorticoids.

CONTEXT: The mechanisms by which glucocorticoids (GCs) increase skeletal fragility are not well understood. OBJECTIVE: The objective of the study was to evaluate the microarchitecture, trabecular morphology, and biomechanical properties of bone in postmenopausal women treated with GCs. DESIGN: This was a case-control study. SETTING: The study was conducted at a university hospital outpatient facility. PATIENTS: Postmenopausal women treated with oral GCs for longer than 3 months (n = 30) and age/race-matched controls (n = 60) participated in the study. MAIN OUTCOME MEASURES: Areal bone mineral density aBMD (BMD) by dual-energy x-ray absorptiometry (DXA) was measured. Trabecular and cortical volumetric BMD (vBMD) and microarchitecture by high-resolution peripheral computed tomography of the distal radius and tibia were also measured. Whole-bone stiffness was estimated by finite element analysis. A novel technique, individual trabecula segmentation, was used to evaluate trabecular type (as plate or rod), orientation, and connectivity. RESULTS: DXA T-scores did not differ significantly at any site. GC subjects had significantly lower total, cortical, and trabecular vBMD and thinner cortices, fewer, thinner, more widely, and irregularly spaced trabeculae. They had fewer trabecular plates, fewer axially aligned trabeculae, and lower trabecular connectivity. Differences ranged from 4% to 65% for these trabecular measures and 5% to 17% for the cortical measures. Whole-bone stiffness was significantly lower (11%-16%) in GC subjects. Markers of bone formation (osteocalcin and amino-terminal propeptide of type I procollagen) and resorption (C-telopeptide) were lower in the GC subjects. CONCLUSIONS: Despite similar areal BMD by DXA, GC-treated women had abnormal cortical and trabecular vBMD and microarchitecture at both the radius and tibia, including fewer trabecular plates, a less axially aligned trabecular network, lower trabecular connectivity, thinner cortices, and lower whole-bone stiffness. Further research into these abnormalities as mechanisms for fracture in GC-treated women is warranted.

Skeletal structure in postmenopausal women with osteopenia and fractures is characterized by abnormal trabecular plates and cortical thinning.

The majority of fragility fractures occur in women with osteopenia rather than osteoporosis as determined by dual­energy X­ray absorptiometry (DXA). However, it is difficult to identify which women with osteopenia are at greatest risk. We performed this study to determine whether osteopenic women with and without fractures had differences in trabecular morphology and biomechanical properties of bone. We hypothesized that women with fractures would have fewer trabecular plates, less trabecular connectivity, and lower stiffness. We enrolled 117 postmenopausal women with osteopenia by DXA (mean age 66 years; 58 with fragility fractures and 59 nonfractured controls). All had areal bone mineral density (aBMD) measured by DXA. Trabecular and cortical volumetric bone mineral density (vBMD), trabecular microarchitecture, and cortical porosity were measured by high­resolution peripheral computed tomography (HR­pQCT) of the distal radius and tibia. HR­pQCT scans were subjected to finite element analysis to estimate whole bone stiffness and individual trabecula segmentation (ITS) to evaluate trabecular type (as plate or rod), orientation, and connectivity.Groups had similar age, race, body mass index (BMI), and mean T­scores. Fracture subjects had lower cortical and trabecular vBMD, thinner cortices, and thinner, more widely separated trabeculae. By ITS, fracture subjects had fewer trabecular plates, less axially aligned trabeculae, and less trabecular connectivity. Whole bone stiffness was lower in women with fractures. Cortical porosity did not differ. Differences in cortical bone were found at both sites, whereas trabecular differences were more pronounced at the radius.In summary, postmenopausal women with osteopenia and fractures had lower cortical and trabecular vBMD; thinner, more widely separated and rodlike trabecular structure; less trabecular connectivity; and lower whole bone stiffness compared with controls,despite similar aBMD by DXA. Our results suggest that in addition to trabecular and cortical bone loss, changes in plate and rod structure may be important mechanisms of fracture in postmenopausal women with osteopenia.

Predictors of renal function in primary hyperparathyroidism.

CONTEXT: Current guidelines for parathyroidectomy in primary hyperparathyroidism (PHPT) include an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m(2). Although the biochemical abnormalities associated with PHPT could impair renal function, there are currently no data examining whether more severe hypercalcemia, hypercalciuria, or nephrolithiasis are associated with chronic kidney disease (CKD) in mild PHPT. OBJECTIVE: This cross-sectional study evaluated predictors of renal function in PHPT. DESIGN: This is a case series of PHPT patients with (eGFR < 60 mL/min per 1.73 m(2)) and without (eGFR ≥ 60 mL/min per 1.73 m(2)) CKD. SETTINGS AND PARTICIPANTS: We studied 114 PHPT patients in a university hospital setting. OUTCOME MEASURES: We identified predictors of renal function using multiple linear regression. RESULTS: eGFR was associated with age, hypertension, antihypertensive medication use, fasting glucose, and 25-hydroxyvitamin D. eGFR was positively rather than negatively associated with several PHPT disease severity indices including history of nephrolithiasis, 24-hour urinary calcium excretion, and 1,25-dihydroxyvitamin D but not serum calcium or PTH levels. An eGFR less than 60 mL/min per 1.73 m(2) was observed in 15% (n = 17), all of whom had stage 3 CKD (eGFR 30-59 mL/min per 1.73 m(2)). Those with CKD were older, had higher 25-hydroxyvitamin D levels and lower 1,25-dihydroxyvitamin D levels, and were more likely to be hypertensive than those without CKD. There were no between-group (<60 vs ≥60 mL/min per 1.73 m(2)) differences in serum calcium, PTH, nephrolithiasis, or meeting surgical criteria other than eGFR. Multiple linear regression indicated that age and diastolic blood pressure were negatively associated with eGFR, whereas serum calcium, kidney stones, and alcohol use were positive predictors. Calculation of eGFR using either the Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration equation yielded similar results. CONCLUSIONS: PHPT patients with stage 3 CKD do not have biochemical or clinical evidence of more severe hyperparathyroidism compared with those without CKD. Traditional risk factors, rather than clinical or biochemical indices of PHPT, are associated with lower eGFR in mild PHPT.

Association between serum 25-hydroxyvitamin D level and subclinical cardiovascular disease in primary hyperparathyroidism.

CONTEXT: Vitamin D (25OHD) deficiency may be a modifiable cardiovascular (CV) risk factor. 25OHD insufficiency (20-29 ng/mL) and deficiency (<20 ng/mL) are common in primary hyperparathyroidism (PHPT), but their association with CV disease in PHPT has not been systematically investigated. OBJECTIVE: This study evaluated whether low 25OHD is associated with subclinical CV disease in PHPT. DESIGN: This is a cross-sectional analysis of PHPT patients with and without low 25OHD. SETTINGS AND PARTICIPANTS: We studied 110 PHPT patients in a university hospital setting. OUTCOME MEASURES: We measured carotid intima-media thickness; carotid plaque presence/thickness; carotid strain and stiffness; left ventricular mass index; cardiac systolic and diastolic function; and mitral annular calcification. RESULTS: Low 25OHD levels (<30 ng/mL) were observed in 28%, but only 9% had 25OHD deficiency (<20 ng/mL). In the whole group, 25OHD levels negatively correlated with body mass index (r = -0.33, P = .0005), PTH (r = -0.30, P = .001), calcium (r = -0.29, P = .002), renal function, and PHPT duration. CV indices were normal except for carotid intima-media thickness, stiffness, and plaque thickness, which were increased, regardless of 25OHD status. Isovolumic relaxation time was the only CV measure associated with 25OHD (r = -0.26, P = .01). Those with 25OHD less than 20 ng/mL had more severe PHPT and a higher rate of nephrolithiasis. Those with 25OHD less than 30 ng/mL were younger, had higher body mass index, had lower serum phosphate, and were more likely to be male, nonwhite, and Hispanic. Other than lower tissue Doppler e' and higher isovolumic relaxation time within normal range in those with 25OHD less than 30 vs greater than 30 ng/mL, there were no differences in CV indices using either 25OHD threshold. CONCLUSIONS: Patients with mild PHPT have subclinical carotid abnormalities, but low 25OHD is not associated with abnormal carotid or cardiac measures. To the extent that PTH levels differentiated those with 25OHD less than 20 but not 30 ng/mL, these data support a 25OHD threshold of 20 ng/mL as clinically relevant in PHPT.

Grid analysis improves reliability in follicle counts made by ultrasonography in women with polycystic ovary syndrome.

Poor reliability has been reported when counting the total number of follicles in polycystic ovaries using conventional two-dimensional (2-D) ultrasound viewing methods. In the current study, we report good reliability in follicle counts when observers imposed a programmable grid system over the viewing window. Four observers estimated total follicle counts in 45 ovarian ultrasound scans by compartmentalizing the ovary into 9 to 12 grid sections and performing focused follicle counts per section. The mean number of follicles counted per ovary was 44.6 +/- 2.3. The level of inter-observer agreement when making follicle counts was 0.82 and total follicle counts did not differ among observers. The level of intra-observer agreement was 0.93 which further corroborated the utility of this method for making dependable follicle counts. In summary, the ability to obtain reproducible follicle counts will help to establish reliable diagnostic criteria for polycystic ovarian morphology.