Seminars in Arthritis and Rheumatism

Intra-articular Corticosteroid Injection in Osteoarthritis of the Knee and Hip: Factors Predicting Pain Relief—A Systematic Review

George Hirsch, George Kitas, Rainer Klocke — 2013-01-31

Objectives: Variations in the degree of pain relief reported by patients with osteoarthritis following intra-articular corticosteroid injections are well recognized but the reasons for this are not widely understood and factors which might predict variations in response have not been subjected to systematic review. We set out to review systematically the literature relating to predictors of pain reduction following intra-articular corticosteroid injections in patients with knee and hip osteoarthritis.Methods: Searches were performed using Medline, EMBASE, Web of Knowledge and MeSH search of Pubmed, the last search being performed in August 2012. Search terms included knee osteoarthritis, hip osteoarthritis, corticosteroid and related terms, and intra-articular injection. Papers were selected and reviewed by 2 reviewers. For inclusion, papers were required to describe studies in which patients with osteoarthritis of the knee or hip received intra-articular corticosteroid injection as an intervention, contain clearly defined outcome measures relating to pain and contain analysis relating to predictors of clinical response to treatment.Results: Twenty-one studies met criteria for inclusion from a total of 54 papers reviewed in full. Eight of these related to hip OA and 13 related to knee OA. No factors that were investigated as potential predictors of response, including radiographic grade and clinical or sonographic evidence of inflammation or synovial hypertrophy were supported by strong evidence. The review also identified that several plausible potential predictors had not been studied to date.Conclusions: Previous research has not identified reliable predictors of response to IA corticosteroid injections, a widely practised intervention in knee and hip OA. Further studies are required if this question is to be answered.

Baseline Laboratory Test Abnormalities are Common in Early Arthritis but Rarely Contraindicate Methotrexate: Study of Three Cohorts (ESPOIR, VErA, and Brittany)

2013-01-28

Objective: To evaluate the prevalence of baseline abnormalities in standard laboratory tests in patients with early arthritis and their impact on selection of disease-modifying antirheumatic drugs according to American College of Rheumatology (ACR) recommendations and/or of nonsteroidal anti-inflammatory drugs.Methods: In three cohorts of patients with early arthritis (the ESPOIR, VErA, and Brittany cohorts), we evaluated the prevalence of anemia (hemoglobin <1 3g/dL in men and 12g/dL in women), leukopenia (<3500 per mm3), thrombocytopenia (<150000 per mm3), renal dysfunction (mild, creatinine clearance [CrCl]=60–89.9mL/min; moderate, CrCl=30–59.9mL/min; or severe, CrCl<30mL/min), liver cytolysis (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]>N or>2N), and systemic inflammation (erythrocyte sedimentation rate [ESR]>20 and C-reactive protein [CRP]>6).Results: We evaluated 1393 patients (1018 women and 375 men). Anemia was present in 363/1366 (26.5%) patients, leukopenia in 18/1372 (1.3%), and thrombocytopenia in 13/1371 (0.9%). ESR elevation was seen in 50.4% of patients and CRP elevation in 62.7%. The level of AST was above normal in 4% and of ALT in 10% of patients. No patient had severe renal dysfunction, 5.6% had moderate renal dysfunction, and 42.6% had mild renal dysfunction. Among the 1094 patients who had undergone all the tests, only 18 (1.64%, 95% confidence interval, 1–2.64) had a formal contraindication to methotrexate therapy according to ACR recommendations (4 had leukopenia, 12 had high ALT levels, and 2 had high ALT and AST levels).Conclusion: Patients with recent-onset arthritis often have anemia, mild or moderate renal dysfunction, and abnormal liver function. However, fewer than 2% have laboratory test abnormalities contraindicating methotrexate therapy.

The Interaction of Physical Function and Emotional Well-being in Rheumatoid Arthritis—What is the Impact on Disease Activity and Coping?

2013-01-31

Objective: To evaluate the impact of the interaction of physical function and emotional well-being on disease-related parameters and coping with rheumatoid arthritis.Methods: A cross-sectional survey among 177 RA patients included demographic and disease-related variables as well as the following patient-reported outcome measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) (physical function), Mental Component Summary Scale of the SF-36 (MCSS) for emotional well-being, Rheumatoid Arthritis Disease Activity Index (RADAI), and Coping with Rheumatoid Arthritis Questionnaire (C-RAQ). Based on HAQ-DI and MCSS, six categories representing various levels of physical and emotional impairment were formed. Multivariate analysis of variance and a subsequent discriminant analysis were used to evaluate whether demographic and disease-related variables and coping strategies differed between these categories.Results: Patients with moderate to high impairment of physical function and emotional well-being reported significantly higher disease activity and a more frequent use of distancing and active problem solving coping strategies than patients with low-level impairment (p<0.001–0.043). Furthermore, these patients reported experiencing significantly higher levels of helplessness (p<0.001–0.032). Results from the discriminant analysis highlighted a combination of disease activity and helplessness to differentiate best between patients with either low or high impairment of physical function and emotional well-being (p<0.001).Conclusion: Aside from perceived disease activity, helplessness, and distancing as well as active problem solving allowed for a good discrimination between the different levels of impairment of physical function and emotional well-being. Encouraging and educating patients on how to cognitively reframe their current situation might play a key role in reducing the level of helplessness resulting from impairments of physical function and emotional well-being.

Improvement in Wrist Pain with Ultrasound-guided Glucocorticoid Injections: A Meta-analysis of Individual Patient Data

2013-01-10

Objectives: This meta-analysis compares change in wrist pain following ultrasound-guided (US-guided) intra-articular glucocorticoid injections with change in pain after palpation-guided injections in persons with inflammatory arthritis or osteoarthritis.Methods: Data sources included MEDLINE, Cochrane, BIOSIS, CINAHL, ACR/AHRP abstracts, and ClinicalTrials.gov. Studies that assessed change in wrist pain with direct comparison of US-guided and palpation-guided injections were included in the meta-analysis. Subject-level data was sought from authors of all relevant studies.Primary outcome was mean change in wrist pain from baseline to 1–6 week follow-up by visual analog scale (VAS). Mean difference in VAS was calculated for comparative studies. Secondary outcome was proportion attaining Minimal Clinically Important Improvement (MCII), defined as VAS reduction≥20%. Odds ratios (ORs) of MCII were calculated for comparative studies. Mean differences in VAS and ORs for MCII for comparative studies were combined using fixed and random effects meta-analysis.Results: Ten studies were eligible, and adequate data was available from 4 studies with direct comparison of US-guided and palpation-guided treatment arms. The difference in mean VAS reduction (US-guided minus palpation-guided) ranged from−0.2 to 1.3, with a combined estimate of 1.0 (95% CI 0.3, 1.7). OR for MCII in comparative studies ranged from 1.0 to 12.4, with a combined OR of 3.2 (95% CI 1.2, 8.5) in favor of ultrasound.Conclusions: US-guided glucocorticoid injections to the wrist result in greater reductions in pain, and greater likelihood of attaining MCII than palpation-guided injections at 1–6 weeks follow-up.

Skin Nontuberculous Mycobacterial Infection in Systemic Lupus Erythematosus: An Unusual Skin Infection Mimicking Lupus Vasculitis

Zahi Touma, Amir Haddad, Dafna D. Gladman, Elizabeth M Uleryk, Murray B. Urowitz — 2013-01-18

Objectives: To report 2 cases of skin nontuberculous mycobacteria (NTM) occurring in lupus patients and to systematically review the medical literature addressing skin NTM in lupus.Methods: We reported 2 cases of skin NTM in lupus patients followed at the Toronto Lupus Clinic. We conducted a systematic review of the literature on NTM in lupus patients. Ovid Medline (1946 to March 12, 2012) and Embase (1980 to March 12, 2012) were searched for relevant publications.Results: Of the 1356 retrieved abstracts, 19 publications were identified and 25 cases of skin NTM were extracted. Skin presentations in this review ranged from papules, plaques, and nodules to ulcerative lesions and abscesses. Skin lesions occurred in the setting of active and inactive lupus and while patients were maintained on steroids and sometimes immunosuppressants. The pathogen species included Mycobacterium chelonae, Mycobacterium haemophilum, Mycobacterium kansasii, Mycobacterium avium, Mycobacterium scrofulaceum, Mycobacterium fortuitum, Mycobacterium marinatum, and Mycobacterium szulgai. The duration of antimycobacterial drugs ranged from 3 to 12 months. Skin excision, drainage, and debridement might be required in some cases. Empirical monotherapy was used initially, and the final choice of antibiotics was based on the susceptibility determined in culture. Overall, the outcomes of the skin lesions resulted in either complete recovery or improvement.Conclusions: A high index of suspicion in lupus patients is required to diagnose NTM, as the initial presentation of NTM can mimic lupus skin manifestations.

Ophthalmologic Manifestations of Systemic Necrotizing Vasculitides at Diagnosis: A Retrospective Study of 1286 Patients and Review of the Literature

2012-12-26

Objective: To determine the frequencies and types of ophthalmologic manifestations in patients with systemic necrotizing vasculitides (SNV), including polyarteritis nodosa (PAN) and ANCA-associated vasculitides (granulomatosis with polyangiitis (Wegener's, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA); Churg–Strauss syndrome (CSS)) and review the literature on eye involvement in these diseases.Methods: This retrospective analysis was conducted on the ophthalmologic manifestations of SNV patients entered into the French Vasculitis Study Group database between July 1955 and August 2008.Results: Among the 1286 identified patients, 214 (16.6%) had ophthalmologic manifestations at diagnosis, significantly more often in GPA (117/343, 34.1%) than in EGPA (30/270, 11.1%; P = 0.0001), PAN (42/393, 10.7%; P = 0.0001) or MPA (25/280, 8.9%; P = 0.0001). The 3 most common recorded ophthalmologic manifestations were conjunctivitis (89, (7%)), episcleritis (56, (4%)), and/or blurred vision (44, (3%)), mainly caused by retinal vasculitis in 5, oculomotor nerve palsy in 4, uveitis in 4 and/or optic neuropathy in 3. Orbital inflammatory tumor, another common feature was rather specific to GPA (23/349, 6.6% (P = 0.0001)) compared to other SNV. The literature on ophthalmologic manifestations of SNV is limited to case reports except for GPA, in which the eye involvement frequency ranged from 29% to 57%.Conclusions: Eye manifestations were more common in GPA than MPA, PAN and EGPA, but can be sight-threatening in any SNV. Given the heterogeneity of ophthalmologic involvement in SNV, close collaboration between the ophthalmologists and internists is critical.

Predictors for Outcomes in Patients with Severe ANCA-associated Glomerulonephritis who were Dialysis-dependent at Presentation: A Study of 89 Cases in a Single Chinese Center

Zhi-Ying Li, Shen-Ju Gou, Min Chen, Ming-Hui Zhao — 2013-01-18

Objective: Anti-neutrophilcytoplasmic autoantibody (ANCA)-associated vasculitis may cause rapid deterioration of renal function, resulting in high prevalence of end-stage renal disease and mortality. The current study investigated factors associated with restoration of renal function and early mortality in patients with severe ANCA-associated glomerulonephritis, i.e. dialysis-dependent at presentation, in a single Chinese cohort.Methods: Eighty-nine Chinese patients with ANCA-associated glomerulonephritis who were on dialysis at the time of diagnosis were included in this study. All these patients received immunosuppressive therapy plus intravenous methylprednisolone, plasma exchange, or both. The predictive value of the clinical and histological parameters for renal and patient outcome was analyzed.Result: On the sixth month, 25 (28.1%) patients achieved dialysis independence, 45 (50.6%) patients progressed to end stage renal disease, and 19 (21.3%) patients died. Nine out of the 19 deaths were therapy-related. Factors independently associated with renal function restoration were percentages of normal glomeruli (P<0.05), extent of tubular atrophy (P<0.05) and extent of interstitial fibrosis (P<0.05) in the renal specimens. Age and pulmonary hemorrhage were independently associated with all-cause death (P=0.003 and P=0.007, respectively) and therapy-related death (P=0.037 and P=0.043, respectively).Conclusions: Among patients with severe ANCA-associated glomerulonephritis who were dialysis-dependent at presentation, those with a higher percentage of normal glomeruli and less extent of tubular atrophy/interstitial fibrosis have more chance of restoration of renal function. Increased risk for all-cause death and therapy-related death appears to be older age and pulmonary hemorrhage.

Lactulose Breath Test to Assess Oro-cecal Transit Delay and Estimate Esophageal Dysmotility in Scleroderma Patients

2013-01-28

Objectives: To assess the correlation between delayed oro-cecal transit time (OCTT) and esophageal motility abnormalities in a cohort of systemic sclerosis (SSc) patients.Methods: We prospectively enrolled 50 consecutive SSc patients and 60 healthy volunteers (HVs) as controls. Both groups underwent glucose breath test (GBT) to exclude small intestine bacterial overgrowth, lactulose hydrogen, and octanoic acid breath tests (LHBT and OBT) to measure OCTT and gastric emptying (GE), respectively, and manometry to assess esophageal motility.Results: Thirty-one (63%) SSc patients presented ineffective esophageal motility (IEM) compared with 3 HVs (5%; P<0.01), 37 (74%) had an abnormal OCTT compared with 4 HVs (7%; P <0.01), and 16 (32%) had an altered GE compared with 4 HVs (7%; P <0.01). The median OCTT and gastric t½ were longer in SSc than in HVs (165min vs. 101min and 125min vs. 78min, respectively; P <0.01). A delayed GE was present in 12/37 (32%), whereas IEM in 27/37 (73%) SSc patients with prolonged OCTT. The prevalence of IEM increased in parallel with the prolongation of OCTT (31% when OCTT<150min, 73% when OCTT≥150min, and up to 85% when OCTT>180min, P<0.01).Conclusions: Abnormalities of both esophageal and small intestine motility are frequent in SSc patients and esophageal motility is altered in most cases with small bowel involvement. Delayed GE plays a limited role in prolonging OCTT. LHBT is a non-invasive, cheap, well-tolerated diagnostic tool that may be useful to estimate intestinal involvement and also to estimate a higher risk of esophageal hypomotility in SSc patients.

Estimating the Prevalence of Systemic Sclerosis in the Lorraine Region, France, by the Capture–recapture Method

2013-01-03

Objective: To assess the prevalence of systemic sclerosis (SSc) in the Lorraine region, France.Methods: Data from three sources – general practitioners and community and hospital specialists, medical records departments, and regional and national laboratories−and a capture–recapture method with log-linear models were used to estimate SSc prevalence in the region. Double recording was checked, and reported cases were validated after a review of medical records.Results: We identified 560 records of suspected SSc cases corresponding to 327 unique suspected SSc cases existing on June 30, 2006, in Lorraine. On the basis of the 193 validated cases (22 [11.4%] with diffuse disease, 136 [70.5%] with limited disease, 31 [16.1%] with limited involvement and 4 unknown), the observed overall crude prevalence of SSc was 105.4 cases per million adult inhabitants (95% confidence interval [CI]: 91.0; 121.4). With the capture–recapture method, the estimated number of SSc cases was 233 (95% CI: 217.3; 260.0), so an estimated 40 cases were not identified by the three sources. The estimated overall prevalence was 132.2 cases per million adult inhabitants (95% CI: 115.8; 154.0).Conclusions: Our study provides the first estimate of SSc prevalence in the Lorraine region. The capture–recapture method allowed us to estimate an additional 21% of unobserved cases and is a good alternative to the community-based study design for estimating the prevalence of rare diseases.

Childhood Obesity Case Statement

Paul W. Esposito, Paul Caskey, Lisa E. Heaton, Norman Otsuka — 2013-01-28

Objective: The goal of this publication is to raise awareness of the impact of childhood obesity on the musculoskeletal health of children and its potential long-term implications.Methods: Relevant articles dealing with musculoskeletal disorders either caused by or worsened by childhood obesity were reviewed through a Pub Med search. Efforts to recognize and combat the childhood obesity epidemic were also identified through Internet search engines. This case statement was then reviewed by the members of the pediatric specialty group of the US Bone and Joint Initiative, which represents an extensive number of organizations dealing with musculoskeletal health.Results: Multiple musculoskeletal disorders are clearly caused by or worsened by childhood obesity. The review of the literature clearly demonstrates the increased frequency and severity of many childhood musculoskeletal disorders. Concerns about the long-term implications of these childhood onset disorders such as pain and degenerative changes into adulthood are clearly recognized by all the member organizations of the US Bone and Joint Initiative.Conclusions: It is imperative to recognize the long-term implications of musculoskeletal disorders caused by or worsened by childhood obesity. It is also important to recognize that the ability to exercise comfortably is a key factor to developing a healthy lifestyle and maintaining a healthy body weight. Efforts to develop reasonable and acceptable programs to increase physical activity by all facets of society should be supported. Further research into the long-term implications of childhood musculoskeletal disorders related to childhood obesity is necessary.

Rare Bone Disease Research ‐ Future Directions: A Symposium Devoted to a Discussion of Rare Bone Diseases

2013-04-01

Fibrous dysplasia of bone

Michael T. Collins — 2013-02-11

Fibrous dysplasia (FD) is caused by somatic mutations in GNAS and activation of the cAMP-regulating protein, Gs alpha (gsp). gsp inhibits differentiation of stem cells to mature osteogenic cells, resulting in replacement of normal bone with a highly proliferative stroma composed of cells that express osteogenic markers. Apoptosis follows, leaving affected regions with bone that may no longer harbor significant numbers of mutated cells, but is deformed and mechanically unsound. Key features of FD that relate to the pathophysiology are overexpression of the bone remodeling proteins RANK/RANKL and the mineral metabolism-regulating hormone, FGF23. Extraskeletal manifestations include a number of hyperfunctioning endocrinopathies, which can worsen FD. The mainstay of treatment for FD is surgical. Outcomes have improved due to a better understanding of the natural history of FD, improvement in surgical techniques and devices, and recognition that curettage with bone grafting is often futile. Bisphosphonates effectively relieve bone pain and there are promising preliminary data that the anti-RANKL drug denosumab may be beneficial. An effort is underway at the NIH to identify molecules that target gsp, with the goal to develop drugs to treat FD and associated endocrinopathies. Hope for further progress resides in continued support of ongoing research, establishment of an international network of investigators/centers of excellence, and compilation and sharing of high-quality data – best accomplished through integrated and collaborative efforts involving government agencies, academic centers, cohesive patient-based support groups, and industry.

Albright hereditary osteodystrophy: Current progress and new frontiers

Emily L. Germain-Lee, Lee S. Weinstein — 2013-02-11

Albright hereditary osteodystrophy (AHO) is a rare genetic disorder characterized by phenotypic abnormalities including brachydactyly, brachymetacarpia, short stature, subcutaneous ossifications, and dental abnormalities. This disorder is caused by heterozygous, inactivating mutations in GNAS, the gene encoding the alpha chain of the heterotrimeric G protein, Gs, that couples with receptors for many hormones and neurotransmitters for the activation of adenylyl cyclase. Transcripts encoding Gαs are preferentially expressed from the maternally inherited allele in the renal proximal tubule, thyroid, gonad, and pituitary. AHO patients who have GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones (including PTH, TSH, gonadotropins, and GHRH) as well as obesity and cognitive deficits. This condition is termed pseudohypoparathyroidism type Ia (PHP Ia) and is due to tissue-specific paternal imprinting. Conversely, patients with AHO and GNAS mutations on their paternally inherited alleles have no evidence of hormonal resistance, are typically not obese, and cognitive function may be normal. This condition is termed pseudopseudohypoparathyroidism (PPHP). Current knowledge as well as the research in progress in both humans and mouse models regarding the major clinical problems in AHO will be reviewed. Dr. Germain-Lee will focus on her past and current research involving clinical trials with growth hormone in patients with AHO, as well as her research on the heterotopic ossifications that develop in this condition, which she is examining through the use of a mouse model. Her research on the etiology and mechanisms underlying the formation of the heterotopic ossifications has broader implications in terms of the potential to understand more about the mechanisms of osteogenesis overall. In addition, Dr. Germain-Lee will discuss her clinical findings related to the severe obesity in pseudohypoparathyroidism type Ia; this severe obesity is not present in pseudopseudohypoparathyroidism. Dr. Weinstein will discuss his basic science research on metabolism and obesity in AHO, which is based on his studies of his mouse models of this condition. In addition, he will discuss his current ongoing clinical studies of obesity and metabolism in AHO.

Hypophosphatasia

Michael Whyte — 2013-02-11

Hypophosphatasia (HPP) reveals a critical role for the “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP) in skeletal mineralization. Its biochemical hallmark, subnormal serum ALP activity, results from loss-of-function mutation(s) within TNSALP, the gene that encodes TNSALP. HPP spans an extraordinary range of severity partly explained by autosomal recessive versus autosomal dominant or recessive transmission causing severe and mild HPP, respectively. Perinatal HPP is usually fatal due to profound skeletal hypomineralization. Infantile HPP presents before the age of 6 months with rickets, failure-to-thrive, and sometimes hypercalcemia, craniosynostosis, or vitamin B6-responsive seizures. Respiratory failure and death often follow progressive chest deformity. Childhood HPP features loss of deciduous teeth from cementum hypoplasia, rickets, and weakness from static myopathy. Adult HPP causes osteomalacia with fractures and sometimes, inorganic pyrophosphate (PPi) deposition leading to arthropathy. Odonto-HPP refers to premature tooth loss alone. Discovery of phosphorethanolamine (PEA), PPi, and pyridoxal 5′-phosphate (PLP) accumulation in HPP demonstrated that TNSALP hydrolyzes several substrates of nanomolar or micromolar concentrations, and therefore is at much lower levels than the artificial substrates and pH of laboratory assays. Thus, “alkaline phosphatase” is a misnomer. Vitamin B6 disturbances in HPP reveal that TNSALP is a cell-surface enzyme. Membrane-impermeable PLP accumulates in plasma, but normal plasma concentrations of its hydrolysis product PL explain absence of symptoms of vitamin B6 deficiency or toxicity in all but the most severely affected HPP babies who can have vitamin B6-responsive seizures. PEA may derive from the GPI anchor for many cell-surface proteins. In HPP, hydroxyapatite (HA) crystals form normally in matrix vesicles (MVs) during “primary mineralization”, but excess PPi inhibits their growth after MVs rupture during “secondary mineralization” causing rickets or osteomalacia. Bone-targeted recombinant TNSALP therapy is emerging as an effective treatment.

Fibrodysplasia ossificans progressiva (FOP): A disorder of extraskeletal endochondral ossification

Eileen M. Shore — 2013-02-11

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder in which extraskeletal bone forms in soft connective tissues, initiating during childhood and continuing throughout adult life. This heterotopic bone is qualitatively normal and forms through endochondral ossification. Episodes of bone formation often occur in response to injury. In addition to heterotopic ossification, FOP is associated with altered skeletal development, the most characteristic of which is malformation of the great toes. All FOP patients that we have examined carry mutations in ACVR1, the gene encoding the ALK2 BMP type I receptor. Most patients are heterozygous for the same mutation in codon 206 (R206H) in the GS domain of the receptor. This ACVR1/ALK2 mutation induces mild constitutive activation of the BMP pathway and enhances signaling in response to BMP. The identification of the causative gene in FOP, together with the development of in vivo and in vitro models for heterotopic ossification and mesenchymal cell differentiation, is providing opportunities to understand the cellular and molecular mechanisms that regulate chondrogenesis and osteogenesis and control the pathological induction of heterotopic bone formation. This knowledge will lead to novel approaches to modulate BMP signaling and bone formation and to the development of treatments for FOP and other disorders of bone and cartilage.

X-Linked hypophosphatasia syndromes (XLH): Update on XLH research; gaps in knowledge

Michael Econs — 2013-02-11

Pathogenesis of MHE: Recent advances and prospects for therapies

Maurizio Pacifici — 2013-02-11

Multiple hereditary exostoses (MHE) is a congenital autosomal-dominant disorder caused by mutations in the Golgi-associated heparan sulfate (HS)-synthesizing enzymes, EXT1 or EXT2, leading to HS deficiency throughout the body. The disease is characterized by the presence of exostoses (known also as osteochondromas) that are cartilage-capped outgrowths forming next to, but never within, the growth plates of limb and trunk skeletal elements. The exostoses interfere with growth plate function and the MHE children could display growth retardation and skeletal deformities, as well as chronic pain, impingement of nerves and tendons, urinary obstruction, or other symptoms. To elucidate the mechanisms of exostosis formation and growth, we have created mouse models in which Ext1 or Ext2 were ablated broadly or conditionally. We will describe published and unpublished data from our recent studies that provide insights into the genesis and preferential anatomical location of the exostoses in the growing skeleton. In particular, the data suggest that the exostoses are triggered by a redistribution and aberrant activation of prochondrogenic signaling proteins within the growth plate and/or adjacent perichondrium, with the possible involvement and recruitment of local progenitor cells including those in the groove of Ranvier. We will also present data from in vitro cellular studies that provide insights into underlying biochemical and molecular mechanisms. Our studies are leading to a better understanding of MHE pathogenesis and point to prospects for possible future therapies.

Osteogenesis imperfecta: Bench to bedside

Jay R. Shapiro, Emily L. Germain-Lee — 2013-02-11

The Bench: There has been a significant expansion in our understanding of the molecular biology of OI. The number of genes responsible for the disorder has increased from 2 (COL1A1 and COL1A2) in 2007, to 9 in 2012 (CRTAP, LEPRE1, PPIB, Hsp47/SERPINH1, SERPINF1, FKBP10 and most recently, adding IFITM5). Also, there has been additional categorization of clinical OI types since Sillence first recognized 4 OI types in 1978. An issue is the nosology of OI: should that be based on each mutation or should a broad clinical classification be retained? Although multiple mutations have been defined, we have not progressed in our understanding of how each mutation translates to disordered bone and connective-tissue cell function. Although mutations alter osteoblast type I collagen synthesis, the effects on osteoblast cell biology, for example on cell growth, are undefined. The question of genotype/phenotype relationships is exemplified by the wide clinical variability seen in the phenotypic of OI type V where there is apparent consistency in expression of the mutation IFITM5, (genotype) among affected kindreds, more so than occurs in other OI types where multiple mutations are expressed in a particular OI phenotype.The Bedside: Two clinical issues which are interrelated are: (a) Understanding the pain syndrome in OI, and (b) the status of fracture prevention treatment for children and adults: this includes considerable variability among centers in drug selection (pamidronate vs. zoledronic acid), drug doses which vary from 4 to 9mg/kg/year in children, and treatment schedules which vary from 4 to 6 months, particularly in children who have already had several years of treatment.

Gorham-Stout disease and generalized lymphatic anomalies

Cameron C. Trenor, Matthew L. Warman — 2013-02-11

We postulate that there exist two distinct lymphatic malformation disorders that affect bones and cause significant morbidity and mortality. Gorham-Stout disease (G-SD) is characterized by the progressive disappearance of trabecular and cortical bone. Generalized lymphatic anomaly (GLA) is characterized by missing areas within trabecular bone and sparing of cortical bone. It is likely that both diseases have a genetic etiology because they often affect multiple noncontiguous sites; however, neither disease is heritable. Both disorders cause focal skeletal fragility. Pleural, pericardial, and peritoneal effusions also frequently complicate these conditions. Case reports and small series suggest that radiation and medical therapies (predominantly interferon and/or bisphosphonates) can stabilize progressive disease. These studies are limited by inconsistent phenotyping, variation in length of therapy and follow-up, and publication bias. We performed a retrospective study of 102 patients who have been referred to our center (24 with G-SD and 78 with GLA). Our data suggest medical therapies may allow remineralization; however, we do not know whether all patients benefit or whether those that do have sustained improvement. Important next steps include a thorough study of natural history and responses to therapy in large patient cohorts, prospective interventional trials with clearly defined outcome measures, and discovery of the genetic cause(s). Recent technologic and analytic advances in DNA and RNA sequencing, improvements in recreating human disease-causing mutations in model organisms, and in high-throughput screening for new therapeutic agents create optimism that the scientific and medical community will soon achieve a detailed understanding of the causes of G-SD and GLA and devise improved therapies for patients.

Melorheostosis

Michael Whyte — 2013-02-11

Melorheostosis (MEL) refers to “flowing hyperostosis” (dense bone), typically in the limbs, appearing radiographically like wax dripping down a candle. Reports of ∼200 cases show sporadic occurrence (not inherited), although MEL can appear in the genetic “spotted bone” disorders, osteopoikilosis (OPK) and Buschke-Ollendorff syndrome (BOS). MEL typically presents during childhood in one limb, and otherwise is asymmetrical. Skin changes may overlie dense bone and can include scar-like tissue, excessive hair, and small blood vessels. The collagen appears normal, i.e., linear melorheostotic scleroderma. Pain and stiffness are major symptoms. Affected joints can contract and deform. Leg-length inequality sometimes occurs from soft-tissue contractures or premature fusion of growth plates. The skeletal lesions seem to progress most during childhood. In adults, MEL may gradually extend, but pain is especially frequent. Thickening of the inner cortical bone occurs during childhood, and then at the surface during adulthood. Irregular, eccentric, osteosclerosis is the radiographic consequence. Any bone may be affected, but most commonly within lower limbs. Ectopic bone can develop, particularly near joints. MEL bone is hyperemic and causes a “hot” bone scan. Routine biochemical studies are unremarkable. Its anatomic distribution in sclerotomes, myotomes, and dermatomes suggests a segmentary defect during embryogenesis. Linear scleroderma may reflect the primary abnormality that descends into bone. Affected skin has an altered expression of several adhesion proteins. Germline mutation of LEMD3 causes OPK and BOS, but not classic MEL. Contractures or neurovascular compression can require surgery, but it is challenging and recurrent deformity is common. Distraction techniques have been promising.

Studies of osteoclast pathogenesis of craniometaphyseal dysplasia (CMD) in a mouse model and in patient-specific IPS cells

2013-02-11

Rare genetic bone disorders are of significant clinical relevance because of their number and their life-time debilitating impact on patients. Treatment options are often limited due to insufficient knowledge of their pathogenesis. Studies have been plagued by the unavailability of primary cells/tissues and suitable animal models. Patient-specific induced pluripotent stem (iPS) cells offer new avenues for studying bone cells from patients with rare diseases. We study craniometaphyseal dysplasia (CMD) utilizing a knock-in mouse model and patient-specific iPS cells. CMD is characterized by hyperostosis of craniofacial bones concurrent with widened metaphyses in long bones. Mutations for autosomal dominant CMD have been identified in the ANK gene (ANKH). A knock-in (KI) mouse model expressing a human Ank mutation (Phe377del) replicates many features of CMD. We observed defects in AnkKI/KI osteoclast (OC) cultures including (1) decreased OC formation; (2) reduced mineral resorption; (3) reduced OC migration shown by live-cell time-lapse imaging; and (4) altered podosome organization. The bone mass phenotype of AnkKI/KI mice is partially rescued by wild-type bone marrow transplants. We hypothesize that CMD-causing ANKH mutations decrease the osteoclast activity by negatively affecting the actin cytoskeleton. Our ultimate goal is to test this hypothesis in the human system using patient-specific inducible pluripotent stem cells (iPSCs). We derived iPSCs from peripheral blood mononuclear cells of CMD patients and healthy controls with four separate Sendai-virus vectors encoding OCT3/4, SOX2, KLF4, and c-MYC. The Sendai virus, a cytoplasmic RNA vector, can produce iPSCs free of vector integration into chromosomes. The pluripotency of these iPSCs is tested by (1) expression of hES cell markers; (2) embryoid body formation; and (3) teratoma formation and normal karyotypes are confirmed. iPSCs from a normal control have already been differentiated into multinucleated TRAP-positive OC-like cells. We are currently differentiating OCs from CMD iPSCs and comparing OCs derived from CMD to normal iPSCs. We expect that combining mouse data with findings from human iPS cells will significantly increase our understanding of the CMD pathology. If successful, I believe that this model can serve as paradigm to study other rare genetic skeletal disorders.

The phosphate-lowering effect of nicotinamide is offset by reduced Fgf23 levels in a murine model of familial tumoral calcinosis

Shoji Ichikawa, Austin M. Reilly — 2013-02-11

Familial tumoral calcinosis is caused by mutations in the GALNT3 gene. Lack of GalNAc transferase 3, encoded by GALNT3, destabilizes FGF23, a key hormone that suppresses phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis in the kidney. The destabilized FGF23 is more susceptible to proteolytic cleavage, thereby reducing the secretion of biologically active intact FGF23. Persistent hyperphosphatemia due to decreased FGF23 concentrations leads to often large, ectopic calcific masses in soft tissues, which are usually removed surgically. However, the calcific masses often recur, requiring a more permanent solution to the problem. Nicotinamide is reported to lower serum phosphate by decreasing type IIb sodium-dependent phosphate cotransporter in the gut. This effect of nicotinamide has promoted its use in treatment of limited cases of tumoral calcinosis, though its effectiveness remains largely unclear. Therefore, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease – Galnt3 knockout mice. Initially, nicotinamide (doses 0, 2.5, 5, 7.5, and 10mmol/kg/day) was given to normal mice for 2 weeks. Treatment had no effect on serum phosphate levels; however, Fgf23 was decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (10mmol/kg/day) was tested for 4 weeks in Galnt3 knockout mice on a high-phosphate diet. The radiographic data pretreatment and posttreatments showed that the treatment did not eliminate the calcification, but retarded its growth, while in the untreated mice, calcifications increased in size. The therapy did not change serum phosphate levels despite moderately increased phosphate excretion, likely due to decreased serum intact Fgf23 levels. Quantification of calcium and phosphate contents in hearts and kidneys revealed that the treated mice had significantly high calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels because the phosphate-lowering effect of nicotinamide was diminished by reduction in intact Fgf23 concentrations. The increased calcium in the heart suggests that nicotinamide therapy may also have an adverse effect.

Enchondroma resulting from loss of a Stk11-dependent switch of proliferative chondrocytes to a postmitotic fate

Lick Pui Lai — 2013-02-11

Stk11 (also known as liver kinase b1 (Lkb1)) is a serine-threonine protein kinase that acts upstream of the AMP-activated protein kinase (AMPK) family in coupling energy homeostasis to cell growth, proliferation and survival. Through chondrocyte-specific removal of Lkb1 activity, we showed that Stk11 is required for the normal switch of mitotic chondrocytes to a postmitotic hypertrophic chondrocyte fate. Consequently, it led to a dramatic overgrowth of the growth plate in the Stk11-mutant postnatal skeletal elements. To determine the molecular mechanisms underlying Stk11 action, we examined the mTOR pathway, which is inhibited through AMPK in growth regulation. Strikingly, rapamycin treatment of the pregnant mouse was able to rescue the delay in chondrocyte hypertrophy in Stk11-mutant embryos, suggesting that Stk11 inhibition of mTOR signaling is critical for the switch in chondrocyte fate. Since the dramatic overgrowth of the growth plate is characteristic of enchondroma, we also examined the tumorigenicity of the mutant chondrocytes both in vitro and in vivo. In contrast to wild-type chondrocytes isolated from the postnatal day-30 growth plate, Stk11-mutant chondrocytes proliferated and formed colonies in monolayer and anchorage-independent agar cultures, indicative of a neoplastic transformation in vitro. Similarly, allotransplantation of mutant chondrocytes into immune-deficient NOG mice also resulted in tumor formation in vivo. Gene Ontology analysis of gene expression profiles indicated an augmented activity of cell proliferation and cell cycle regulators within the enchondroma-chondrocyte population compared to chondrocytes in the normal growth plate. Taken together, these data demonstrated an unexpected role of Stk11 in balancing proliferative and nonproliferative hypertrophic states of chondrocyte development through the regulation of mTOR signaling. Stk11 is a known tumor suppressor; our findings raise the possibility that loss of Stk11 may play a role in human enchondroma, a possibility that we are investigating.

Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in Hyp mice

2013-02-11

Enthesopathy is a common feature of X-linked hypophosphatemia (XLH). We have previously shown that the enthesopathy is recapitulated in Hyp mice, a murine model of XLH, and is characterized by significant hyperplasia of mineralizing fibrochondrocytes that coexpress FGFR3/klotho. It is unclear, however, whether it occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels and what is the underlying pathophysiology. Here, we describe two brothers of Lebanese origin with autosomal-recessive hypophosphatemic rickets (ARHR) due to the Met1Val (M1V) mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized enthesopathy. These data suggest that mineralizing enthesopathy is a feature common to phosphate-wasting disorders mediated by FGF23. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). Mice have a biochemical profile and phenotypic traits akin to phosphate-wasting disorders attributed to FGF23. We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions evident by 12 weeks, the period of developmental maturity. The enthesopathy (expressed as a percentage of total enthesis area) is characterized by an expansion of alkaline phosphatase-positive fibrochondrocytes embedded in a mineralized matrix (wild-type mice, 0.75 ± 0.5%; FGF23-TG mice, 15.1 ± 3.4%, p < 0.01; Hyp mice, 21.1 ± 2.1%, p < 0.01). The standard therapy for phosphate-wasting disorders is oral phosphate and calcitriol. However, the impact of treatment on enthesophyte progression is unknown. We thus treated Hyp mice with phosphate (1.93g phosphate/L water) and 1,25(OH)2D3 (0.175μg/kg/day) from weeks 3 to 12. We found that the mineralizing enthesopathy persisted despite the improving bone mass. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 while minimizing both the toxicities and potential morbidities associated with standard therapy.

Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta

Benjamin Sinder — 2013-02-11

Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia, easy susceptibility to fracture, and skeletal deformities. Current treatment options for OI focus on antiresorptive bisphosphonates which have been shown to be effective at increasing vertebral areal bone mineral density and height in clinical trials. However, bisphosphonate effects in long bones are less evident and most pediatric OI trials observe little or no functional benefit. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin is a negative regulator of the Wnt pathway, and a neutralizing sclerostin antibody (Scl-Ab) therapy has proven to be strongly anabolic in other rodent fragility models as well as initial clinical trials. Whether Scl-Ab therapy is capable of stimulating osteoblast activity in animals harboring a typical OI-causing mutation has yet to be demonstrated. The purpose of this project was to evaluate Scl-Ab in a Brtl/+ mouse model of type IV OI with a Gly349Cys mutation on col1a1.We initially sought to determine whether Brtl/+ osteoblasts would respond to short-term Scl-Ab therapy in vivo. Starting with the most well-characterized age in Brtl/+, we treated 8-week old WT and Brtl/+ for 2 weeks with 25mg/kg of Scl-Ab. Scl-Ab proved anabolic and significantly elevated serum osteocalcin levels and also increased periosteal cortical bone-formation rate as measured by dynamic histomorphometry in both WT and Brtl/+ mice. Despite the short-term treatment, Scl-Ab significantly improved cortical bone mass as measured by microCT, which led to greater whole-bone femoral strength as measured by mechanical testing. Fluorescent-guided nanoindentation revealed that Scl-Ab did not change the tissue elastic modulus of the bone formed during the treatment period.These positive results led us to pursue studies of longer term Scl-Ab therapies (5 weeks) at both adult (6 months) and pediatric (3 weeks) ages in Brtl/+. Initial results from these studies in both 6-month and 3-week old Brtl/+ mice indicate that Scl-Ab is strongly anabolic and significantly increases cortical bone mass as well as whole-bone mechanical strength in the femur. In conclusion, Scl-Ab was successfully anabolic in Brtl/+ mice harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in OI.

Masthead

2013-04-01

Current Abstracts

2013-04-01

Seminars in Arthritis and Rheumatism

Intra-articular Corticosteroid Injection in Osteoarthritis of the Knee and Hip: Factors Predicting Pain Relief—A Systematic Review

Baseline Laboratory Test Abnormalities are Common in Early Arthritis but Rarely Contraindicate Methotrexate: Study of Three Cohorts (ESPOIR, VErA, and Brittany)

The Interaction of Physical Function and Emotional Well-being in Rheumatoid Arthritis—What is the Impact on Disease Activity and Coping?

Improvement in Wrist Pain with Ultrasound-guided Glucocorticoid Injections: A Meta-analysis of Individual Patient Data

Skin Nontuberculous Mycobacterial Infection in Systemic Lupus Erythematosus: An Unusual Skin Infection Mimicking Lupus Vasculitis

Ophthalmologic Manifestations of Systemic Necrotizing Vasculitides at Diagnosis: A Retrospective Study of 1286 Patients and Review of the Literature

Predictors for Outcomes in Patients with Severe ANCA-associated Glomerulonephritis who were Dialysis-dependent at Presentation: A Study of 89 Cases in a Single Chinese Center

Lactulose Breath Test to Assess Oro-cecal Transit Delay and Estimate Esophageal Dysmotility in Scleroderma Patients

Estimating the Prevalence of Systemic Sclerosis in the Lorraine Region, France, by the Capture–recapture Method

Childhood Obesity Case Statement

Rare Bone Disease Research ‐ Future Directions: A Symposium Devoted to a Discussion of Rare Bone Diseases

Fibrous dysplasia of bone

Albright hereditary osteodystrophy: Current progress and new frontiers

Hypophosphatasia

Fibrodysplasia ossificans progressiva (FOP): A disorder of extraskeletal endochondral ossification

X-Linked hypophosphatasia syndromes (XLH): Update on XLH research; gaps in knowledge

Pathogenesis of MHE: Recent advances and prospects for therapies

Osteogenesis imperfecta: Bench to bedside

Gorham-Stout disease and generalized lymphatic anomalies

Melorheostosis

Studies of osteoclast pathogenesis of craniometaphyseal dysplasia (CMD) in a mouse model and in patient-specific IPS cells

The phosphate-lowering effect of nicotinamide is offset by reduced Fgf23 levels in a murine model of familial tumoral calcinosis

Enchondroma resulting from loss of a Stk11-dependent switch of proliferative chondrocytes to a postmitotic fate

Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in Hyp mice

Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta

Masthead

Table of Contents

Current Abstracts