scholarly journals AB0781 ONE, NONE, MANY: REFLECTIONS ON A RARE CASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1416.2-1416
Author(s):  
G. Sandri ◽  
L. Belletti ◽  
M. Cavedoni ◽  
C. Galluzzo ◽  
S. Bruni ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Autoimmune Diseases ◽  
Short Stature ◽  
Rare Diseases ◽  
Bone Development ◽  
Therapeutic Interventions ◽  
Cardiac Conduction ◽  
Bone Lesions ◽  
The European Union ◽  
Early Puberty

Background:Rare diseases are all those diseases that present, in the European Union, a prevalence of less than 5 cases per 10,000 people. The number of rare diseases is estimated at roughly 7,000 but there are also longstanding medical conditions that elude diagnosis and could be identified as rare.Objectives:Demonstrate the importance of international research in orphan diseases.Methods:We report a case of 44 y/o female patient who arrived to our observation in 2006. Short stature, early puberty, ligament laxity, BMI <17. From the age of 29: recurrent diarrhea, pain in the spine, osteolytic lesions in spine and endosteal thickening in long bones, muscle contractures, strength deficit, muscular hypotrophy and hypotonia, cardiac conduction and blood pressure disorders, demyelinating MS-lesions, hyperprolactinaemia, slow wound healing, sicca syndrome, osteoporosis. No familiarity for bone lesions. In 2007 her first son (21y/o) began to complain pain at limbs. The young man presented the same bone lesions as the mother and shortening of the PR, prolactinoma, recurrent diarrhea, short stature, early puberty. Over the years numerous pathologies have been first hypothesized and then excluded: multiple sclerosis, bone metastases, Paget’s disease, celiac disease, McCune Albright, Camurati-Engelmann syndrome, mitochondrial disease. No conclusive diagnosis despite the thousands of kilometers traveled, the numerous experts heard and the countless examinations carried out by the patients.Results:In September 2009, the patients had been investigated at the NIH (Washington D.C.) during the “Undiagnosed Diseases Program” but without results until 2013 when the patients were informed of the detection of an ATP6V1H gene mutation never described before in humans. The gene encodes a vacuolar ATPase, a multimeric enzyme that plays several roles: is involved in endocytosis, intracellular trafficking, and protein degradation and energy production, appears to be a risk factor in the development of dyslipidemias and type II diabetes, has a bone resorption function. Also in the patient’s father were founded the same mutation and asymptomatic bone lesions. In 2016 and 2017 studies have reported mouse models of osteoporosis that were generated by knocking out the ATP6V1H gene.Conclusion:from this case it is possible to understand the difficulty of diagnosing a rare disease, the need of an international collaboration in research. From these studies it can be deduced moreover that the ATP6V1H gene could be an important target for therapeutic interventions aimed at preventing bone resorption and treating osteoporosis; evidence to support exploration of MMP9 and MMP13 as therapeutic targets for patients with ATP6V1H deficiency.This mutation seems to affect only one family, but it is possible that the penetrance of the disease-causing mutation is variable. In literature is reported an enhanced expression of MMP-9 in a variety of autoimmune diseases and neurological pathologies (2) therefore the mutation can be at the basis of other much more common pathologies.References:[1]Zhang Y, Huang H, Zhao G, Yokoyama T, Vega H, Huang Y, Sood R, Bishop K, Maduro V, Accardi J, Toro C, Boerkoel CF, Lyons K, Gahl WA, Duan X, Malicdan MC, Lin S. ATP6V1H Deficiency Impairs Bone Development through Activation of MMP9 and MMP13. PLoS Genet. 2017 Feb 3;13(2):e1006481. doi: 10.1371/journal.pgen.1006481.[2]Ram M, Sherer Y, Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol. 2006 Jul;26(4):299-307. doi: 10.1007/s10875-006-9022-6.Disclosure of Interests:Gilda Sandri: None declared, Lorenza Belletti: None declared, Michele Cavedoni: None declared, Claudio Galluzzo: None declared, stefano bruni Consultant of: Genzyme, Employee of: Genzyme, Maria Teresa Mascia: None declared

scholarly journals THU0080 PRECLINICAL CHARACTERIZATION OF TLL018, A NOVEL, HIGHLY POTENT AND SELECTIVE JAK1/TYK2 INHIBITOR FOR TREATING AUTOIMMUNE DISEASES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 252.1-252
Author(s):  
X. Liu ◽  
F. Tan ◽  
C. Liang
Keyword(s):  
Bone Resorption ◽  
Autoimmune Diseases ◽  
Whole Blood ◽  
Significant Inhibition ◽  
Clinical Development ◽  
Therapeutic Window ◽  
Collagen Induced Arthritis

Background:Janus kinases (JAKs) are important regulators of intracellular responses triggered by many key proinflammatory cytokines and are clinically validated therapeutic targets for treating various autoimmune diseases. However, current approved JAK inhibitors failed to achieve maximal clinical benefit in part due to their unfavorable selectivity for individual JAKs such as JAK2 and/or JAK3, leading to dose-limiting toxicities or severe toxicities (e.g., thrombosis, anemia, immune suppression). Selective inhibition of JAK1 and/or TYK2 may minimize or avoid some of the toxicities and potentially offer a better therapeutic window for treating autoimmune diseases. No highly selective JAK1/TYK2 inhibitor has been reported to date.Objectives:Discovery of a highly selective JAK1/TYK2 inhibitor that maximally avoids JAK2 and JAK3 inhibition. We described preclinical characterization of a novel, highly potent and selective JAK1/TYK2 inhibitor TLL018 and its potential utility in treating autoimmune diseases such as rheumatoid arthritis (RA).Methods:Using predicting SAR, TLL018 was designed to achieve exquisite selectivity for both JAK1 and TYK2 while sparing JAK2, JAK3 and other human kinases. Its enzyme and cell activities, kinase selectivity, andin vivoefficacy were assessed in a battery of relevant enzyme, cell and whole blood assays, andin vivoarthritis animal models. Additional preclinical DMPK and toxicology studies were conducted to support its clinical development.Results:TLL018 is a highly potent and selective, orally bioavailable JAK1/TYK2 inhibitor against JAK1 (IC50= 4 nM) and TYK2 (IC50= 5 nM) as measured inin vitrokinase assays with ATP concentrations at individual Km. Its potency against JAK2 or JAK3 is greater than 1 µM. Profiling against a panel of over 350 human kinase showed that TLL018 is exclusively selective for JAK1 and TYK2, with ≥ 90-fold selectivity against all other kinases tested. TLL018 exhibited potent cellular activity for JAK1-mediated IL-6 signaling (IC50= 0.6 µM) with greater than 100-fold selectivity against JAK2-mediated cytokine (e.g., TPO) signaling in human whole blood-based assays.Oral administration of TLL018 demonstrated dose-dependent efficacy in commonly studied rat adjuvant-induced arthritis (rAIA) model and mouse collagen-induced arthritis (mCIA) model. Significant inhibition of inflammation, bone resorption, splenomegaly and body weight change was observed in adjuvant-induced disease in rats. In addition, significant inhibition of inflammation, cartilage destruction, bone resorption and histological signs was demonstrated in collagen-induced arthritis in mice. Noticeably, TLL018 exhibited significant anti-inflammation activity at doses that only blocked JAK1 and TYK2 and exerted little inhibition of JAK2 and JAK3.In support of clinical development of TLL018, preclinical ADME and PK studies and IND-enabling toxicology and safety pharmacology studies were completed, confirming that TLL018 possesses excellent ADME and PK properties, and exhibits a clean on-target safety profile.Conclusion:TLL018 is a highly potent and selective JAK1/TYK2 inhibitor that demonstrated excellent efficacy and tolerability in relevant mouse and rat arthritis models. The collective data of its preclinical pharmacology, PK and toxicology showed a favorable pharmaceutical profile, further supporting its development for treating autoimmune diseases including RA. Clinical evaluation of TLL018 is ongoing.Disclosure of Interests:Xiangdong Liu Shareholder of: I own shares of TLL Pharmaceutical LLC, Employee of: I am employed by TLL Pharmaceutical LLC, Fenlai Tan Shareholder of: I own shares of TLL Pharmaceutical LLC, Employee of: I am employed by TLL Pharmaceutical LLC, Chris Liang Shareholder of: I own shares of TLL Pharmaceutical LLC, Employee of: I am employed by TLL Pharmaceutical LLC

scholarly journals The latest orphan drug designations and the Commission Communication on Regulation (EC) 141/2000

2005 ◽  
Vol 11 (3) ◽  
Author(s):  
Rashmi R Shah
Keyword(s):  
European Union ◽  
Rare Diseases ◽  
European Medicines Agency ◽  
Biological Plausibility ◽  
The European Union ◽  
Medicinal Products ◽  
Market Exclusivity ◽  
Community Regulation ◽  
Orphan Medicinal Products ◽  
Patient Groups

The implementation of Community Regulation on orphan medicinal products in the European Union in April 2000 has resulted in a deluge of applications for designation of medicinal products as orphan for rare diseases. By April 2004, the Committee for Orphan Medicinal Products had already given positive opinion on 63 per cent of the 316 applications considered by them. A significant number of these positive designations have already matured into full marketing authorisations. Three major reasons – failure to meet prevalence or significant benefit criteria or provide evidence of biological plausibility – have equally contributed to either the negative opinion on or the applicants withdrawing the remaining applications. In July 2004, the European Commission issued a communication setting out its position on certain matters relating to the implementation of the designation and market exclusivity provisions. The Commission, the European Medicines Agency (EMEA) and the Committee for Orphan Medicinal Products (COMP) continue to be proactive and provide as much guidance and incentives as practical, engaging themselves with sponsors, patient groups and academia. As experience builds up and issues are clarified, there are expectations that the Community Regulation on orphan medicines will prove to be a spectacular success.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

1989 ◽  
Vol 7 (12) ◽  
pp. 1909-1914 ◽  
Author(s):  
R Bataille ◽  
D Chappard ◽  
C Marcelli ◽  
P Dessauw ◽  
J Sany ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cell Mass ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Mass Reduction

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

scholarly journals The effect of moderately and severely restricted dietary magnesium intakes on bone composition and bone metabolism in the rat

1999 ◽  
Vol 82 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Annette Creedon ◽  
Albert Flynn ◽  
Kevin Cashman
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Development ◽  
Dry Weight ◽  
Male Rats ◽  
Average Weight ◽  
Mrna Levels ◽  
Adequate Diet ◽  
Wistar Strain ◽  
Restricted Group

Forty 3-week-old male rats, Wistar strain, average weight 59 g, were randomized by weight into five groups of eight rats each. Three groups were fedad libitumon a semi-purified diet containing (per kg) 400 (adequate), 200 (moderately Mg-restricted) or 20 (severely Mg-restricted) mg Mg for 3 weeks while two groups were pair-fed with the Mg-adequate diet in the same quantities as those consumed by the two Mg-restricted groups respectively. While weight gains and food conversion efficiency values for the Mg-restricted groups were similar to those of the corresponding pair-fed control groups, serum and kidney Mg, and femoral dry weight were reduced by 70, 7 and 9 % respectively in the severely Mg-restricted group and were unaffected in the moderately Mg-restricted group. Significant reductions were observed in urinary pyridinoline (Pyr) (by 44 and 34 %) and deoxypyridinoline (Dpyr) levels (by 40 and 33 %) (markers of bone resorption), serum osteocalcin levels (by 46 and 28 %) (marker of bone formation), femoral Mg levels (by 52 and 14 %) and osteocalcin mRNA levels (by 46 and 22 %) compared with the corresponding pair-fed controls, in the severely and moderately Mg-restricted groups respectively, and these reductions, except for those in urinary Pyr and Dpyr, were more marked in the severely Mg-restricted group. Femoral Ca and P concentrations were unaffected by dietary Mg restriction. These results show that not only severe but also moderate dietary restriction of Mg over 21 d results in qualitative changes in bone (i.e. reduced Mg concentration) as well as in aberrant bone turnover in young growing rats (i.e. severely depressed rates of bone formation and bone resorption), which may impair bone development and bone strength.

scholarly journals PROGNOSTIC VALUE OF THE BONE TURNOVER MARKERS IN MULTIPLE MYELOMA

2017 ◽  
Vol 39 (1) ◽  
pp. 53-56 ◽  
Author(s):  
D Auzina ◽  
S Lejniece
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Turnover ◽  
Bone Disease ◽  
Diagnostic Marker ◽  
Control Group ◽  
Bone Lesions ◽  
Bone Resorption Marker ◽  
Baseline Values ◽  
Turnover Markers

Background: Multiple myeloma (MM) is characterized by osteolytic bone disease resulting from increased osteoclast activity and reduced osteoblast function. Aim: The aim of our research was to determine connection between bone turnover markers and presence of bone lesions, their degree of severity, to monitor MM bone disease and to assess effectiveness of anti-myeloma treatment. Materials and Methods: Serum samples and clinical data from 123 patients with newly diagnosed MM were collected at Riga East Clinical University Hospital (Riga, Latvia) from June 2014 to June 2016. Bone lesions detected by radiography, CT scans, MRI, and PET/CT were divided into degrees from 0 to 3 (0 — no bone involvement, 1 — ≤ 3 bone lesions, 2 — ≥ 3 bone lesions, 3 — fracture). Staging was performed applying Durie/Salmon (DS) and International Staging System classifications. Progressive disease was defined as development of one or more new bone lesions. The levels of bone metabolic markers β-isomerized C-terminal telopeptide of collagen type I (β-CTX) and bone-specific alkaline phosphatase (bALP) were monitored regularly in the year. Results: Bone lesions were found in 86 (69%) patients. From these 6 (4%) patients had 1st degree, 11 (9%) had 2nd degree and 69 (56%) had 3rd degree bone lesions. Level of the bone resorption marker β-CTX in the control group was 0.41 ng/ml, which is lower than in MM patients (p < 0.001). Spearman correlation coefficient analysis found a positive and statistically significant correlation (rs = 0.51, p < 0.001) between bone lesions degree and β-CTX levels. Mean β-CTX for patients without bone lesions was 0.72 ng/ml (SD = 0.64), but for patients with 3rd degree bone lesions it was 1.34 ng/ml (SD = 0.65) difference being 38% (p < 0.001). In patients who responded to therapy after 6 months of treatment reduction of β-CTX was found compared to baseline values (M = –0.65). In contrast, in patients who did not respond to therapy, there was a statistically significant (p < 0.001) increase in β-CTX values after six months of treatment compared to baseline values (M = 0.42). Exact cutoff value of β-CTX is 0.79. When analyzing mean bALP, no significant difference between MM patients and control group was found. ANOVA statistical analysis showed no statistically significant differences in bALP levels at different degrees of bone lesions (p = 0.95) in MM patients. Analysis of bALP suitability as MM diagnostic marker using receiver operating characteristics curve showed that bALP is not applicable for clinical diagnosis of MM (AUC 0.5, p > 0.05). However, β-CTX was found to be an excellent diagnostic marker for MM (AUC 0.91; 95% confidence interval, 0.88–0.94; p < 0.001). Conclusions: Patients with MM and bone lesions have increased value of bone resorption marker β-CTX. There is a correlation between bone resorption marker and degree of bone lesions. Changes in β-CTX levels may be used to monitor the effectiveness of myeloma treatment.

scholarly journals Bilateral coxa vara and tibia vara associated with severe short stature in a girl manifesting a constellation of bone lesions with exclusive involvement of the lower limbs

2018 ◽  
Vol 6 (3) ◽  
pp. 63-69
Author(s):  
Ali Al Kaissi ◽  
Franz Grill ◽  
Rudolf Ganger ◽  
Susanne Gerit Kircher
Keyword(s):  
Short Stature ◽  
Skeletal Dysplasia ◽  
Lower Limbs ◽  
Bone Lesions ◽  
Coxa Vara ◽  
Tibia Vara ◽  
Osteolytic Lesions ◽  
Fibrocartilaginous Dysplasia ◽  
Medial Cortex ◽  
Severe Short Stature

In most instances, a toddler is seen with unilateral varus of the tibia, usually the deformity appearing slightly more distal than the knee joint. Radiographs of the focal fibrocartilaginous dysplasia show a characteristic abrupt varus at the metaphyseal — diaphyseal junction of the tibia. Cortical sclerosis is in and around the area of the abrupt varus on the medial cortex. A radiolucency may appear just proximal to the area of cortical sclerosis. The aetiology of such defects and the pathogenesis of the deformity are mostly unknown. Many of the associated factors suggest that the condition at least partly results from a mechanical overload of the medioproximal tibial physis. The evaluation of a child with suspected pathologic tibia vara begins with a thorough history. A complete birth and developmental history should include the age at which the child begun walking. The medical history should identify any renal disease, endocrinopathies, or known skeletal dysplasia. The physical examination also should include the child’s overall lower extremity alignment and symmetry, hip and knee motion, ligamentous hyperlaxity, and tibial torsion. We describe on a 17 year-old-girl who manifests severe short stature associated with multiple orthopaedic abnormalities, namely, bilateral coxa vara and tibia vara. Radiographic documentation showed bilateral and symmetrical involvement of the lower limbs with the extensive form of fibrocartilaginous dysplasia, osteoporosis, and osteolytic lesions. The constellation of the malformation complex of osteolytic lesions, fibrocartilaginous changes and the polycystic like fibromas are not consistent to any previously published reports of fibrocartilaginous dysplasia. To the best of our knowledge, it seems that fibrocartilaginous changes are part of a novel type of skeletal dysplasia.

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