Bone Manifestations Research Articles

Novel Management of Immune Thrombocytopenia in Gaucher Disease Patients

Type I Gaucher disease (GD) the is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and infiltration of bone marrow by lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in GD patients. In GD ERT treated patients, manifesting persistent low platelet counts, immune thrombocytopenia (ITP) should be considered.Treatment of GD with concomitant ITP is a challenge. Splenectomy may worsen bone manifestations in GD patients and is controversial. Steroids should be used with caution because of possible induction of osteopenia and joints avascular necrosis. Thrombopoietin receptor analogues (TPO-RA) are therapeutic option in GD patients with ITP. Beneficial use of TPO-RA is reported in 2 cases.Patient 1: 39 YO male with new onset of purpura and low platelet count failed treatment with 1 mg/kg of Prednisone. Bone marrow biopsy (BM) showed Gaucher cells infiltration, numerous atypical megakaryocytes, normal erythropoiesis and myelopoiesis with no fibrosis. Low level of ß-glucocerebrosidase activity with compound heterozygosity for 84GG /R495H mutations, established the diagnosis of Type I GD. Low C4 and detection of IgG platelet antibodies added to the diagnosis of concomitant immune thrombocytopenia. ERT with taliglucerase alfa (ElelysoTM) 60 Units/kg/month was given with Prednisone for six weeks. Occurrence of retinal bleeding and purpura, with decrease of platelet count necessitated addition of high-dose IVIG with no response regarding platelet counts. Splenectomy was not considered due to known bony complication risk in splenectomised GD patients. Rituximab was given to prevent wet purpura recurrence with short response regarding platelet count. Romiplostim was initiated raising platelet count from 29,000/µL to 60,000/µL after 3 wks. and to 90,000/µL after 8 wks. enabling corticosteroids withdrawal. Same dose Romiplostim is maintained for the last 30 months with platelet counts of 90,000 - 110,000/µL with no bleeding events. Repeated BMB showed no increase in collagen fibrosis.Patient 2: 63 YO female patient diagnosed with Gaucher at age 33 with a history of purpura, ecchymosis, and occasional vaginal bleeding episodes. At age 53 the platelet count dropped to < 20,000/µL with presence of Anti Platelets Ab (IgG). BMB revealed megakaryocytic hyperplasia with atypical forms, focal infiltration by Gaucher cells and no fibrosis. Combined therapy by ERT (Imiglucerase® followed by Velaglucerase Alfa®), Prednisone (1mg/kg/d for 2 months) and one course of IVIG yielded no increase in platelet count. The patient refused Rituximab®. Romiplostim was initiated increasing platelet count to100,000/µL maintained throughout a year of follow up. Repeated BMB showed slight increase of fibrosis and marked hyperplasia of atypical megakaryocytes.Discussion: Thrombocytopenia is often present in GD and may be severe in approximately 15% of the patients. Persistent cytopenias may be caused by other underlying pathologies such as autoimmune disorders and are important to be recognized and addressed. Before ERT era GD patients with hypersplenism and severe cytopenia were splenectomised. Risks of splenectomy include serious bacterial infection and vascular complications limiting its use in chronic refractory ITP. Splenectomy is avoided in Gaucher patients, due to risk of exacerbating skeletal complications (bone infarcts, avascular necrosis). Stable bone marrow results regarding fibrosis in our patients are consistent with data from a recent 2-year follow-up of 100 ITP patients receiving Romiplostim treatment with no evidence of BM fibrosis.Conclusion: In patients with type I Gaucher disease and concomitant ITP, adjunctive treatment with Romiplostim was successful in maintaining haemostatic platelet counts with no adverse effects. Traditional treatment regimens of corticosteroids and splenectomy should be used with caution or avoided in GD patients due to possible aggravation of Gaucher skeletal disease and the risk of osteopenia and avascular necrosis resulting in increased morbidity in this cohort of patients. Use of TPO-RA should be considered in GD patients with ITP. DisclosuresOff Label Use: Romiplostim in gaucher patients.

Gaucher disease and bone manifestations.

Gaucher disease is a relatively rare metabolic disease caused by the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Gaucher disease affects multiple organs, among which is the skeleton. Bone involvement occurs frequently in Gaucher disease, and is one of its most debilitating features, reducing the quality of life of patients. Bone status is an important consideration for treatment to ameliorate symptoms and reduce the risk of irreversible complications. We have conducted a systematic review of all the various aspects of Gaucher disease, focusing on different skeletal manifestations, pathophysiology of bone alterations, clinical symptoms, and current diagnostic and therapeutic approaches.

Etanercept in the treatment of SAPHO syndrome: Which place?

Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO) is a rare disease combining skin, bone, and joint manifestations. Its treatment remains a debated issue in the absence of a valid therapeutic strategy. The experience with tumor necrosis factor alpha (TNF alpha)-blocking agents is still small but encouraging. This therapy is reserved for refractory cases. The most commonly used agent is infliximab. Only few cases treated by etanercept have been reported in the literature. We report a new case treated by this biologic therapy and discuss its place in the treatment of SAPHO syndrome. A 30-year-old male, with a history of left clavicular osteitis that required surgical bone biopsy to rule out infection and malignancy, was admitted to the rheumatology department because of recurrent anterior chest pain, lower limb arthralgia, and sacroiliac pain. Laboratory findings revealed an inflammatory syndrome. Conventional radiography and computed tomography (CT) scan of the sternocostoclavicular region showed sclerosis and hyperostosis of the left clavicle. Right sacroiliitis was diagnosed based on the radiographic findings. Moreover, the patient reported palmoplantar pustulosis, thereby strengthening the diagnosis of SAPHO syndrome. As conventional treatment based on methotrexate, corticosteroids, and zoledronic acid was not effective, etanercept was initiated with good and rapid clinical and biological improvement. The diagnosis and treatment of SAPHO syndrome are challenging due to the heterogeneity of symptoms and unknown pathogenesis. Etanercept can be an effective therapy, especially in refractory cases. Further studies are needed in order to establish a therapeutic strategy.

Role of heritable connective tissue diseases phenotypes in assessing the risk for internal diseases

Aim. To identify the prevalence of main phenotypes of polygenic heritable connective tissue diseases in patients with internal diseases and to assess the prevalence of different internal diseases in such patients. Methods. The study involved 600 patients (254 males, 346 females) aged 18 to 64 years. Average age of males was 52±3.8 years, females - 47±2.2 years. Patients were examined to reveal the signs of different phenotypes of heritable connective tissue diseases in patients with internal diseases, as well as the severity of connective tissue diseases, and possibilities for it screening using the wrist and thumb hypermobility tests. Results. Signs of heritable connective tissue diseases were revealed in 147 (24.5%) patients with internal diseases. In females, those signs were observed in 104 (30.0%) cases, of which 44 (42.3%) were graded as mild, 35 (33.7%) - moderate, 25 (24.0%) - severe. In males, signs of heritable connective tissue diseases were revealed in 43 cases (16.9%), including mild - 17 (39.5%), moderate - 14 (32.5%) and severe - 12 (28.0%). Ehlers-like phenotype was the most common (52.0%), Marfan-like phenotype was observed in 14.0% of cases, primary mitral valve prolapse was diagnosed in 7.0% of patients, unclassifiable phenotype was observed in 11.0% of cases. Joint hypermobility syndrome was revealed in 31.0% of patients, presenting both as specific phenotypes (Marfan-like, Ehlers-like) and as a self-phenotype (31.9% of all the patients with heritable connective tissue diseases phenotype). Benign joint hypermobility was observed in 6.1% of cases. Symptoms of heritable connective tissue diseases were more frequent in patients with gastrointestinal and musculoskeletal diseases. Conclusion. The most common phenotype of heritable connective tissue diseases is Ehlers-like with skin, bone and systemic manifestations. Presence of heritable connective tissue diseases was most commonly associated with gastrointestinal and musculoskeletal diseases.

AB0841 Tendon Involvement in Chronic Tophaceous Gout Detected by Dual-Anergy-Computertomography

BackgroundGout is the most prevalent metabolic arthritis and affects about 8,3 million inhabitants in the USA. Epidemiologic data from Europe are comparable and indicate that gouty arthritis or chronic tophaceous...

AB0804 Bone Manifestations in Patients with Gaucher Disease

BackgroundGaucher Disease (GD), the most prevalent glycolipid storage disease, is an autosomal recessive metabolic disorder that is caused by an inherited deficiency of the lysosomal enzyme, glycocerebrosidase. This defect leads...

Biological treatments for SAPHO syndrome: an update.

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular manifestations. Since the identification of the syndrome many immunosuppressive drugs have been used for the management of SAPHO, with variable results. The use of anti- TNF-α agents as a therapeutic option for SAPHO cases unresponsive or refractory to conventional drugs, demonstrated their efficacy for bone, skin and joints manifestations. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β , IL-6 and IL-8, involved in inflammation, acute-phase response induction and chemotaxis. IL-1 inhibition strategies with Anakinra have proven their efficacy as first and second line treatment. We herein review the literature concerning the use of biological drugs in patients with SAPHO syndrome. In addition, we describe for the first time the use of Ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and Anakinra. This anti-IL12/IL23 agent could be a promising therapeutic option, also considering the opportunity to interfere with the IL23/TH17 pathway, which we recently found disturbed. Furthermore, a rationale emerges for the use of the new anti-IL-1 antagonists or the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.

Examining the impact of bone pathology on type I Gaucher disease

Gaucher disease (GD) is an autosomal recessively inherited lysosomal disorder caused by mutations in GBA gene leading to deficient activity of the lysosomal enzyme acid β glucocerebrosidase. Phenotipically, three different forms can be distinguished, type I GD being the most frequent, and characterized by the absence of involvement of the CNS. Affected organs are the spleen, liver, bone marrow and bone and, in severe cases, also the lung and kidney. Bone manifestations include bone pain, bone crises, osteopenia, osteoporosis, avascular necrosis and pathological fractures. Nowadays, skeletal alterations are the major cause of morbidity for patients, and a major concern for physicians who treat them, owing to the variable grade of response and refractoriness of bone pathology to treatment. Pathological mechanisms of bone alterations in GD are still poorly understood. Advances are being achieved in the knowledge of cellular and molecular mechanisms; by application of basic knowledge from osteoimmunology. GD ...

Rethinking fatigue in Gaucher disease

Background Gaucher disease (GD) is a rare lysosomal storage disease caused by deficiency in the enzyme beta-glucocerebrosidase. Along with visceral, hematologic, and bone manifestations, patients may experience chronic fatigue resulting in functional disability and reduced quality of life. Management of the disease includes therapeutic intervention, supportive therapies, and regular monitoring of all clinically relevant disease signs and symptoms. However, current practice guidelines do not include measurement of fatigue or therapeutic goals for fatigue.

Imaging of Disorders Affecting the Bone and Skin

There are a variety of conditions that manifest not only in bone but also in skin. Bone and skin structures can share common embryologic origins, and genetic defects that occur early in cell differentiation may lead to disease in both organ systems. Alternatively, diseases of bone and skin may be caused by defects in genes that participate in directing or controlling both systems. Many diseases of bone and skin can manifest with atypical radiologic findings or mimic malignant bone lesions. Upon encountering such a disease process, a radiologist who is familiar with both aspects of the disorder and consequently looks for associated skin findings can greatly benefit the patient by making a definitive diagnosis. Similarly, a clinician who encounters suggestive skin lesions should be prompted to look for concomitant skeletal lesions. By synthesizing knowledge of bone and skin manifestations, radiologists and clinicians can help correctly diagnose a number of these disease processes, thereby helping patients avoid further, often nonspecific invasive workup and advancing patient care.

TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS WITH NITROGEN CONTAINING BISPHOSPHONATES, EARLY SIDE EFFECTS AND THEIR PREVENTION

Infusions of aminobisphosphonates are now established therapies ofpostmenopausal osteoporosis. Their use is associated with fever and musculoskeletal pain in some subjects, referred to as the acute phase response (APR). The purpose of the study was to explore tolerability of zoledronic acid in the treatment of postmenopausal osteoporosis. In a 36-month open label, prospective study patients with postmenopausal osteoporosis iv received zoledronic acid at a dose of 5 mg every 12 months. We then analyzed the tolerability of the treatment at the hospital and via telephone interviews during the next 14 days and every 3 months after the infusion. Prevention of APR was carried out with paracetamol 500 mg x 3 times a day on the day of first infusion and the next 2 days. Symptoms of APR were recorded in 39% (n=43) of patients with prevention therapy. APR developed in the first 12-24 hours after infusion of zoledronic acid. Among women without prevention APR developed in 65% (n=75) of cases. (OR=0.34 CI (0.2-0.59)). After the 2 nd infusion symptoms of APR were noted in 27.9% (n=26) (р&lt;0.05) of 93 patients, after the 3 rdin 6.6% (n=2) of 30 patients. Thus, in &gt;90% of cases the symptoms were of mild or moderate severity, with resolution within 3 days after infusion of zoledronic acid. The most frequent symptoms were bone and muscular manifestations and a flu-like syndrome (p&lt;0.05). APR developed during the first 12-24 hours after infusion of zoledronic acid. ARR developed 2.5 times more often in the cases when zoledronic acid was used for the first time. If paracetamol treatment was administered, APR cases were documented 1.7 times less often with lesser degree and length of manifestations. Frequency of APR dropped after repeated zoledronic acid infusions.

Prognostic role of early versus late onset of bone metastasis in patients with carcinoma of the ovary, peritoneum and fallopian tube

BackgroundBone metastases are a rare manifestation in the management of ovarian cancer and thought to be associated with a poor prognosis as sign of distant spread. Only few data exist on this rare condition. The present study aimed to more information on this very distinct patient collective. Patients and methodsA retrospective chart review was carried out including all patients who had been treated from 1994 to 2009 for histologically confirmed ovarian, peritoneal and fallopian tube cancer. Overall, 1717 cases were detected and screened. Patients with bone metastasis were identified and analyzed regarding survival as well as various clinical variables. ResultsA total of 26 women who had been diagnosed with bone metastases ante mortem could be identified, resulting in an incidence of 1.50%. The majority of patients presented multiple bone lesions (80.8%) and bone spread was symptomatic in 62.5% of the cases. Mean overall survival from primary diagnosis of EOC was 50.5 months (range: 2.5–142.5 months). Median overall survival after diagnosis of bone metastases was 7.2 months. When divided into two subsets depending on timepoint diagnosis of bone metastases, there was a significant difference in overall survival. The mean overall survival from primary diagnosis of EOC in the early-onset group (n = 8), defined as occurence of bone manifestation within 12 months, was 11.2 months. The mean overall survival in the late-onset group (n = 15) was 78.4 months (P = 0.000001). ConclusionsThe time interval from diagnosis to appearance of bone metastases is a prognostic factor in ovarian cancer. While early onset bone spread has a strong negative prognostic impact, late-onset bone diagnosis of bone metastases hardly influences the prognosis at all. This finding should be considered in the management of patients with bone metastases from ovarian cancer.

Vitamin D Deficiency in Serbian Patients With Rett Syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder. Bone manifestations of RTT include osteopenia and fractures. Studies addressing serum vitamin D levels in patients with RTT are scarce. The goals of this study were (1) to determine the prevalence of vitamin D deficiency in patients with RTT, (2) to compare serum vitamin D levels between patients with RTT and those with other neurological diseases, and (3) to explore the correlation between demographic and clinical characteristics of patients with RTT and vitamin D levels. Demographic and clinical characteristics included age, body mass index Z-score, mutation status, clinical severity score, presence of epilepsy, number of antiepileptic drugs, history of fractures, scoliosis, and ambulation ability. Laboratory parameters included serum 25-hydroxyvitamin D [25(OH)D], PTH, calcium, and alkaline phosphatase. The study included 35 patients with RTT and 35 age-matched females with other neurological diseases. The median serum 25(OH)D concentration in the RTT group was 26.25 nmol/L, with values <75 nmol/L in all participants. Severe deficiency (<25 nmol/L) was detected in 17 of 35 (48.6%) patients. The median 25(OH)D concentration was significantly lower in patients with RTT than in control subjects. The risk for fracture by 12 years of age in patients with RTT was 35.3%. An inverse correlation of the 25(OH)D level to age and PTH level was detected. Patients receiving antiepileptic polytherapy had a 3.3 times greater chance for severe vitamin D deficiency than patients receiving monotherapy. The prevalence of vitamin D deficiency in patients with RTT is higher than that in patients with other neurological diseases. The high risk for vitamin D deficiency should be accounted for in the strategy of antiepileptic treatment in RTT, especially when polytherapy is considered.

Osteomyelitis variolosa: A probable mediaeval case combined with unilateral sacroiliitis

Osteoarticular sequelae of smallpox (osteomyelitis variolosa) are uncommon today. Such lesions may be observed occasionally, however, in countries where the disease has been endemic. Without other forms of documentation, it is possible to suggest a diagnosis of smallpox in ancient skeletal remains and thus make a significant contribution to understanding the history of this disease. We have examined a subadult male (Skeleton 833), 15–17 years old at the time of death, who presents bilateral bone manifestations of the elbows suggestive of smallpox. No other bone is similarly affected. In addition, he presents a left sacroiliitis deemed to be a brucellar manifestation. Skeleton 833 is one of at least 730 individuals from an exhaustive excavation of a mediaeval necropolis at Pont-sur-Seine (Aube, north-eastern France). Radiocarbon dating of his bones yields a date of between AD 1022 and 1155 (calibrated), thus apparently the oldest case described to date. The other published cases correspond to more recent periods with a well established historical context. We argue that this example of osteomyelitis variolosa.

SAT0535 Diagnosis, Disease Burden and Disease Manifestations of the Sapho Syndrome in Germany: Results from a Nationwide Patient Survey

BackgroundThe term SAPHO syndrome describes a rare, probably underdiagnosed and heterogeneous disease entity. Characteristic disease features include skin, bone and joint manifestations and a predisposition for involvement of the anterior...

OP0112 Cystic fibrosis related arthritis in adults in south east england

BackgroundAlthough bone and joint manifestations are common in children with cystic fibrosis (CF), they have received little attention in adults. CF-related arthropathy (CFA) is a relatively infrequent complication previously reported...

WIELOOGNISKOWA, KOSTNA MANIFESTACJA CHOROBY DEKOMPRESYJNEJ U ZAWODOWEGO PILOTA - OPIS PRZYPADKU

Decompression sickness is a group of pathological processes occurring in the body, following its exposure to an excessive drop in atmospheric pressure. The paper presents a case of a 62-year-old patient with no substantial disease history, a long-standing professional military pilot who was diagnosed with multifocal, bone manifestation of decompression sickness during the diagnosis of right knee joint injury following a torsion injury. The case was presented to draw attention to the usefulness of occupational history in the process of diagnosing osteoarticular system diseases.

Traitement de la gonarthrose du jeune sportif

In the practice of sports, it is the traumatisms more than the over-sollicitation that induce arthrosis. The main principles of rehabilitation rest upon the conservation of range motion, decompression of the knee, muscular renforcement but also the control of overweight in the same time as the control of statical disorder by plantar orthesis. It seems important to distinguish two groups of arthrosis: the synovial manifestation in arthrosis for which the insers of NSAI in first intention seems logical (ponctions and local injection of corticoid) and the arthrosis with major bone manifestations (with the help of images) should be considered as a real osteo-chondral disease. It is theses types without swelling that the visco-induction should be used.

Achievement of Therapeutic Goals with Low-Dose Imiglucerase in Gaucher Disease: A Single-Center Experience

Gaucher disease, a lysosomal storage disorder, is a multisystem disorder with variable and unpredictable onset and severity. Disease-specific enzyme replacement therapy (ERT) has been shown to reverse or ameliorate disease-specific hepatosplenomegaly and anemia and thrombocytopenia. ERT also impacts bone manifestations, including bone crises, bone pain, and appearance of new osteonecrosis, and improves bone mineral density to varying degrees. The objective of this study was to assess achievement of predefined therapeutic goals based on international registry outcomes for Israeli patients with Gaucher disease receiving imiglucerase for four consecutive years on a low-dose regimen followed in a single center. All data were taken from patient files. The therapeutic goals were taken from standards published in the literature for disease-specific clinical parameters. Among 164 patients at baseline, values for spleen and liver volumes, hemoglobin and platelet counts, and Z-scores for lumbar spine and femoral were significantly different from the goal. After four years ERT, there was a significant improvement (P = 0.000) in each of the therapeutic goal parameters from baseline. 15.2% of these patients achieved all hematology-visceral goals. In children, there was achievement of linear growth and puberty. This survey highlights the good overall response in symptomatic patients receiving low-dose ERT with imiglucerase in Israel.

Bone Turnover Markers in Patients with Type 1 Gaucher Disease

Bone complications occur frequently in Gaucher disease (GD) and reduce the quality of life of these patients. Skeletal involvement is an important indication for treatment to ameliorate symptoms and reduce the risk of irreversible and debilitating disease. Bone biomarkers have been used to assess disease status and the response to therapy in a number of bone disorders. Here, we examine the literature for evidence of abnormalities in bone turnover markers in patients with type 1 GD to assess whether they might be useful for the assessment of bone involvement in GD. We have found that bone biomarkers in GD show highly variable results which do not currently support their routine use for clinical assessment of bone status, as an indication for therapy initiation, or for monitoring the response to therapy. A greater understanding of bone markers and their relation to the bone manifestations of GD is required.