The Prevalence Of Osteoporosis Is Low in Adult Cutaneous Mastocytosis Patients.

BACKGROUND: Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside MC abnormalities, and whether MC clonality is sufficient to trigger osteoporosis. OBJECTIVE: To describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics with those of nonadvanced SM patients (bone marrow mastocytosis and indolent systemic mastocytosis). METHODS: We retrospectively analyzed clinical, biological, and densitometric data of 27 CM, 13 MMAS, and 135 SM patients from the Mastocytosis Expert Center (CEREMAST) in Toulouse, France. RESULTS: The OP (respectively 3.7, 30.8, and 34.1%) and VFs (0.0%, 15.4%, and 20%) were less frequent in CM than in MMAS and SM, despite the presence of clonal MCs in the bone marrow. Most patients with OP and VFs in the non-SM groups had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow KIT mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and VFs occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility. CONCLUSIONS: Our findings suggest that, in most CM patients, the meaning and management of OP differs from that of OP in MMAS and nonadvanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP.

Sjögren's syndrome associated with erosive rheumatoid arthritis alters its prognosis and long-term therapeutic response: a case-control study.

10% of rheumatoid arthritis (RA) cases are associated to so-called secondary Sjögren's syndrome (SS). These RA cases have higher DAS, fewer remissions. Is this linked to a poor response to DMARDs (disease-modifying anti-rheumatic drugs)? No study has addressed this question to date. Does the association between secondary Sjögren's syndrome (SS) and rheumatoid arthritis (RA) affect the therapeutic response to DMARDs and long-term prognosis? We conducted a retrospective case-control study: 39 RA associated with SS was (anti-SSA antibodies and/or Chisolm stage III or IV) were compared to 39 isolated cases of erosive RA matched by age, duration of progression and gender. The DAS CRP was higher in the RA + SS group in patients with disease progression of 16 years: 2.6 (1.5-4.5) compared to the RA group: 1.6 (1.3-2.8) (p = 0.0001) while fewer patients were in remission: 61 vs. 92% (p = 0.002). A higher number of B DMARDs have been prescribed: RA + SS = 3.04 (1-7); RA = 1.7 (1-5) (p = 0.004). Anti-TNFs are less effective when RA is associated with SS: 30 vs. 70%. Conversely, Rituximab is more effective when RA is associated with SS: 80 vs. 30%. Erosive RA-related SS exacerbates the clinical course of the condition: higher DAS, fewer remissions. This is linked to reduced treatment efficacy: higher number of DMARDs prescribed, reduced efficacy of anti-TNF drugs. RA-related SS could modify sensitivity to biotherapies: lower percentage of remissions and resistance to anti-TNF drugs.

No impact of anti-Rank ligand and PTH analogs on cardiovascular risk in postmenopausal osteoporosis: a systematic literature review and meta-analysis.

The mutual effects of drugs used in osteoporosis and cardiovascular diseases are a point of interest. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis; these treatments do not appear to have any effect. INTRODUCTION: Two meta-analyses have been conducted to explore the cardiovascular effects of bisphosphonates. There is no review for other osteoporosis treatments. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis. METHODS: A systematic review was conducted in December 2017 in the PubMed, Embase, and Cochrane databases and updated on PubMed in July 2019, selecting trials with a treatment and a control group. We also conducted a search for abstracts of the French Rheumatology Society, American College of Rheumatology, and European League Against Rheumatism's annual meetings over the past 4 years. The main endpoint was the occurrence of cardiovascular events; the secondary was mortality (all causes). RESULTS: Of the 2782 reports initially found, 16 articles were used for the meta-analysis (6 for the anti-Rank ligand and 10 for the PTH analog group). After meta-analysis, there was no significant difference between the placebo group and the anti-Rank ligand group for overall mortality (p = 0.13), the combined endpoint (overall mortality, coronary artery disease, and stroke; p 0.77), and the individual risk of coronary artery disease (p 0.53), arrhythmia (p 0.95), and stroke (p 0.62). After meta-analysis, there was no significant difference between the placebo group and the PTH analogs group for overall mortality (p 0.77), the combined endpoint (p = 0.95), and the individual risk of coronary artery disease (p = 0.74), arrhythmia (p = 0.28), and stroke (p = 0.61). CONCLUSIONS: The anti-Rank ligand and PTH analogs have no impact on cardiovascular risk and overall mortality in idiopathic osteoporosis. To better answer the question whether these treatments can reduce the long-term cardiovascular risk, further comparative studies with longer duration are required.

Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases.

There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2). We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

DKK1 and sclerostin are early markers of relapse in multiple myeloma.

Recent studies have shown that Dickkopf-related protein (DKK1) and sclerostin decrease when a complete response (CR) is obtained after chemotherapy in myeloma multiple (MM). To study variations in DKK1, sclerostin and P1NP in patients treated for MM, between complete response (CR) and relapse, we carried out a prospective study ancillary to the IFM 2009 protocol (IFM). The aim of IFM was to compare progression-free survival between patients treated with chemotherapy with or without transplantation. We selected 69 patients who reached CR and relapsed. We assayed by ELISA: DKK1, sclerostin and P1NP at 3 end points T1: CR, T2: 4 months before relapse and T3: relapse. There was a significant increase in DKK1 and sclerostin between T1, T2 and T3. (DKK1 medians (IQR): T1 = 30 pmol/l (20.4-41.1), T2 = 37.4 pmol/l (29.8-49.4), p < 0.0001, T3 = 42 pmol/l (33.8-55.5), p < 0.0001 sclerostin medians (IQR): T1 = 0.57 (0.47-0.69), T2 = 0.62 ng/ml (0.53-0.79), p < 0.0001, T3 = n0.64 ng/ml (0.56-0.79), p = 0.005). No significant variation was detected in the levels of P1NP. No association was observed between the characteristics of the MM, or the treatment received and the variation between T1-T3 for DKK1, sclerostin or P1NP. A significant increase in DKK1 and sclerostin was observed four months before relapse.

Prevalence and risk factors for fragility fracture in systemic mastocytosis.

OBJECTIVES: Systemic mastocytosis (SM) is characterized by the accumulation of mast cells in tissues other than the skin. Bone involvement although frequent has not been thoroughly evaluated. Primary objective was to determine risk factors associated with fragility fractures (FF) in SM. Secondary objectives were to evaluate the ability of bone marrow tryptase (BMT) level to identify patients with FF, and to describe bone involvement in SM. METHODS: We analyzed retrospectively all consecutive patients seen in our expert center, with a diagnosis of SM according to the 2001 WHO criteria, and with complete bone assessment. We collected data about lifetime fractures, types of cutaneous manifestations, degranulation symptoms, blood and BMT levels, bone mineral density assessed by densitometry and KIT mutation. We performed a univariate analysis investigating the factors associated with FF and then a logistic multivariable regression analysis. We assessed the ability of bone marrow tryptase to identify patients with FF. RESULTS: Eighty-nine patients with SM were included. Thirty-six patients (40.4%) suffered from osteoporosis and twenty-five (28.1%) experienced lifetime FF. Univariate analysis identified age at diagnosis and disease onset, presence of telangiectasia macularis eruptiva perstans, digestive symptoms, mast cells activation symptoms, elevated BMT, low femoral and lumbar BMD, as associated with FF. Multivariate analysis identified elevated BMT, low femoral T score and older age at diagnosis as independently associated with FF. CONCLUSIONS: Low femoral T-score, BMT level, and older age at diagnosis are markers associated with FF in SM. BMT may represent an important biomarker to predict FF in SM patients.

Osteoporosis and ischemic cardiovascular disease.

Osteoporosis and cardiovascular disease were long viewed as independent of each other. However, numerous epidemiological studies, which are discussed in the first part of this review, have provided incontrovertible evidence of a link. Thus, the risk of coronary artery disease and stroke is higher in patients with a history of osteoporotic fracture or low bone mineral density than in non-osteoporotic patients. In the other direction, patients with cardiovascular disease are at higher risk for bone loss and osteoporotic fracture. The link between osteoporosis and cardiovascular disease is due in part to shared conventional risk factors such as estrogen deprivation in women, smoking, low physical activity, and diabetes. In addition, atheroma plaque calcification involves cytokines and growth factors that also play a role in bone turnover, including proinflammatory cytokines (IL-6 and TNFα), osteoprotegerin, sclerostin, matrix GLA protein, and FGF-23. Several recent studies have provided support for these pathophysiological hypotheses. Thus, elevation of osteoprotegerin, sclerostin, or FGF-23 levels may explain and predict the occurrence of both osteoporotic fractures and cardiovascular events. The association between osteoporosis and cardiovascular disease found in most epidemiological and pathophysiological studies suggests a need for evaluating potential benefits from routine bone absorptiometry and osteoporotic fracture detection in patients with cardiovascular disease and from exercise testing and arterial Doppler imaging in patients with osteoporosis.

Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement.

BACKGROUND: Telangiectasia macularis eruptiva perstans (TMEP) has not been fully characterized. OBJECTIVE: We sought to estimate the frequency and clinical characteristics of TMEP in a cohort of adult patients with cutaneous mastocytosis, and to assess the presence of systemic involvement. METHODS: We included all consecutive patients evaluated for cutaneous mastocytosis in 2 centers: the Mastocytosis Competence Center of the Midi-Pyrénées from May 2006 to December 2013, and the French Reference Center for Mastocytosis from January 2008 to September 2013. Skin phenotype, histopathology, presence of KIT mutation in the skin, and assessment of systemic involvement according to World Health Organization (WHO) criteria were prospectively investigated. RESULTS: Of 243 patients with cutaneous mastocytosis, 34 (14%) were given a diagnosis of TMEP. The diagnosis of systemic mastocytosis was established in 16 patients (47%) with TMEP. Three patients (9%) had aggressive systemic mastocytosis (C-findings according to WHO). In all, 32 patients (94%) exhibited at least 1 mast cell activation-related symptom. LIMITATIONS: Patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis so that the clinical findings and incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. CONCLUSION: TMEP accounts for about 14% of patients with cutaneous mastocytosis. The disease manifests as mast cell activation symptoms in almost all patients and can be associated with systemic involvement in about 50% of cases.

[Vitamin D deficiency prediction by patient questionnaire and secondary hyperparathyroidism in a cohort of 526 healthy subjects in their fifties]. / Le déficit en vitamine D, très fréquent, n'entraîne qu'exceptionnellement une hyperparathyroïdie secondaire chez des sujets sains de la cinquantaine: cohorte de 526 sujets.

INTRODUCTION: Can vitamin D deficiency be predicted by patient questionnaire? Does it lead to secondary hyperparathyroidism that may cause excessive bone resorption? We studied non-osteoporotic subjects in their fifties, in whom vitamin D levels are often tested. PATIENTS AND METHODS: Patients hospitalised for degenerative osteoarthritis or consulting for assessment of menopause, without renal failure and not treated with vitamin D, completed a questionnaire on sun exposure and underwent measurement of serum calcium, creatinine, 25OH vitamin D, PTH and CTX. RESULTS: Five hundred and twenty-six subjects, mean age 54.6 years (71% women), were investigated throughout the year. 25OH vitamin D levels were correlated with sun exposure and varied according to the month of the year, unlike PTH and CTX levels. From November to May, over 90% of subjects had 25OH vitamin D levels<30ng/mL. Of the subjects who did not expose their face, arms and legs to the sun for at least 20min/day, 94% had 25OH vitamin D levels<30ng/mL. PTH levels were negatively correlated with those of 25OH vitamin D. Serum CTX levels were not correlated with PTH or 25OH vitamin D. Only 13% of subjects presented with secondary hyperparathyroidism, characterised by serum calcium<2.55mmol/L and PTH>65pg/mL, associated with increased CTX levels. CONCLUSION: Vitamin D deficiency can be predicted by patient questionnaire. It very rarely leads to secondary hyperparathyroidism.

Risedronate slows or partly reverses cortical and trabecular microarchitectural deterioration in postmenopausal women.

During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double-blind placebo-controlled studies that included 161 younger (Group 1, ≤ 55 years) and 163 older (Group 2, ≥ 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High-resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross-linking telopeptide of type 1 bone collagen (CTX-1) and serum amino-terminal propeptide of type 1 procollagen (P1NP) by ∼50%. In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% ± 1.6% (p = 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p = 0.02) in controls and decreased by 1.6% ± 0.6% (p = 0.005) in the risedronate-treated group. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate-treated group (0.9% ± 0.4%, p = 0.047). No between-group differences reached significance. Results were comparable at the distal tibia. Between-group differences were significant for compact-appearing cortex porosity (p = 0.005). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy.

Dual-energy X-ray absorptiometry and biochemical markers of bone turnover after autologous stem cell transplantation in myeloma.

OBJECTIVES: To evaluate the effect of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) on bone turnover and bone mineral density in a cohort of 39 consecutive patients with multiple myeloma (MM). METHODS: Phosphorus and calcium parameters, bone turnover markers, and bone mineral density were studied. Timepoints were diagnosis (T1), just before ASCT (T2), 6 months (T3) after ASCT, and 1 yr (T4) after ASCT. RESULTS: No bone mineral loss was shown on dual-energy X-ray absorptiometry (DXA) at T1 (lumbar Z-score -0.02, femoral neck Z-score 0.77) or during follow-up. Chronic vitamin D deficiency (25OHD3 11.7 ± 7.7 ng/mL at T1) and relative hyperparathyroidism from T2 to T4 were observed. In spite of this moderate hyperparathyroidism, serum C-telopeptide of type I collagen (CTX) decreased significantly between T1 and T4. Bone alkaline phosphatase levels were low at diagnosis and showed no significant change after ASCT, unlike DKK1 levels that were high at diagnosis and decreased 6 months after ASCT in patients not previously treated with bisphosphonates. CONCLUSION: Bone demineralization is moderate in multiple myeloma. ASCT induces a decrease in bone resorption but no changes in bone formation, remaining low despite the decrease in DKK1. Bone mineral loss, evaluated by DXA, is moderate in multiple myeloma. High-dose chemotherapy followed by ASCT leads to decreased bone resorption but osteoblastic bone formation remains low, in spite of reduced circulating DKK1.

Heterogeneity of biological bone markers in idiopathic male osteoporosis.

In men with idiopathic osteoporosis, histomorphometric studies reported both increased resorption and decreased remodeling. We aimed at examine bone remodeling in these patients by biological marker measurement. We compared pre-treatment carboxy-terminal cross-linking telopeptide of type I collagen (CTX) and bone alkaline phosphatase (bALP) levels in 49 men, mean age 59 ± 14 year, with idiopathic osteoporosis with fractures (40 patients) or osteoporosis diagnosed by densitometry (9 patients) with 50 age-matched controls. The influence of baseline remodeling level on alendronate efficacy was studied. Bone remodeling markers (CTX and bALP) did not significantly differ between patients and controls and were correlated in both groups. There was no correlation between these markers, vitamin D and PTH levels. Twenty-one patients underwent repeat densitometry after 1 year of alendronate (70 mg/week). Mean annual BMD increase, spine +4.1 ± 3.9%, and hip +1.5 ± 1.2% showed no correlation with baseline CTX. Bone remodeling is very heterogeneous and formation and resorption remain biologically coupled in both idiopathic male osteoporosis and controls. Baseline remodeling level does not affect the action of alendronate on BMD.

Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis.

BACKGROUND: The mechanism of osteoporosis with fracture secondary to mastocytosis is little known, and its treatment is poorly codified. METHODS: Ten patients with a mean age of 52.5 years with systemic mastocytosis and osteoporotic fractures were treated with interferon alpha 1.5 million U 3 times per week, combined with monthly pamidronate infusions (1 mg/kg) for 2 years, followed by pamidronate infusions every 3 months. RESULTS: Before treatment, the mean number of vertebral fractures was 3.5, spinal T-score was -3±1, hip T-score was -1.9±0.7, serum C-terminal telopeptide was 357±258 pg/mL (N=80-800), bone alkaline phosphatase was 20±3.2 IU (N=8-25), and tryptase was 49±36 µg/mL (N<10). Interferon alpha was discontinued in 2 patients because of poor tolerance. Mean follow-up was 60 months. No patient developed a fracture under treatment. In the 8 patients treated with interferon alpha and pamidronate, the mean annual increase in spinal bone mineral density was 12.6%±5.6% and 1.93% in hip bone mineral density. Serum C-terminal telopeptide decreased by 66%, bone alkaline phosphatase decreased by 25%, and tryptase decreased by 34%. In the 2 patients treated with pamidronate alone, mean annual bone mineral density increase was 2.4%±0.1% at the spine and 0%±01% at the hip. CONCLUSION: Osteoporosis secondary to mastocytosis mainly affects trabecular bone, and markers of bone remodeling are normal. Combined treatment with low doses of interferon and pamidronate markedly increased bone density.

Bent spine syndrome (camptocormia): a retrospective study of 63 patients.

OBJECTIVES: Bent spine syndrome (BSS) is characterized by involuntary forward flexion of the trunk in the standing position but not in the recumbent position. We assessed the causes of BSS based on findings in 63 patients. METHODS: We retrospectively reviewed the records of all patients with BSS evaluated at a teaching hospital in Toulouse, France, between 1995 and 2006. For each patient, we recorded the findings from the following investigations: physical examination, electromyogram (EMG), creatine phosphokinase (CPK) assay, computed tomography (CT), and surgical muscle biopsy. RESULTS: We identified 63 patients, 46 females and 17 males, with a mean age of 70 ± 6.9 years. Among them, 40 had delayed-onset paraspinal myopathy, with fatty infiltration predominantly affecting the paraspinal muscles. In 40% of these patients, CT disclosed mild fatty infiltration of the gluteal and posterior thigh and leg muscles in addition to the paraspinal muscle abnormalities. Paraspinal muscle histology showed lobular endomysial fibrosis, as previously described and ruled out other forms of muscle dystrophy. The remaining 23 patients (14 females and nine males) had either another neurological disease or myopathic involvement of other muscles, with a definite diagnosis; nevertheless, forward bending of the trunk was the most prominent symptom and the reason for the initial physician visit. CONCLUSION: In our case-series, delayed-onset paraspinal myopathy accounted for 64% of cases of BSS. The most informative investigation was CT, which showed a patchy decrease in paraspinal muscle density.