Calcinosis In Systemic Sclerosis Research Articles

A rare form of calcinosis in patients with systemic sclerosis-myositis overlap: report of four cases.

Calcinosis is a well-described entity that occurs in patients with systemic sclerosis (SSc) and dermatomyositis (DM). Calcinosis in SSc typically occurs over pressure points and is usually nodular. We present a case series of four patients with SSc with a much rarer, diffuse form of calcinosis to illustrate this poorly recognized pattern of extensive and debilitating disease. Four patients with SSc and extensive calcinosis were identified from patients attending a tertiary rheumatology centre in the preceding 3 years. Their electronic case notes, radiographic images and medical photographs were reviewed. All four patients had the diffuse cutaneous subtype of SSc (dcSSc) and additionally a myositis overlap. This was in the context of 102 of 461 (22%) patients with SSc whose clinical details had been recorded in the preceding 3 years having dcSSc. Their ages at diagnosis ranged from 27 to 65 years. Three were female, two were anti-Scl70 antibody positive, and two were anti-PMScl antibody positive. Development of calcinosis occurred between 1 and 6 years after onset of SSc. Plain radiography showed very extensive calcinosis in various sites, distributed in a pattern akin to sheets of calcium-containing deposits in the skin and subcutaneous tissue. Although calcinosis is common in SSc, extensive sheet-like calcinosis is very rare. Our experience suggests that when this form of calcinosis does occur, this is in the context of the diffuse cutaneous subtype of disease and with myositis overlap. The four cases described should raise awareness of this unusual and extensive pattern of disease.

Sedimentation Sign in Tumoral Calcinosis in Systemic Sclerosis.

Sedimentation Sign in Tumoral Calcinosis in Systemic Sclerosis.

Calcinosis in systemic sclerosis.

To provide updated information on the prevalence, pathogenesis, diagnostics, and therapeutics of calcinosis cutis associated with systemic sclerosis (SSc). Observational studies show ethnic and geographical differences in the prevalence of calcinosis. In addition to clinical and serological associations, biochemical studies and in-vivo models have attempted to explain theories behind its pathogenesis, including prolonged state of inflammation, mechanical stress, hypoxia, and dysregulation in bone and phosphate metabolism. Long-term use of proton pump inhibitors may increase the risk for calcinosis in SSc. Few single center observational studies have shown mild benefit with minocycline and topical sodium thiosulfate. Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It affects up to 40% of SSc patients and causes significant morbidity. Long disease duration, features of vascular dysfunction, and osteoporosis have been associated with calcinosis. Altered levels of inorganic pyrophosphate and fibroblast growth factor-23 have been implicated in dysregulated phosphate metabolism that may lead to calcinosis in SSc. Plain radiography can help with diagnosis and quantifying the calcinosis burden. Surgical treatment remains the most effective therapy when feasible. At present, no medical therapies have proven efficacy in large randomized controlled trials.

Scrotal Calcinosis in Juvenile Systemic Sclerosis.

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues, frequently associated with autoimmune connective tissue diseases, including systemic sclerosis (SSc).1 Calcinosis in SSc presents as subcutaneous nodules of variable size and shape, most frequently on the fingers, but can also affect other locations.2.

Calcinosis in systemic sclerosis.

The aim of this study was to provide updated information on the prevalence, pathogenesis, diagnostics and therapeutics of calcinosis cutis associated with systemic sclerosis (SSc). Observational studies show ethnic and geographical differences in the prevalence of calcinosis. In addition to clinical and serological associations, biochemical studies and in-vivo models have attempted to explain theories behind its pathogenesis, including prolonged state of inflammation, mechanical stress, hypoxia and dysregulation in bone and phosphate metabolism. Long-term use of proton pump inhibitors may increase the risk for calcinosis in SSc. Few single-centre observational studies have shown mild benefit with minocycline and topical sodium thiosulfate. Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It affects up to 40% of SSc patients and causes significant morbidity. Long disease duration, features of vascular dysfunction and osteoporosis have been associated with calcinosis. Altered levels of inorganic pyrophosphate and fibroblast growth factor-23 have been implicated in dysregulated phosphate metabolism that may lead to calcinosis in SSc. Plain radiography can help with diagnosis and quantifying the calcinosis burden. Surgical treatment remains the most effective therapy when feasible. At present, no medical therapies have proven efficacy in large randomized controlled trials.

Subcutaneous calcinosis: Is it different between systemic sclerosis and dermatomyositis?

Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It is a manifestation of several autoimmune connective tissue diseases, most frequently with systemic sclerosis and juvenile dermatomyositis, followed by adult dermatomyositis. Autoimmune connective tissue disease-associated calcinosis is of the dystrophic subtype, which occurs at sites of damaged tissue in the setting of normal serum calcium and phosphate levels. In juvenile dermatomyositis, calcinosis is considered a marker of ongoing disease activity and possibly inadequate treatment, while in adult dermatomyositis, it is a hallmark of skin damage due to chronic rather than active disease. Calcinosis is associated with long disease duration in systemic sclerosis and dermatomyositis, anti-polymyositis/sclerosis autoantibodies in systemic sclerosis and NXP-2 and melanoma differentiation-associated gene 5 in dermatomyositis. Calcinosis in systemic sclerosis occurs most frequently in the hands, particularly the fingers, whereas in dermatomyositis, it affects mainly the trunk and extremities. The primary mineral component of calcinosis is hydroxyapatite in systemic sclerosis and carbonate apatite in dermatomyositis. Calcinosis in dermatomyositis and systemic sclerosis share some pathogenic mechanisms, but vascular hypoxia seems to play a more important role in systemic sclerosis, whereas the release of calcium from mitochondria in muscle cells damaged by myopathy may be a primary mechanism contributing to dermatomyositis-related calcinosis. Multiple treatment strategies for dermatomyositis and systemic sclerosis-related calcinosis have been used with variable results. Early aggressive treatment of underlying myositis in patients with dermatomyositis may improve long-term outcomes of calcinosis. A better understanding of the pathogenesis of calcinosis is needed to improve treatment options.

Кальциноз при системній склеродермії: поширеність, клініка, менеджмент, ускладнення

У даному літературному огляді підсумовано сучасні дані щодо епідеміології, патофізіології, діагностики та лікування шкірного кальцинозу у пацієнтів із системною склеродермією (ССД). Проведено аналіз обсерваційних досліджень, що описують частоту кальцинозу при ССД і асоційованих з ним клінічних ознак; молекулярних досліджень, що вивчають потенційні патогенетичні механізми; наведені клінічні випадки, що описують нові діагностичні підходи і методи лікування кальцинозу. Шкірний кальциноз — це відкладення нерозчинного кальцію в шкірі і підшкірних тканинах. Кальциноз — одна з основних, погано керованих клінічних проблем у пацієнтів із ССД, яка зачіпає щонайменше одну четверту частину хворих. Кальциноз асоційований з більшою тривалістю хвороби, дигітальними виразками, акроостеолізом, позитивними антицентромерними і антитопоізомеразними антитілами. Хоча патогенез кальцинозу остаточно невідомий, є докази, що підтверджують роль місцевої хронічної травматизації, хронічного запалення, судинної гіпоксії і дисрегуляції білків кісткового матриксу як потенційних механізмів розвитку цього патологічного стану у пацієнтів із ССД. Діагноз може бути встановлений на основі клінічних даних або за допомогою стандартної рентгенографії. Кілька фармакологічних методів лікування були застосовані у пацієнтів із кальцинозом зі змінними і не такими значущими результатами, у свою чергу, хірургічне видалення депозитів кальцію залишається основним методом лікування.

Characteristics of Japanese patients with systemic sclerosis complicated with calcinosis.

Calcinosis is often observed in systemic sclerosis (SSc), but its pathogenesis remains unclear. The aim of the present study was to explore the association of clinical features with calcinosis in patients with SSc. A retrospective cohort study was performed analyzing 416 SSc patients from our SSc database. We examined the clinical features with relation to calcinosis and SSc. Calcinosis was observed in 24.0% of patients with SSc. The group with calcinosis comprised more female patients (P<0.05) and diffuse cutaneous types (P<0.001) than the group without calcinosis. Complications of Raynaud's phenomenon (P<0.05), nail fold bleeding (NFB) (P<0.001), peripheral bone resorption (P<0.001), myositis (P<0.001), and pulmonary hypertension (P<0.05) were more frequently observed in patients with calcinosis compared with those without calcinosis. The group with calcinosis had a higher modified Rodnan total skin-thickness score (mRSS) than the group without calcinosis (P<0.001). The factors that affected calcinosis in multivariable analysis were peripheral bone resorption (partial correlation coefficient 0.46, 34%), anti-Scl-70 antibody (partial correlation coefficient 0.29, 20%), diffuse type (partial correlation coefficient 0.34, 16%) and NFB (partial correlation coefficient 0.23, 11.2%). Calcinosis in SSc is associated with Raynaud's phenomenon, NFB, and pulmonary hypertension, so peripheral circulatory insufficiency seems to be one of the causes of calcinosis. Furthermore, as it is related to mRSS and the diffuse cutaneous type, common factors related to skin fibrosis are considered to be involved.

P155 Modelling calcinosis in systemic sclerosis through disease microenvironment-stem cell interactions: effect of novel therapeutic peptide RP832c

Abstract Background/Aims Systemic sclerosis (SSc) is a rare and progressive connective tissue disease that is more common in women in the third to fifth decades of life and is rare in children. Calcinosis cutis, the deposition of calcium deposits within the subcutaneous tissue, remains a challenging non-lethal complication of SSc. The development of calcinosis cutis is a poorly understood area and there are no functional mouse models or laboratory models for calcinosis in SSc. In this study we present clinical database analysis plus two potential in vitro models for examining calcinosis in the setting of SSc. Methods Clinical modelling through database analysis of n = 79 SSc patients with and without calcinosis was attempted. In tissue culture studies, the first model system utilised adipose-derived mesencyhmal stem cells (MSCs) stimulated with interstitial fluid from healthy controls or SSc patients (both n = 4). In a second model, macrophages from patients with SSc (n = 4 lines) were used to stimulate MSCs in co-culture. We examined the impact that this has on the deposition of calcium hydroxyapatite production after prolonged culture in osteogenic media, measured using a scale (scored 0-4) to describe the degree of alizarin red uptake. We also investigated the role of an inhibitor of TGFβ signalling, SB432542 (10µM), and RP832c,(10µM), a peptide therapy which targets and repolarises activated SSc macrophages via CD206, in reducing calcium hydroxyapatite production. Results Clinical database analysis demonstrated that 35% of patients had evidence of calcinosis, but the only significant factor between the calcinosis and non-calcinosis group was the presence of digital ulcerations (p = 0.0008). The tissue fluid based model of calcinosis demonstrated that on day 21 the blister fluid obtained from SSc patients induced a significant increase in calcium deposition as compared to the culture media alone (3.9 vs 2.5, p = 0.00071), whereas SB431542, reduced calcium production by SSc fluid treated cells (3.9 vs 3.0, p = 0.2147). In the cell based model, macrophages derived from SSc patients induced the production of mineralised deposits. Both the TGFβ inhibitor SB432542 and the RP832c peptide reduced calcinosis in this model (SB431542 0.5 vs 1.3 p = 0.0547, RP832c 0.2 vs 1.3 p = 0.0147). Conclusion Our understanding of the underlying pathogenesis of calcinosis within SSc remains poor leading to therapeutic challenges for clinicians. From this analysis, it appears that presence of digital ulceration is associated clinically with calcinosis, possibly implicating aberrant tissue repair or ischaemia. Both tissue culture models presented here may recreate certain aspects of calcinosis in patients with SSc and may provide a basis for further evaluation of therapeutic inhibitors. At present there are no therapies that have been consistently found to be effective but our data support a possible role for macrophage - mesenchymal stem cell interactions and for TGFβ. Disclosure B.G.T. Coumbe: None. S.N. Ahmad: None. G. Thomas: None. L. Borukhson: None. B. Ahmed Abdi: None. H. Lopez: None. C. Garvin: None. J. Jaynes: None. C. Yates: None. G. Martin: None. C. Denton: None. D. Abraham: None. R.J. Stratton: None.

Calcinosis in systemic sclerosis.

Calcinosis in systemic sclerosis.

Calcinosis in Systemic Sclerosis: Updates in Pathophysiology, Evaluation, and Treatment.

Calcinosis is a common complication of systemic sclerosis with no known effective pharmacologic therapy. We reviewed the literature regarding systemic sclerosis-related calcinosis as well as other disorders of biomineralization in order to identify targets of future study for calcinosis. Patients with systemic sclerosis-related calcinosis demonstrate systemic abnormalities in mineralization pathways, including decreased levels of the mineralization inhibitor inorganic pyrophosphate. Insights from other mineralization disorders suggest that local and systemic phosphate metabolism pathways involving the ABCC6, ENPP1, and NT5E genes play a critical role in regulation of ectopic calcification. Knockout models of these genes may lead to an appropriate murine model for study of calcinosis. Poly(ADP-ribose) polymerase (PARP) enzymes may also play a critical role in hydroxyapatite nucleation and warrant future study in systemic sclerosis. Study of local and systemic mineralization pathways, particularly phosphate metabolism pathways and PARP enzymes, should provide greater insight into the pathogenesis of systemic sclerosis-related calcinosis.

High proton pump inhibitor exposure increases risk of calcinosis in systemic sclerosis

To investigate the association between proton pump inhibitor (PPI) use and the presence and severity of calcinosis in SSc. We analysed data from two SSc cohorts from a single centre. Cohort 1 included 199 patients reviewed over 10 years, for whom retrospective data on PPI use and calcinosis were available. Cohort 2 was recruited prospectively and included 215 consecutive patients, who underwent clinical assessment. Outcomes of interest were presence of current calcinosis (CC) or calcinosis at any time (CAT). The cohort 1 data analysis showed that among patients on standard dose PPI 20% had calcinosis, while in those on high doses of PPI calcinosis was present in 39% (P = 0.003). Analysis of the data from cohort 2 confirmed these findings, demonstrating that the odds of CAT increased significantly with longer PPI exposure [odds ratio (OR) 1.04, 95% CI: 1.02, 1.06; P < 0.001], longer disease duration (OR 1.08, 95% CI: 1.05, 1.12; P < 0.001) and greater age (OR 1.03, CI: 1.01, 1.05; P = 0.010). Multivariable logistic regression showed that higher exposure to PPI remained a significant predictor of calcinosis, with PPI exposure >10 years increasing the risk of CAT >6-fold, compared with no PPI (OR 6.37, 95% CI: 1.92, 21.17; P = 0.003) after adjusting for disease duration and antibodies. We confirm a significant association between high PPI exposure with severity of calcinosis in SSc. Given the clinical impact of calcinosis and reflux in SSc, PPI exposure as a potentially modifiable risk factor for calcinosis requires further evaluation.

Pseudotumoral calcinosis in systemic sclerosis: Data from systematic literature review and case series from two referral centres

ObjectivesWe aimed to clarify the definition, distribution, clinical association and outcomes of large calcinosis in patients with systemic sclerosis (SSc). MethodsWe conducted a systematic literature review (SLR) focusing on SSc-related large calcified masses. Upon updating the terminology and definition, all cases of “pseudotumoral” calcinosis seen at the Cochin and Padova University Hospitals were reviewed. ResultsThe SLR yielded 30 SSc cases, with large calcified masses mainly defined as “tumoral” or “pseudotumoral”. Among the 629 SSc cases included in the Cochin and Padova cohorts, 19 (3%) living and 7 deceased patients were affected by pseudotumoral calcinosis; among these, the great majority had a severe vascular phenotype. The mean age in the whole population (56 cases) was 59 ± 11.4 years with a median disease duration at calcinosis onset of 7 (5–10) years. Twenty-five out of 56 patients (44.6%) had the diffuse cutaneous form of SSc. Anti-topisomerase I and anticentromere were found equally. Pseudotumoral calcinosis were commonly symmetrical and the size ranged from 2 to 15.5 cm. Most patients had multiple site involvement: 52% hand/wrist, 29% shoulders and elbows, 20% hips and 25% spinal calcinosis. Fistulization/ulceration and infections were reported in 32% and 23% of cases, respectively; nerve compression was found in 40% of spinal calcinosis and in one patient with limb calcinosis. There was no clear evidence of clinical and radiological improvement with any treatment. A partial improvement was seen in 7 patients that underwent surgery. ConclusionPseudotumoral calcinosis may occur in about 3% of SSc patients, commonly symmetrical and in multiple sites without differences regarding the cutaneous subtypes but often in those with a severe vascular phenotype. Medical treatment seems ineffective, whereas a surgical approach may be considered.

133 Coexistent tophaceous gout and calcinosis in systemic sclerosis

133 Coexistent tophaceous gout and calcinosis in systemic sclerosis

Imaging calcinosis in patients with systemic sclerosis by radiography, computerised tomography and magnetic resonance imaging

IntroductionObjective outcome measures are needed to facilitate clinical trials of much needed treatments for calcinosis in systemic sclerosis (SSc). Our primary aim was to compare radiography, computed tomography (CT) and magnetic resonance imaging (MRI) to measure calcinotic lesions. Secondary objectives included to examine reproducibility of radiography and MRI, and inter-rater reliability of MRI. Materials and Methods15 patients with SSc and clinically apparent calcinosis were studied. On one hand, radiography, CT and MRI were performed. The number (all techniques), area (radiography) and volume (CT and MRI) of calcinotic areas were extracted by ‘blinded’ musculoskeletal radiologists. ResultsNo significant difference (P = 0.289) in the mean (SD) number of lesions (per hand) was seen between radiography: 5.4 (4.6), CT: 6.3 (6.5) and MRI: 5.2 (3.9). Mean (SD) lesion volumes were systematically higher as measured by CT: 656.7 (1939.9) mm3 compared to MRI: 442 (1083.2) mm3. Radiographic area was highly correlated (P = <0.0001) with volume for both CT and MRI (rho=0.91 and 0.87, respectively). DiscussionIt was possible to measure calcinotic lesions by radiography, CT and MRI, with CT volume being higher than MRI volume. Radiographic area was highly correlated with CT and MRI volume, suggesting that low cost radiographs may give comparable information to 3-dimensional imaging. Our findings provide further insight into the development of objective outcome measures to facilitate future calcinosis clinical trials.

Demographic and clinical characteristics of spinal calcinosis in systemic sclerosis: Possible association with peripheral angiopathy.

The objective was to evaluate the demographic and clinical characteristics of systemic sclerosis (SSc) patients with spinal calcinosis. Paraspinal and intraspinal calcinosis was assessed blindly by orthopedic surgeons specializing in spinal diseases using chest high-resolution computed tomography (CT) that was performed for the screening and prospecting of interstitial lung disease in 159 Japanese SSc patients. Among these patients, we identified 27 (17%) with spinal calcinosis, and the most common site was cervical level at 77.8% (21/27). The frequency of spinal calcinosis in the late stage was higher than in the early stage (44.4% vs 29.6%). Multiple calcinosis was identified in 18.5% (5/27). The frequency of paraspinal calcinosis only was 59.3%, intraspinal calcinosis only 18.5%, and both intraspinal and paraspinal calcinosis 22.2%. Among SSc patients, 4.4% (7/159) had CT-based evidence of spinal cord compression. Among cases with spinal cord compression, only one had neurological symptoms, and surgical removal improved the symptoms. The other six SSc patients with spinal calcinosis (3.8% of 159) had no symptoms. Male sex (29.6%) and severe peripheral vasculopathy such as digital ulcers (55.6%) and acro-osteolysis (33.3%) were significantly more frequent in the SSc patients with spinal calcinosis than in the SSc patients without spinal calcinosis (10.6%, 32.6% and 14.4%, respectively). Our results suggest that severe peripheral vasculopathy may be associated with the development of spinal calcinosis. Because SSc patients are prone to spinal calcinosis, when SSc patients claim symptoms such as pain, numbness and movement disorder of the extremities, spinal calcinosis is a complication that should be taken into consideration.

Calcinosis in scleroderma.

To provide an update on the available literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc). We identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features; molecular studies exploring potential pathogenic mechanisms; and case reports and case series describing new diagnostic approaches and treatments. Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.

206 Proton pump inhibitor use is associated with calcinosis in systemic sclerosis

206 Proton pump inhibitor use is associated with calcinosis in systemic sclerosis

Calcinosis in systemic sclerosis: subsets, distribution and complications.

To retrospectively analyse the features of calcinosis in a cohort of SSc patients. Charts of SSc patients attending the Ulcer Unit of the Rheumatology Department, University of Florence and presenting a clinical suspicion of calcinosis were considered in the study. Data on clinical history, including recent skin changes, and clinical examination of all areas with suspected calcinosis, radiological imaging of the calcinotic area, demographics and SSc-related organ involvement and pain measured by a visual analogue scale were recorded. In 52 of 112 SSc patients, a total of 316 calcinoses were recorded and were divided into visible and palpable {154 [47.4%], clustered according to their macroscopic features as mousse [49 (31.8%)] and stone [: 105 (68.2%)]} and non-visible but palpable {: 162 [52.6%]: net [5 (3%)], plate [22 (13.8%)] and stone [135 (83.2%)]}. The X-ray-based classification of all calcinoses, both visible and non-visible, was as follows: stone, 289 (91.4%); net, 12 (3.8%) and plate, 15 (4.8%). Skin ulcers complicated 154 of 316 calcinoses (48.7%). Mousse calcinosis was associated with pulmonary arterial hypertension, the stone subset was suggestive of pulmonary involvement and justified further investigation and the net subset was the slowest to heal. Our data indicate that calcinosis may be classified in SSc as mousse, stone, net and plate according to its clinical and X-ray features. This classification awaits validation for a possible use in clinical practice and to support early treatment and prevention of complications.

Calcinosis: pathophysiology and management.

This article reviews the most updated literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc). Our review identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features, genetic studies in animal models of heritable disorders leading to calcium deposition, and case series and case reports describing new diagnostic approaches and therapeutic interventions. Calcinosis cutis is the deposition of calcium in the skin and subcutaneous tissues. It affects almost one quarter of patients with SSc, and is associated with longer disease duration, digital ulcers, acroosteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Local trauma, chronic inflammation, and vascular hypoxia have been proposed as potential pathomechanisms. The development of mouse models that mimic heritable ectopic mineralization disorders are contributing to the understanding of the process of calcification. Diagnosis can be made clinically or with plain radiography. Experimental diagnostic studies include ultrasonography, multidetector computed tomography, and dual-energy computed tomography. Several pharmacologic therapies have been tried for calcinosis with variable results, but surgical excision of calcium deposits remains the mainstay of treatment.