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SYSTEMIC SCLEROSIS-RELATED CALCINOSIS SHORT TITLE: Systemic sclerosis-related calcinosisAriane L. Herrick, MD, FRCP1 and Andrzej Gallas, PhD2Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester UK, and NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.Manchester School of Pharmacy, The University of Manchester, Manchester UK. Corresponding author: Ariane Herrick, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester UK. Telephone: 0161 275 5993. Email: ariane.herrick@manchester.ac.uk MANUSCRIPT WORD COUNT: 3814 ABSTRACTPurpose. To provide an update on the clinical burden of calcinosis (subcutaneous or intracutaneous deposition of calcium salts) in patients with systemic sclerosis (SSc), and discuss advances in our understanding of pathogenesis, associates, and measurement techniques, as well as an overview of the current approach to management. Methods. Four case scenarios are presented, to illustrate the clinical spectrum of calcinosis. Epidemiology (including associates), pathogenesis, imaging and measurement, and treatment are reviewed.Results. Calcinosis represents a major clinical problem in patients with SSc. Up to 40% of patients are affected, the proportion depending in part on how carefully calcinosis is looked for. Associates of calcinosis include longer disease duration, anticentromere antibody, and digital ulceration. When severe, calcinosis causes pain, disability, and disfigurement. Pathogenesis is unknown, but tissue ischaemia, microtrauma, and loss of balance between calcification stimulants and inhibitors are likely contributors. Calcinosis deposits are mainly composed of hydroxyapatite. They are very visible on plain radiographs and radiographic scoring systems are being developed, and other imaging modalities (including computed tomography and ultrasound) are being explored. Despite a number of proposed treatments, currently there is no effective ‘disease-modifying’ therapy for calcinosis and the main aspects of management are antibiotics, analgesics, multidisciplinary team input, and surgical debulking. Conclusions. Up until recently, SSc-related calcinosis has received very little attention in terms of research into pathogenesis, measurement, and treatment. This imbalance is now being redressed and although we still do not have an effective treatment, progress is being made. KEY WORDS: CALCINOSIS, IMAGING, PATHOGENESIS, SYSTEMIC SCLEROSIS, TREATMENT INTRODUCTION Calcinosis (subcutaneous or intracutaneous deposition of calcium salts) is a major clinical problem in patients with systemic sclerosis (SSc, also termed ‘scleroderma’). In the order of 20-40% of patients with SSc are affected (1-6) and develop calcinotic deposits or ‘lumps’, usually over pressure points for example in the fingers, and over the elbow, knee and ischial tuberosities. Calcinotic lumps are often painful and disabling, and they can become infected (7) especially when they ulcerate through skin. As discussed in detail below, there is currently no treatment which has proven efficacy.SSc-related calcinosis has been a neglected area in terms of research. However, the situation is changing, with recent papers describing associates of calcinosis, how to measure calcinosis, and some anecdotal reports of treatment response. The aim of this review is to describe the clinical burden of calcinosis (exemplified by some short scenarios), and to discuss advances in understanding of associates, pathogenesis, and measurement of disease process. Lastly we shall review treatment, discussing the various approaches which have previously been suggested, and discussing possible future developments. EPIDEMIOLOGY OF CALCINOSIS IN PATIENTS WITH SSC, INCLUDING ASSOCIATES OF CALCINOSISPrevalence of calcinosis amongst patients with SSc is in the order the order of 20-40% (1-6). Although it is commonly thought that calcinosis occurs predominantly in the limited cutaneous subtype of SSc (lcSSc, previously often termed CREST – Calcinosis, Raynaud’s, Esophageal involvement, Sclerodactyly, Telangiectases), patients with diffuse cutaneous SSc (dcSSc) can also develop very severe calcinosis. Akesson and Wollheim in 1989 reported similar frequencies of calcinosis in limited and diffuse cutaneous disease (32% and 24%, respectively) (2). The prevalence increases with disease duration (1,5,6): Steen et al (1) reported that in patients with disease duration less than 5 years, calcinosis was present in 43% of anticentromere positive and in 9% of anticentromere negative patients, whereas in patients with disease duration of more than 15 years, 72% of anticentromere positive and 29% of anticentromere negative patients were affected. Calcinosis has been associated with certain SSc-specific autoantibodies. As above, Steen et al. (1) over 30 years ago reported an association with anticentromere antibody, a finding since confirmed by other authors (5,6,8-10). An association between anti-PM-Scl antibody and calcinosis has recently been reported (11,12). Conversely a negative association with anti-topoisomerase (Scl-70) antibody has been described (5,6,9,10). A recent retrospective cohort study of over 5000 patients with SSc reported that the strongest associates of calcinosis were digital ulcers and osteoporosis (6). As discussed under pathogenesis, several other studies have suggested (albeit indirectly) an association with severity of digital ischaemia. A history of surgical debridement has also been associated with calcinosis (5). Prevalence depends on how carefully calcinosis is defined and looked for. For example, a small study demonstrated that 9 of 30 (30%) 20% of unselected patients with SSc had clinically apparent calcinosis and in addition 6 (20%) had subclinical calcinosis, as identified on hand radiographs (13). Therefore the prevalence of clinically apparent calcinosis (palpable lumps, or a good history of extrusion of calcinotic material) is lower than a composite of clinically and/or radiographic calcinosis. THE CLINICAL PROBLEM, WITH SCENARIOSAlthough subclinical (but radiographically apparent) calcinosis is of interest regarding pathophysiology, patients are only concerned with calcinosis posing problems in terms of pain, superimposedadded infection, ulceration, loss of function and cosmesis. While calcinosis tends to occur at subcutaneous pressure points, other areas including spine can be affected. Patients often complain of ‘toothpaste-like’ material coming out through the skin. When this occurs, there is always a concern that the point of ulceration may act as a site of entry for infection. Four cases are presented briefly, exemplifying some of the challenges of SSc-related calcinosis.Scenario 1 - Calcinosis of hands and kneeThis 71 year old woman with a 14 year history of lcSSc (anticentromere positive) and calcinosis had major problems relating to her hands and knees over several years. The calcinosis overlying the knees (Figure 1a,b) became recurrently infected (Figure 1c), and in 2007 she required surgical incision and drainage of the right prepatellar bursa. The calcinotic lumps of her hands (Figures 1d,e,f) frequently ulcerated through skin and she had several surgical debridements including of her right thumb, and left index and middle fingers. Key aspects of her management included early antibiotic therapy (sometimes intravenous (IV)) for any suspicion of infection, careful wound care (with rapid access to a nurse-led clinic), and rapid access to hand surgery for debridement if deemed necessary for increasing pain and limitation of function. Her calcinosis was the most prominent aspect of her disease. Scenario 2 - ‘Sheet calcinosis’ and calcinosis overlying spinous processesThis 55 year old woman with an eight year history of dcSSc (anti-RNA polymerase positive) developed calcinosis approximately three years after her initial diagnosis. In early 2014 she complained of increasing ‘hardness’ of her upper arms, which felt much harder than would be expected from skin thickening alone. Plain radiographs confirmed sheet-like calcinosis (Figure 2). Another major problem was a non-healing ulcer over an area of calcinosis overlying her lower thoracic/upper lumbar spine, which 4 months previously had become infected requiring IV antibiotics. The calcinosis contributed to the ulceration, and extruded through it (Figure 3a). Computed tomography (CT) of the thoracic spine showed subcutaneous calcinosis at the level of L1/L2 (Figure 3b). The mainstay of management was careful wound care. She had very major intestinal involvement of her SSc with difficultly maintaining her nutrition, as well as pulmonary fibrosis, and she died 9 months later. Scenario 3 - Spinal calcinosisThis 56 year old woman with a seven year history of dcSSc (anti-RNA polymerase positive) developed neck pain around one year after diagnosis. Plain radiography demonstrated spinal calcinosis, in addition to multilevel spondylotic change, confirmed on CT (Figure 43). The neurosurgical team felt no surgery was indicated, given that there was no clinical evidence of neurological compromise, although she was advised to report any new symptoms which would require reassessment. Over the years she had continuing neck pain with restriction of movement. Scenario 4 - Intra-articular calcinosis This 61 year old woman with a seven year history of dcSSc/rheumatoid arthritis overlap (anti-Scl-70 positive, anti-Ro positive and rheumatoid factor positive) developed increasing wrist pain. On examination the wrists were swollen with synovitis, but with an unusual hardness to the swelling. Plain radiographs showed extensive calcification (right hand shown in Figure 54a) and CT scans showed these to be intra-articular (Figure 54b). Over the subsequent 3 years she has had ongoing problems with her wrists. Current drug treatment includes methotrexate and low-dose prednisolone. These case histories demonstrate a number of key points: The clinical burden of calcinosis. This occurs mainly because of pain (with or without skin ulceration) and functional limitation. Patients can have significant compromise of (for example) hand function, including restriction of movement caused by encasement of joints and of peri-articular structures. The feet may also be affected (14). Different ‘patterns’ of calcinosis occur. The most common type is heterogeneous ‘nodular’ masses (sometimes described as ‘tumoral’ especially when extensive). Less commonly calcinosis can occur in sheets (linear calcification, Scenario 2), as has been described also in dermatomyositis, and is well demonstrated on plain radiographs (15,16). Calcinosis can affect spinal and paraspinal tissues (Scenario 3). This is under-recognised although has now been described in multiple case reports and small series (17-24), and is well visualised on CT. Cervical, thoracic or lumbar spine may be affected (24). Surgery may be required to debulk the calcinosis, if associated with nerve root or spinal cord compression (17-22). Calcinosis may rarely be intra-articular (Scenario 4) (25). When intra-articular, the joint may be severely restricted in movement. Chalky white synovial fluid containing apatite was described in a report from 1977 of a 26 year old patient with SSc and extensive calcification around the knee (26). Although SSc-related calcinosis can (rarely) affect the breast, this diagnosis must be made with extreme caution, and referral to a breast surgeon is always indicated to exclude other causes of calcific breast lesions.PATHOGENESISWhy calcinotic deposits develop in SSc is currently unknown. They are not related to either hypercalcaemia or hyperphosphataemia (although, rarely, patients with SSc may develop calcification for 'other' reasons, the discussion here relates to SSc-related calcinosis). It has been suggested that ischaemia may drive calcinosis. In favour of this are:A report by Vaysiarrat et al. (10) suggested that calcinosis was associated with increased severity of microvascular change as demonstrated by nailfold capillaroscopy, compared to patients without calcinosis, although this was not confirmed in another study (27). Calcinosis associates with severity of digital ischaemia as measured by digital ulceration (4,6,28-29) and (as above) with surgical debridements (5). Also, severe calcinosis was found to be associated with acro-osteolysis (30) and although the pathogenesis of SSc-related acro-osteolysis is unknown, it seems highly likely that this is driven by ischaemia. Expression of advanced glycation/lipoperoxidation end products (AGEs) and their receptor (RAGE) were increased in forearm skin of patients with SSc-related calcinosis compared to those without calcinosis (31). (R)AGEs are a marker of oxidative stress, which is thought to contribute to (and result from) the ‘vascular’ pathogenesis of SSc. Also, expression of hypoxia-associated glucose transporter molecule, GLUT-1, was increased in forearm skin of patients with lcSSc with calcinosis compared to those with lcSSc without calcinosis (32).However, despite these pointers, the relationship (if any) between SSc-related calcinosis and ischaemia remains unclear. The fact that calcinotic deposits often occur over pressure points suggests that calcinosis may be dystrophic (occurring in abnormal tissue, for example inflamed or injured), and that mechanical pressures from the external environment are contributory. Calcinosis more commonly affects the thumb than other fingers (33), supporting this hypothesis. The increasing prevalence of calcinosis with SSc disease duration (1,5,6) (and therefore longer duration of exposure of ischaemic tissues to repetitive pressures), is also consistent. Repeated pressures may trigger microinjuries of subcutaneous blood vessels and subsequent inflammation. However, shear forces acting on the skin are of random directions and intensities, possibly explaining inconsistent morphology of calcinotic deposits (Figure 65).Additionally, existing evidence in the literature indicates similarities between SSc-related calcinosis and vascular calcification, including:Similar sequence of pathological events: calcium deposition is preceded by tissue injury and inflammation and followed by tissue necrosis (34).Vascular calcification is associated with loss of balance between calcification stimulants and inhibitors (35). This has also been reported for SSc-related calcinosis: (I) Expression levels of osteonectin (also termed SPARC (Secreted Protein Acidic and Rich in Cysteine) or basement-membrane protein (BM-40)) and matrix gamma-carboxyglutamic acid protein (MGP) are higher in forearm skin of patients with SSc with calcinosis compared to those without (36). Osteonectin is viewed as a calcification stimulant, while MGP is both an inhibitor and stimulant depending on the γ-carboxylation and phosphorylation status of its domains: carboxylated/phosphorylated MGPs inhibit, while non-modified MGPs promote calcification (35). (II) Overexpression of a calcification stimulant, transforming growth factor (TGF) beta, has been reported around calcific deposits in a patient with SSc (37). (III) Belloli et al. (38) reported that fetuin-A (also termed AHSG (α-2-Heremans-Schmid Glycoprotein)) serum concentrations were significantly lower in patients with SSc with calcinosis than in those without calcinosis, suggesting that this calcification inhibitor may also play a role in pathogenesis. (IV) Serum levels of another calcification inhibitor, osteoprotegerin, have been reported to be increased in patients with SSc and calcinosis (39). (V) Oxidative stress markers: (R)AGEs (see above) have been demonstrated to accelerate formation of vascular calcifications (40).Calcific deposits in both conditions are mainly composed of hydroxyapatite and carbonated apatite (41-43) (Figure 6). Additionally, formation of hydroxyapatite crystals is preceded by the appearance of microdeposits (42,44). Presence of bone minerals is also why ossification-related pathways may play a role in pathogenesis of both conditions (42).Vascular calcifications have been reported to originate from different type of cells: pericytes in microvessels, pericyte-like, calcifying vascular cells in the aortic intima, smooth muscle cells in the media and myofibroblasts in the adventitia (42). Analysis of biopsy samples obtained from the forearms of patients with calcinosis indicates that the abnormal expressions of SPARC, MGP and (R)AGEs have been associated with microvascular endothelial cells (31,36). It is therefore possible that formation of calcific deposits in SSc may originate in microvessels (31,42).Although it is likely that pathogenesis of SSc-related calcinosis and vascular calcifications share similarities, the exact mechanisms and relationships remain unclear.Since the above do not adequately explain why only some patients with SSc develop calcinosis, it is likely that other, currently unknown factors contribute. IMAGING AND MEASUREMENT To research calcinosis, it must be measurable. This poses a new set of challenges. How does one measure the clinical burden of calcinosis in, for example, Scenarios 1 and 2? However, progress is being made. Calcinosis is very visible on plain radiographs (Figures 1a,b,f, 2b, 43a, 54a). Chung et al. (45) have recently developed a radiographic scoring system for hand calcinosis, based on 22 anatomic locations in each hand. The scoring system takes into account the percentage area (of each anatomic location) covered with calcium, the density (on a 1 to 3 scale), and a weighting for anatomic location. The study which involved twelve raters reported excellent inter- and intra-rater reliability (45). These reliabilities were superior to those of a much simpler 0 to 3 scoring (used in an earlier study examining the relationship between calcinosis and acro-osteolysis (30,45)) which is unlikely to be sufficiently sensitive to examine change over time. Both scoring systems require validation for use in longitudinal studies. A number of other imaging modalities offer promise in quantifying calcinosis. CT scanning produces three dimensional images which have the potential of measuring calcinosis ‘volume’, and gives a very visual demonstration of the extent of calcinosis (e.g. Figures 3b, 43b,c and 54b and (46)). Hsu et al. (47) reported recently that dual-energy CT performed better than plain radiography in imaging calcinosis in 16 patients with SSc: advantages of CT were that location and degree of bone destruction could be more accurately determined, especially in patients with contractures. Multidetector CT has also been advocated (48) and can very accurately gauge the size and exact location of calcinotic deposits: Freire et al. concluded that multidetector CT may therefore have a role in pre-operative assessment and in treatment follow-up. However, the radiation involved weighs against CT for development for use in clinical trials. MR imaging gives good visualisation of surrounding structures and any associated oedema, but gives poorer definition of the calcinotic lesions themselves. Ultrasound scanning has been suggested as a sensitive imaging modality for calcinosis detection, but is very operator dependent. A study including 44 patients with SSc (49) reported that plain radiography and ultrasound had similar sensitivity in detecting calcinosis in the hands and wrists. All these methodologies warrant further research into their ability to characterise and measure SSc-related calcinosis. Patient reported outcome measures are being developed (50). TREATMENT Treatment is considered under the heading of ‘general measures’, and ‘specific therapies aimed at reducing calcinosis’ (drug treatment and procedures).General measures including antibiotic treatment Antibiotics and analgesia. Patients with calcinosis should be advised to seek urgent medical advice if any of the calcinotic areas becomes infected. If the patient presents early, then prompt treatment with oral antibiotics may suffice. A swab for microbiology should be sent from any ulcerated lesion, to inform the choice of antibiotic. If a patient is clinically septic and/or there is spreading cellulitis, then admission for IV antibiotics may be required as in Scenarios 1 and 2. ‘Flares’ of calcinosis (whether or not infected, and this can be very difficult to tell clinically) are painful, and so the analgesic regime must be reviewed and consideration given to a short course of a non-steroidal anti-inflammatory drug, bearing in mind that patients with SSc are at increased risk of adverse effects including upper gastro-intestinal and renal.It is likely that some large areas of calcinosis, especially those that recurrently ulcerate through skin, are chronically infected. This poses a clinical dilemma because the calcinosis then acts essentially as an infected foreign body and, as discussed below, surgery is unlikely to ever completely remove calcinosis (only debulk). Multidisciplinary team (MDT) input. Expert wound care, possibly with involvement of the tissue viability team, is another important aspect of management. When calcinosis involves the toes, then podiatry input is important to ensure that appropriate footwear minimises the chances of pressure points over calcinotic lumps developing into ulcerations. Occupational therapy is another important aspect of management, for example in patients with compromised hand function. Specific therapies aimed at reducing calcinosis – drug treatmentsThere have been no controlled clinical trials of therapy specifically for SSc-related calcinosis. Over the years a number of different therapies have been advocated on the basis of case reports or small series, some of which have also included patients with dermatomyositis-related calcinosis. It should be remembered that anecdotal reports of treatment efficacy/inefficacy have to be interpreted against the background that symptoms of calcinosis may ‘improve’ spontaneously (including by discharging through skin) and that the burden of calcinosis (as discussed above) is difficult to measure (and therefore progression and regression difficult to quantify). Whether any treatment is of any benefit is very questionable: most clinicians agree that at present there is no known ‘disease-modifying’ therapy for calcinosis. Some of the different approaches which have been tried are described briefly below. This is not an exhaustive list, and in recent years several detailed reviews of suggested treatments for calcinosis have been published (51-56) which discuss other treatments which have been advocated (but not discussed here) including intra-lesional injection of corticosteroids, IV immunoglobulins, and aluminium hydroxide. Warfarin. Low-dose warfarin was one of the first drugs advocated, the rationale being that it hinders carboxylation of glutamic acid, and therefore reduces levels of gamma-carboxyglutamic acid thought to be implicated around calcinotic tissue (57). A small randomised double-blind placebo-controlled study in which 7 of 8 patients with SSc and/or dermatomyositis completed 18 months’ treatment (4 had SSc, two in overlap) showed no clinical benefit, but two of three patients randomised to warfarin and who completed 18 months' treatment had some improvement in isotope bone scan scores, compared to none of the four patients who received placebo for 18 months (57). Anecdotal reports include a report of two patients with SSc-related calcinosis who improved on warfarin (as opposed to a third with more severe and longer established calcinosis who did not improve) (58). Especially given that there have been concerns that warfarin might promote calcification through undercarboxylated MGP (59), which as discussed above could stimulate tissue calcification, there seems no good reason to recommend warfarin. Colchicine. Some clinicians advocate this as a first line therapy (54) although there is very little evidence base. In the Mayo Clinic retrospective series of 78 patients with calcinosis (of whom 24 had SSc) (60) the only patient having a complete response to medical therapy alone was one of the eight patients treated with colchicine (this patient also received methotrexate), with two other patients having a partial response. Given that areas of calcinosis can ‘flare’, presumably due to shedding of crystals into the soft tissues, there is some rationale for this approach. Diltiazem. Early reports suggested that treatment with this calcium channel blocker might lead to regression of calcinosis (61,62), and in the Mayo series, 9 of 17 patients treated with diltiazem were described as having a partial response (60). However, no overall beneficial effect from 60 mg three times daily (prescribed for Raynaud’s) was observed in the 12 patients in a retrospective study in whom repeat hand radiographs were available (10). Minocycline. Robertson et al. (63) reported that in an open-label study of 50mg or 100mg minocycline daily, eight of nine patients with SSc experienced improvement in calcinosis (after a mean of 4.8 months) in terms of reduced ulceration, inflammation or size of lesion. This study deserves to be followed up with a placebo-controlled trial. Bisphosphonates. There are anecdotal reports of beneficial effects from bisphosphonates in juvenile dermatomyositis-related calcinosis (64,65) and in other connective tissue diseases (55). Although there is therefore a case for trying bisphosphonate therapy in patients with SSc-related refractory calcinosis, there is no good evidence base for this approach and controlled studies are required. Sodium thiosulphate. Intravenously administered sodium is used in the treatment of calciphylaxis in patients with end-stage renal disease (ESRD). Malbos et al. (66) recently reported improvement in four patients with tumoral calcinosis related to ESRD, following IV sodium thiosulphate (usually 25g three times per week after each dialysis session): patients reported pain relief within the first few weeks of treatment. Case reports and small series so far reported only in abstract form, describe variable responses to IV sodium thiosulphate: clinical improvement in a patient with SSc and in another with myositis (67), and in a single patient with dermatomyositis (68), but no improvement in a series of four patients with SSc and one with juvenile dermatomyositis, although the authors were careful to point out that the treatment time was short (ranging from three to seven months) (69). Topical treatment with sodium thiosulphate (70,71) deserves assessment in the context of patients with SSc. Larger studies, and preferably a controlled trial, are required before sodium thiosulphate (either IV or topical) can be recommended. Biologic agents. There have been anecdotal reports of regression of calcinosis in patients with SSc treated with rituximab for other indications (e.g. lung disease, arthritis) (52,72,73), although conversely Hurabielle et al. reported progression of calcinosis on rituximab (74). Tosounidou et al. (75) reported improvement with infliximab in a patient with an SSc-myositis overlap and very extensive calcinosis refractory to other therapies. Specific therapies aimed at reducing calcinosis – proceduresCarbon dioxide laser. Early reports of successful treatment with carbon dioxide laser (76,77) have not been followed up with more comprehensive studies, and the application of lasers in this clinical setting deserves further research. Extracorporeal shock-wave lithotripsy. Although lithotripsy (potentially in combination with other treatments) seems a promising line of therapy, it has been very little studied (78,79).Surgery. Indications for surgery (80,81) are pain, loss of function (e.g. difficult gripping), and (rarely) debridement and washout of heavily infected areas. It is important to warn the patient that surgery will not remove the calcinosis completely, and that this may ‘regrow’. A major challenge to the surgeon is that calcinotic deposits are infiltrative and (in the fingers) the digital neurovascular bundle may run through the calcific mass (81). Some surgeons use a high speed drill to break up calcium deposits (82). Hand surgery in patients with SSc carries risks, and should be performed in specialist centres. CONCLUSIONS AND POSSIBLE FUTURE DEVELOPMENTSIt is now recognised that calcinosis is a major source of morbidity (including pain) in a substantial proportion of patients with SSc. Calcinotic deposits comprise primarily hydroxyapatite. While pathogenesis is unknown, it is possible that ischaemia-driven mechanisms contribute. Currently, the main aspects of management are antibiotics, analgesics, MDT input and surgical debulking. Advances in imaging techniques, and research validating image analysis, should facilitate clinical studies of different treatment approaches including novel therapies. 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Arrows indicate right thumb calcinosis. Figure 2. Scenario 2. Extensive ‘sheet’ calcinosis of the right upper arm. Clinical photograph, demonstrating multiple areas of ulceration (a) and plain radiograph (b). Figure 3. Scenario 3Area of ulceration over spine, with calcinotic material extruding (a), and (b) the calcinosis demonstrated on spinal CT (axial view). Figure 43. Scenario 3. Calcinosis involving cervical spine, as demonstrated on (a) plain radiography (the calcinosis is most marked to the right of the mid-cervical spine) and (b) CT scanning approximately one month later (3D surface rendered reconstructions) including (c) a lateral oblique view. Figure 54. Scenario 4. Calcinosis of the wrists as demonstrated on (a) plain radiography and (b) CT scanning (3D surface rendered reconstructions, two different views). Figure 65. Optical (a and d) and X-ray computed tomography (b and c) images of calcinotic deposits obtained from two patients. Despite similar oval-like macroscopic shape, porosity of the deposits is very different, which may be dependent onf a number of factors, including chemical composition and exposure to external forces during deposit formation.Figure 6. Fourier transform infrared (A) Raman (B) spectrographs of calcium carbonate (light grey), calcific deposit from a single patient (black) and hydroxyapatite (dark grey). Graphs suggest that hydroxyapatite is the key component of the deposit. However, the presence of carbonate should not be excluded.? ................
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