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УДК616.5-004.1+617.577 DOI: 10.22141/2224-1507.9.2.2019.172122
Ye.D. Yehudina1, I.Yu. Golovach2
'State Institution "Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine», Dnipro, Ukraine
2Feofaniya Clinical Hospital of the State Management of Affairs, Kyiv, Ukraine
Calcinosis in systemic sclerosis: prevalence, clinical picture, management,
complications
For cite: Bol', sustavy, pozvonocnik. 2019;9(2):108-119. doi: 10.22141/2224-1507.9.2.2019.172122_
Abstract. This literature review summarizes current data on the epidemiology, pathophysiology, diagnosis and treatment of calcinosis cutis in patients with systemic sclerosis (SSc). The article deals with the analysis of observational studies of the frequency of calcinosis in SSc and associated clinical features, molecular research of potential pathogenetic mechanisms, clinical cases describing new diagnostic approaches and methods for the treatment of calcinosis. Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. Calcinosis is one of the main, poorly managed clinical problems in patients with SSc, affecting at least one quarter of patients with SSc. Calcinosis is associated with a longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere and anti-topoisomerase antibodies. Although the pathogenesis of calcification is not fully known, there is evidence supporting the role of local chronic traumatization, chronic inflammation, vascular hypoxia and malregulation of bone matrix proteins as potential mechanisms for the development of this pathological condition in patients with SSc. The diagnosis can be established on the basis of clinical data or using plain X-ray. Several pharmacological treatment methods have been applied in patients with calcinosis with variable and not so significant results; in turn, surgical excision of calcium deposits remains mainstay of treatment. Keywords: calcifications; calcinosis cutis; systemic sclerosis; pathophysiology; clinical picture; management; review
Introduction
Calcinosis cutis refers to insoluble calcium deposits in the skin and subcutaneous tissue [1]. The most representative samples of calcinosis cutis associated with systemic sclerosis could be found on the Fig. 1 (a, b).
There are five calcinosis subtypes: dystrophic, metastatic, iatrogenic, idiopathic calcinosis, and calcifilaxia [3]. Metastatic calcification refers to calcium deposition in the normal skin or subcutaneous tissues, associated with an elevated calcium and/or phosphate levels in blood serum, often registered together with malignant neoplasm disintegration [3]. Dystrophic calcinosis is a subtype associated with autoimmune connective tissue diseases (ACTD), such as dermatomyositis (DM), and especially in its juvenile form (JDM), systemic sclerosis (SSc), mixed connective tissue disease, and more rarely, systemic lupus erythematosus (SLE) [4]. In the majority of cases, pathology afflicts upper limbs, especially fingers;
calcinosis is associated with an acute pain syndrome, periodic flares of local inflammation and significant functional disorders. Although the detailed pathophysiology of calcinosis cutis is not completely clear, the generalized mechanism of dystrophic calcinosis presupposes deposition of calcined matter in the damaged tissue even if the calcium and/or phosphate levels in blood serum are normal [4]. This article reviews and summarizes the recent literature data, dealing with calcinosis prevalence, associated clinical factors, pathogenesis, diagnostics and treatment options suggested for dystrophic calcinosis accompanied by SSc.
Prevalence and associated clinical factors of calcinosis accompanied by SSc
The prevalence of calcinosis accompanied by SSc varies from 18 to 49 %. This wide margin may be attributed to different diagnostic methods, based on discrepant clinical
© 2019. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
Для корреспонденции: Головач Ирина Юрьевна, доктор медицинских наук, профессор, MBA, заслуженный врач Украины, руководитель центра ревматологии, Клиническая больница «Фео-фания» Государственного управления делами, ул. Академика Заболотного, 21, г. Киев, 03680, Украина, e-mail: [email protected]
For correspondence: Iryna Golovach, MD, PhD, Professor, MBA, Honored Doctor of Ukraine, Head of the Center of rheumatology, Clinical Hospital "Feofaniya" of the Agency of State Affairs, Academic Zabolotny st., 21, Kyiv, 03680, Ukraine, e-mail: [email protected] Full list of author information is available at the end of the article.
and/or X-ray data, as well as to differences in the patient population [5, 6]. This prevalence increases among patients with a long-term SSc history; with calcinosis usually manifesting itself after 10 or more years after diagnosis being established [4, 7]. Small monocentral studies show that risk factors associated with calcinosis include male gender, digital ulcers, digital scars, acroosteolysis, telangiectasiae, anticentromere antibodies (ACAs) and antitopoisomerase/Scl antibodies [8]. The international cohort study recruiting 5218 patients confirmed calcinosis connection with digital ulcers, telangiectasiae, ACAs, and established the new predisposing factor — osteoporosis [9].
Demographic features:
• Older age
• Longer disease duration
• Limited form of systemic sclerosis
Physical features:
• digital ulcers
• digital scars
• acroosteolysis
• telangiectasiae
• heart damage
• gastrointestinal diseases
• lung hypertension
• arthritis
• osteoporosis
Autoantibodies:
• positive anticentromere antibodies (ACAs)
• positive antitopoisomerase/Scl antibodies
• positive anticardiolipin antibodies
However, the recent studies demonstrate various calcinosis clinical associations, depending on the studied population group. It cast doubts on the earlier found pre-
dictors. In the monocentral US study recruiting 215 patients with SSc, calcinosis was associated with a limited SSc form (LF-SSc) [10]; however, in the Mexican and Malaysian cohorts it was associated with a diffuse SSc form (DF-SSc) [6]. Antinuclear and anti- Scl-70 antibodies are more prevalent in the Mexican calcinosis patients than ACAs [6], and antitopoisomerase (Scl-70) antibodies served as calcinosis predictors in the cohort of 1305 SSc patients, according to the Canadian Scleroderma Research Group (CSRG) register, including patients from Canada and Mexico [11]. Furthermore, in the multicen-tral study of 1009 US Blacks with SSc there were no associations found with skin form, male gender or ACAs [5].
Clinical picture
SSc-accompanied calcinosis manifests itself with subcutaneous nodes on fingers or in the pressure sites, such as elbows, knees or ischial tuberosities. Calcinosis is most often afflicting hands and feet (65-83 %), proximal upper limbs (27 %), knee joints or proximal lower limbs (1022%) and thighs (6,7 %) [6]. Calcinosis sites may occur on the trunk, chest, buttocks and other occult places, such as maxillary sinuses, spine and paravertebral tissues [12]. Calcinosis may be accompanied by painful sensations, soft tissue swelling, ulcers with an aligned infection or deformations, especially at the hands, resulting in significant functional limitations [12]. Patients may also complain of whitish discharge, resembling toothpaste, from the infection opening gate sites.
Diagnosis
Although calcinosis is easily palpated or even seen during the objective examination, imaging diagnostic techniques help corroborating the diagnosis in case of
Fig. 1. Hand calcinosis resulting in joint contracture (borrowed from [2])
subclinical complications. X-ray is a sensitive method for ascertaining calcinosis and is considered an imaging method of first line for ACTDs (Fig. 2-5).
X-ray point-based system of hand calcinosis evaluation was recently developed and suggested in order to standardize measurements of calcium deposit sizes for clinical and research purposes [14]. This point-based system considers the affected site, density, number and anatomical position of deposits to evaluate the degree of calcinosis, making characteristic expert (intra- and interexpert) evaluations of various conclusions' reliability (Fig. 6, 7).
Another method of calcinosis categorization was suggested taking into account clinical and X-ray features of lesions' form and structure [15]. This approach subdivides calcinosis into four subtypes: 'mousse', 'stone', 'net' and 'plate'. Researchers show that 'net' requires the longest therapeutic duration (140 ± 22 days on average) while 'stone' calcinosis — the shortest (30 ± 12 days), in case this categorization has any clinical significance and predictive value [15].
There is an ever increasing number of evidence proving ultrasound (U/S) efficacy while evaluating the SSc-accompanied calcinosis. V. Freire et al. (2013) report that U/S's sensitivity for calcinosis is 89 %, which is not significantly lower than that of X-ray [16]. The latest study of 10 SSc patients suggests that PDI could be used to reveal inflammations around the calcium deposits, identifying the lesion area and thus targeting the anti-inflammatory therapy [17]. Furthermore, U/S used
for revealing microcalcificates in breast tissues, may also differentiate hydroxyapatite deposits typical for SSc from other calcificates [17].
Other experimental research methods include mul-tidetector computed tomography (MDCT), serial two photon (STP) tomography and MRI. MDCT has a higher resolution and 3D capacities absent in the regular CT, and thus enables more precise evaluation of the degree and prevalence of calcinosis [18]. Fig. 8 compares calcinosis imaging techniques: standard X-ray, MDCT and 3-D MDCT. Diagnostics of 16 SSc patients with STP
Fig. 3. Anterior pelvis X-ray of a 57-year-old woman with systemic sclerosis. Advanced calcinosis around right thigh and adjacent soft tissues. Calcium deposits also differentiated around left thigh and left half of pelvic bones (borrowed from [2])
Fig. 2. Calcinosis sites on hand X-ray (borrowed from [2])
Fig. 4. Anterior-posterior right shoulder joint X-ray of a 58-year-old woman with a long SSc -accompanied calcinosis history. Deposits around shoulder and acromioclavicular joint, calcification distally spreading along the intertubercular sulcus. Linear haziness visible at the right lung's base. Sclerosis-associated interstitial lung disease (borrowed from [2])
tomography demonstrated a high efficacy of revealing calcinosis in subcutaneous tissue, fasciae, carpal canal and adjacent muscles [19]. MRI is similarly effective for revealing calcinosis deposits, ensuring a better imaging of swelling and/or inflammation of tissues, potentially pointing towards calcinosis [20].
Pathophysiology of calcinosis
Among all the calcinosis types, dystrophic is the best researched one in terms of its pathophysiology. There are several mechanisms suggested: chronic inflammation, vascular hypoxia, recurring trauma and bone matrix protein anomaly. High levels of 1, 6, 1P interleukins, tumor necrosis factor a (TNF-a) were revealed in JDM patients with calcinosis confirming the role of inflammation in this pathologic process [21].
Furthermore, a case-control study recruiting 90 SSc patients from the Australian cohort and 90 matched control patients dealt with levels and polymorphism of man-nose binding lectin (MBL) and ficolin-2 in blood serum; these two being lectin complement pathway receptors. As a result, researchers found association between these specific markers of SSc patients and calcification along with vascular disorders. They also revealed that mannose binding lectin (MBL) was significantly higher in SSc patients with calcinosis, compared to SSc patients without calcinosis (2,1 vs. 0,8 mg/ml, р = 0,005), and in SSc
patients with digital ulcers and scars (2,7 vs. 0,8 mg/ml, p = 0,007) [22].
According to a number of studies, vascular ischemia also promotes calcinosis. С.А.Davies et al. demonstrate an elevated expression of hypoxia-associated glucose transporter 1 (GLUT1) in the skin biopsy of SSc patients with calcinosis [23]. Several studies [9] also show that presence or history of digital ulcers [11] and/or acrooste-olysis [6] predict calcinosis, underlining the role of ischemia. Another study shows vascular endothelial growth factor (VEGF), also known as a potential angiogenic factor induced by hypoxia, when activated, becomes associated with an increased osteoclast activity in SSc patients with acroosteolysis, 73 % of them diagnosed with calcinosis [24]. This hypoxia-induced osteoclast activity is a factor in calcinosis development and may explain the calcinosis-osteoporosis connection [10]. In a similar
Fig. 6. Anatomical locations for X-ray point-based system (borrowed from [14])
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Fig. 5. Numerous calcinosis sites on the left hand of SSc patient (borrowed from [13])
Fig. 7. Samples of % area coverage for X-ray point-based system (borrowed from [14])
way, it was established that expression of the ascertained oxidative stress markers, end products of the progressive glycation/peroxidation of lipids and their receptors was higher in SSc patients' derma, especially if they had calcinosis, compared to the healthy controls [25].
Calcinosis is predominantly localized on the dominant upper limb and other distal sites, suggesting that recurrent trauma/strain also may contribute to its development [26]. It's worth mentioning that the sites facing recurrent traumatization may be more susceptible due to compensatory antiogenesis disorder, characterized by the pro-liferative obliterating vasculopathy attending SSc [27]. C. A. Davies et al. also found an increased bone matrix protein expression, among them osteonectin and matrix gamma-carboxyglutamic acid (Gla)-containing protein (MGP), in the skin of SSc patients with calcinosis [23]. Those proteins take part in the ectopic calcification, activating osteonectin, calcification trigger, along with suppression and reduction of MGP inhibitors [28]. MGP should take its gamma-carboxylated form and bound to the bone morphogenic protein-2 in order to inhibit calcification. This carboxylated form is Vitamin K-dependent [28]. R. Wallin et al. suggested mechanisms according to which oxidative stress, a decisive factor for SSc-attending microvascular lesions, may inhibit Vitamin K and produce nongamma-carboxylated and inactive MGP, thus resulting in the unruly calcification [29]. Further studies are required to understand these mechanisms better and reveal other pathogenetic constructions, favoring SSc-attending calcinosis.
Treatment
General measures and supporting therapy
Calcinosis is an important therapeutic problem for SSc patients. General measures include improving blood flow in the limbs, avoiding traumatization, stress factors and exposure to cold. If there is a suspicion of infected calci-
nosis lesions, antibiotics with antistreptococcal and an-tistaphylococcal action, nonsteroidal anti-inflammatory drugs (NSAIDs) and even opioids for pain relief [30]. If calcinosis turns into ulcers, a standard wound dressing is required [31].
Drug medication
Several groups of drugs were suggested to manage calcinosis, however, their results and efficacy vary. Evidence confirming their effect is mainly received from small retrospective studies, series and single clinical cases (Table 1).
Calcium channel blockers
Calcium channel blockers (CCB) reduce intercellular calcium migration in the damaged tissues, impairing calcium foci production and crystallization. Diltiazem is the most widely used and studied CCB in terms of calcinosis management. Early studies show promising results with a daily Diltiazem dose of 240-480 mg [32-34], which was confirmed in the retrospective cohort study of 78 ACTD patients at the Mayo Clinic. Diltiazem was effective as a first-line therapy in 9 out of 17 patients [35]. However, a large retrospective study could not confirm a positive Diltiazem effect in 12 SSc patients receiving a daily dose of 180 mg from 1 to 15 years, according to X-ray data [36]. Observational study by the Canadian Scleroderma Research Group (CSRG), based on the 5 year period, did not reveal any significant association between CCB and calcinosis outcomes (odds ratio (OR) 0,9; 95% confidence interval (CI) 0,73-1,05). Only those patients whose disease lasted less than 5 years showed a lower risk of calcinosis with CCB (odds ratio (OR) 0,62; 95% confidence interval (CI) 0,45-0,86) [37].
Bisphosphonates
Bisphosphonates may be useful to treat calcinosis with an aim to achieve a reverse calcification by means of macrophage-induced anti-inflammatory cytokine in-
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Fig. 8. Advanced hand calcinosis by a regular X-ray (a), MDCT (b) and 3-D reconstruction MDCT (c) (borrowed from [19])
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hibition and bone resorption rate decrease [38]. Single clinical studies describe improvement of calcinosis course in dermatomyositis (DM) adult patients [40] and JDM patients [39] with intravenous Pamidronate injections. In a similar manner, a series of cases showed a partial reduction of calcinosis when treated with alendronate in 6 out of 9 JDM patients [41]. A clinical case with LF-SSc patient describes calcinosis-induced calcifícate dissolution after 6 month therapy with Risedronate, also used for glucocorticoid-induced osteoporosis treatment [42]. Taking into account a lack of evidence-based studies,
bisphosphonates' efficacy for calcinosis treatments remains unclear.
Warfarin
Considering that Warfarin reduces matrix gamma-carboxyglutamic acid (Gla)-containing protein (MGP) and prevents its carboxylation, a number of studies were made into efficacy of Warfarin's low doses to treat ACTD calcinosis [12]. In a series of clinical observations, among 3 SSc patients receiving Warfarin two of them had calsinosis dissolved after 1 year of treatment [43]. Double
Medications Action mechanisms Doses Patients responding to treatment/total number of treated patients Reference Efficacy
1 2 3 4 5 6
Calcium channel blockers Reduction of intracellular calcium migration into the damaged tissues and local macrophages Diltiazem 240-480 mg per diem - 1-12 years 4/4 Palmieri et al. [32] Moderate
Diltiazem 120 mg per diem - 2 years 1/1 Dolan et al. [33]
Diltiazem 240 mg per diem - 5 years 1/1 Farah et al. [34]
Bisphosphonates Macrophage-induced anti-inflammatory cytokine suppression, calcium metabolism slow-down Risedronate 10 mg - 6 months 1/1 Fujii et al. [42] Low
Warfann Inhibiting calcium-binding gamma-carboxyglutamic acid 1 mg per diem - 1 year 2/3 Cukierman et al. [43] Low
1 mg per diem - 18 months 2/3 Berger et al. [44]
1 mg per diem - 7-28 months 0/1 Lassoued et al. [45]
Sodium thiosulphate (STS) Powerful antioxidant and vasodilator, also chelating and dissolving calcium deposits Local: 25% STS with zinc oxide 2/2 Bair et al. [46] Moderate
Local: 25% sodium metabisulfite (SM) 1/1 Barrio Diaz et al. [47]
Intrafocal: STS 2-3 grams per diem - 1 year 2/2 Goosens et al. [48]
Intrafocal: STS 12.5-275 mg- 1-4 times 5/5 Baumgartner-Nielsen et al. [49]
Intravenous: 20 grams per diem, 5 days a month, no less than 6 times 0/1 Mageau et al. [68]
Anti-TNF-a Inhibiting calcinosis inflammation Infliximab 3 mg/kg intravenously at weeks 0, 2, and 6, every 8 weeks - 7 months 1/1 Tosonidouu et al. 51] Low
Rituximab Chimeric anti-CD20 antibody depleting B-lymphocytes 375 mg/m2 intravenously weekly № 4 1/1 De Paula et al. [52] Low
375 mg/m2 intravenously weekly №4 3/6 Giugglioli et al. [53]
1 gram intravenously №2 with 2-week interval, and after that every 6 months 0/1 Hurabielle et al. [54]
Table 1. Pharmacological treatment of systemic sclerosis-associated calcinosis
Окончание табл. 1
1 2 3 4 5 6
1 gram intravenously №2 with 2-week interval, and after that every year 375 mg/m2 intravenously weekly №4 0/1 Dubos et al. [55]
Minocycline Tetracycline antibiotic with anti-inflammatory action and calcium-binding properties 50-100 mg per diem for 3,5 years 8/9 Robertson et al. [56] High
Ceftriaxone Third-generation cephalosporin able to bind calcium ions and create insoluble calcium complexes 2 grams intravenously for 20 дней 1/1 Reiter et al. [57] Low
Aluminium hydroxide Reduces phosphate rate in blood serum, intestinal absorption, prevents calcification 30 ml per os 4 times per diem 1/1 Hudson et al. [58] Low
Triamcinolone acetonide Anti-inflammatory effect Intrafocal: 20 mg/ml every 4-8 weeks during 6 months 1/1 Hazen et al. [59] Moderate
Colchicine Anti-inflammatory effect due to leukocyte chemotaxis deregulation and phagocytosis by means of inhibited microtubules polymerization 1mg every per diem - 2 months 1/1 Fuchs et al. [60] Moderate
IV Immunoglobulin Anti-inflammatory effect, probably due to the activated macrophage suppression 2 grams per diem during 4 days once a month - 5 times 1/1 Schanz et al. [61] Moderate
blind placebo controlled study of 7 patients with ACTD and numerous subcutaneous calcificates shows a reduction of extraskeletal calcium absorption on total body scintigraphy with Technetium 99m-diphosphonate in 2 out of 3 SSc patients receiving a daily Warfarin's dose of 1mg during 18 months [44]. A series of additional clinical cases demonstrate 2 out of 3 SSc patients having a diffuse calcinosis dissolved on physical examination held 1 year after low-dose Warfarin treatment [43]. However, there are completely opposite findings. In the Mayo Clinic study, 4 out of 19 ACTD patients with calcinosis, who took Warfarin for other indications, did not have any improvement or changes in calcinosis compared to patients who did not take Warfarin [35]. Another study involving 6 patients with diffuse calcinosis (one of them also having SSc) shows that a 14,6-month Warfarin treatment turned out ineffective: in 5 patients calcinosis even got worse [45]. It is true that there are concerns as to the fact that Warfarin may promote calcification due to the inadequately carboxylated MGP [12].
Sodium thiosulphate
Topical (localized), intrafocal and intravenous Sodium thiosulphate (STS) injection was also studied in terms of calcinosis treatment. There are data describing two cases of ulcerous dystrophic calcinosis resistant to local treatment, however responsive to the topical application of 25 % STS in combination with zinc oxide [46]. Four patients with calcinosis (two with SSc, two with DM) had a significant reduction of size, erythema and pains with topical application of 25 % Sodium metabisulfite (SM), STS's metabolite. Researchers suggest that topical SM may dissolve calcium deposits and promote local vasodilation and wound healing [47]. J. Goossens et al. report two cases of STS being used as daily intrafocal injections in a dose of 1—3 g, which led to pain relief, improvement of function and a two-fold diminishing of focal size after 12 months of therapy [48]. A large number of clinical cases describe treatment of 8 calcinosis sites in 6 patients (5 of them with SSc, one with nephrogenic systemic fibrosis) by means of 12,5—275 STS injections of 150 mg/ml
for over 4 weeks. By the 4th and 12th week, lesions diminished by 67 and 90% respectively, all patients reporting pain relief and function restoring [49]. Another series of 4 clinical cases (LF-SSc, DM, JDM, SLE) demonstrates calcinosis being improved after 6 cycles of intravenous STS injections in all patients, but for one with LF-SSc [50]. Further studies of STS efficacy are required for evidence base, to prove it could be used as a treatment alternative.
Biological agents
There are data on Infliximab's efficiency while treating overlap syndrome, i.e. SSc-myositis and refractory calcinosis. Infliximab's dose of 3 mg/kg was injected intravenously during 0, 2 and 6th week, and later every 8 weeks. As a result, calcificates diminished and there were no deposits reported after 41 months when controlled by means of a CT series [51].
Most references on biological therapy against calcinosis focus on Rituximab (RTX). There is a description of one clinical case of RTX №4 (375 mg/m2) daily intravenous use. Researchers observed improvement or a complete dissolution of calcified lesions [52]. Furthermore, a series of clinical observations of 10 SSc patients treated with RTX for interstitial lung disease (ILD), skin fibro-sis and/or arthritis show improvement and dissolution of calcinosis in 3 out of 6 patients [53]. However, the recent findings also demonstrate aggravation of calcinosis in a DF-SSc patient treated with RTX for ILD and arthritis [54]. Similarly, 2 patients receiving RTX had their calcinosis progressing after 6 and 12 months following treatment [55]. At the moment, RTX may not be recommended as a calcinosis treatment option due to a lack of successful controlled studies.
Other medications
In a series of clinical studies with 9 LF-SSc and calcinosis patients, a daily dose of 50 or 100 mg Minocycline during 3. 5 years on average resulted in a reduced acuity and inflammation, and insignificant diminishing of deposit sizes in 8 patients [56]. There are separate reports confirming efficacy of Ceftriaxone [57], Aluminium hydroxide [58], Triamcinolone acetonide injections [59], Colchicine [35, 60], and IV Immunoglobulin use [61] to treat SSc-associated calcinosis. A new, potentially efficient treatment was suggested considering the preliminary data of 'Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma' (PHAROS) study reporting improvement of calcinosis after 6 months of treatment for SSc-associated pulmonary arterial hypertension (PAH) and calcinosis in 2 patients, prescribed subcutaneous Treprostinil for PAH. This improvement was confirmed by X-ray data [62]. Oral Treprostinil is tested at present in a clinical study of patients with SSc and hand calcinosis (NCT02663895).
Procedures
According to a prospective study of 9 calcinosis patients (three of them with SSc), 3 rounds of extracorporeal shockwave lithotripsy (ESWL) every 3 weeks reduced the size of lesions and calcinosis-associated pain syndrome after 6 months [63]. A recent 12-week study reporting 3 weekly ESWL rounds, focused on calcinosis foci in 4 SSc patients, revealed a diminishing of lesion sizes in 3 patients and pain relief in 2 [64]. Laser tissue CO2 vaporization enables perfect imaging and calcium deposit vaporization; this procedure was also attended by pain relief and functional improvement in SSc-calcinosis patients [65].
Patients with large, localized and symptomatic lesions, especially those located over tendons, vessels and nerves are subject to the surgical intervention [66]. At the Mayo Clinic, all 11 patients who had only a surgical removal of calcified foci, as well as 16 out of 17 patients having both pharmaceutical and surgical treatment, responded to it. By contrast, only 7 out of 19 patients, having only pharmaceutical treatment, showed any reponse [35]. Special methods, such as a curettage of calcinosis foci [66] or cytoreduction with a high-frequency microdrill [67], effectively reduced painful sensations and disability of calcinosis patients; however, lesions tended to recur.
Conclusions
Calcinosis is a prevalent problem for SSc patients. Most often, it is associated with upper limb lesions, especially affecting fingers. Although its pathogenesis is yet unclear, there is evidence of such pathogenic mechanisms as chronic inflammation, vascular hypoxia, local trauma-tization and dysregulation of bone matrix proteins. There are no universal and effective treatment methods for SSc-associated calcinosis; however, certain data on pharmacological options were published, among them CCB, bisphosphonates, Warfarin and Sodium thiosulphate. Surgical removal of calcinosis foci remains the fundamental treatment strategy. New clinical trials are required to determine effectiveness of the existing and new calcinosis treatment options.
Conflicts of interests. Authors declare the absence of any conflicts of interests that might be construed to influence the results or interpretation of their manuscript.
References
1. Chander S, Gordon P. Soft tissue and subcutaneous calcification in connective tissue diseases. Curr Opin Rheumatol. 2012 Mar;24(2):158-64. doi: 10.1097/BOR.0b013e32834ff5cd.
2. Varga J, Denton CP, Wigley FM, Masataka Ku-wana YA. Scleroderma from pathogenesis to com-
prehensive management. 2nd ed. New York: Springer Science Business Media; 2017. 739 p.
3. Reiter N, El-Shabrawi L, Leinweber B, Berghold A, Aberer E. Calcinosis cutis: part I. Diagnostic pathway. J Am Acad Dermatol. 2011 Jul;65(1):1-12; quiz 13-4. doi: 10.1016/j.jaad.2010.08.038.
4. Gutierrez A Jr, Wetter DA. Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther. 2012 Mar-Apr;25(2): 195-206. doi: 10.1111/j.1529-8019.2012.01492.x.
5. Morgan ND, Shah AA, Mayes MD, et al. Clinical and serological features of systemic sclerosis in a multicenter African American cohort: analysis of the genome research in African American scleroderma patients clinical database. Medicine (Baltimore). 2017 Dec;96(51):e8980. doi: 10.1097/ MD.0000000000008980.
6. Cruz-Dominguez MP, Garcia-Collinot G, Saa-vedra MA, et al. Clinical, biochemical, and radiological characterization of the calcinosis in a cohort of Mexican patients with systemic sclerosis. Clin Rheu-matol. 2017 Jan;36(1):111-117. doi: 10.1007/s10067-016-3412-9.
7. Galluccio F, Allanore Y, Czirjak L, Furst DE, Khanna D, Matucci-Cerinic M. Points to consider for skin ulcers in systemic sclerosis. Rheumatology (Oxford). 2017 Sep 1;56(suppl_5):v67-v71. doi: 10.1093/rheumatology/kex200.
8. Tolosa-Vilella C, Morera-Morales ML, Simeon-Aznar CP, et al. Digital ulcers and cutaneous subsets of systemic sclerosis: clinical, immunolog-ical, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry. Semin Arthritis Rheum. 2016 Oct;46(2):200-208. doi: 10.1016/j.sem-arthrit.2016.04.007.
9. Valenzuela A, Baron M, Herrick AL, et al. Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: a sclero-derma clinical trials consortium study. Semin Arthritis Rheum. 2016 Dec;46(3):344-349. doi: 10.1016/j. semarthrit.2016.05.008.
10. Pai S, Hsu V. Are there risk factors for scleroderma-related calcinosis? Mod Rheu-matol. 2018 May;28(3):518-522. doi: 10.1080/14397595.2017.1349594.
11. Baron M, Pope J, Robinson D, et al. Calcinosis is associated with digital ischaemia in systemic sclerosis-a longitudinal study. Rheumatology (Oxford). 2016 Dec;55(12):2148-2155. doi: 10.1093/ rheumatology/kew313.
12. Herrick AL, Gallas A. Systemic sclerosis-related calcinosis. J Scleroderma Relat Disord. 2016;1(2):194-203. doi: 10.5301%2Fjsrd.5000211.
13. Makol A, Ytterberg SR. Images in clinical medicine. Calcinosis cutis in systemic sclerosis. N Engl J Med. 2011 Jun 9;364(23):2245. doi: 10.1056/ NEJMicm1011692.
14. Chung L, Valenzuela A, Fiorentino D, et al. Validation of a novel radiographic scoring system
for calcinosis affecting the hands of patients with systemic sclerosis. Arthritis Care Res (Hoboken). 2015 Mar;67(3):425-30. doi: 10.1002/acr.22434.
15. Bartoli F, Fiori G, Braschi F, et al. Calcinosis in systemic sclerosis: subsets, distribution and complications. Rheumatology (Oxford). 2016 Sep;55(9):1610-4. doi: 10.1093/rheumatology/kew193.
16. Freire V, Bazeli R, Elhai M, et al. Hand and wrist involvement in systemic sclerosis: US features. Radiology. 2013 Dec;269(3):824-30. doi: 10.1148/ra-diol.13121994.
17. Suliman YA, Kafaja S, Fitzgerald J, et al. Ultrasound characterization of cutaneous ulcers in systemic sclerosis. Clin Rheumatol. 2018 Jun;37(6): 1555-1561. doi: 10.1007/s10067-018-3986-5.
18. Freire V, Becce F, Feydy A, et al. MDCT imaging of calcinosis in systemic sclerosis. Clin Radiol. 2013 Mar;68(3):302-9. doi: 10.1016/j. crad.2012.07.009.
19. Hsu V, Bramwit M, Schlesinger N. Use of dual-energy computed tomography for the evaluation of calcinosis in patients with systemic sclerosis. Clin Rheumatol. 2015 Sep;34(9): 1557-61. doi: 10.1007/ s10067-015-2998-7.
20. Kimball AB, Summers RM, Turner M, et al. Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile der-matomyositis. Implications for diagnosis and therapy. Arthritis Rheum. 2000 Aug;43(8): 1866-73. doi: 10.1002/1529-0131(200008)43:8<1866::AID-ANR24>3.0.CO;2-6.
21. Shimizu M, Ueno K, Ishikawa S, Kasahara Y, Yachie A. Role of activated macrophage and inflammatory cytokines in the development of calcinosis in juvenile dermatomyositis. Rheumatology (Oxford). 2014 Apr;53(4):766-7. doi: 10.1093/rheumatology/ ket360.
22. Osthoff M, Ngian GS, Dean MM, et al. Potential role of the lectin pathway of complement in the pathogenesis and disease manifestations of systemic sclerosis: a case inverted question mark control and cohort study. Arthritis Res Ther. 2014 Nov 18;16(6):480. doi: 10.1186/s13075-014-0480-6.
23. Davies CA, Jeziorska M, Freemont AJ, Herrick AL. The differential expression of VEGF, VEG-FR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum Pathol. 2006 Feb;37(2):190-7. doi: 10.1016/j.humpath.2005.10.007.
24. Park JK, Fava A, Carrino J, Del Grande F, Rosen A, Boin F. Association of acroosteolysis with enhanced osteoclastogenesis and higher blood levels of vascular endothelial growth factor in systemic sclerosis. Arthritis Rheumatol. 2016 Jan;68(1):201-9. doi: 10.1002/art.39424.
25. Davies CA, Herrick AL, Cordingley L, Freemont AJ, Jeziorska M. Expression of advanced glycation end products and their receptor in skin from patients with systemic sclerosis with and
without calcinosis. Rheumatology (Oxford). 2009 Aug;48(8):876-82. doi: 10.1093/rheumatology/ kep151.
26. Gauhar R, Wilkinson J, Harris J, Manning J,HerrickAL.Calcinosispreferentiallyaffectsthethumb compared to other fingers in patients with systemic sclerosis. Scand J Rheumatol. 2016 Jul;45(4):317-20. doi: 10.3109/03009742.2015.1127412.
27. Cantatore FP, Maruotti N, Corrado A, Rib-atti D. Angiogenesis dysregulation in the pathogenesis of systemic sclerosis. Biomed Res Int. 2017;2017:5345673. doi: 10.1155/2017/5345673.
28. Zebboudj AF, Shin V, Bostrom K. Matrix GLA protein and BMP-2 regulate osteoinduction in calcifying vascular cells. J Cell Biochem. 2003 Nov 1;90(4):756-65. doi: 10.1002/jcb.10669.
29. Wallin R, Wajih N, Greenwood GT, Sane DC. Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med Res Rev. 2001 Jul;21(4):274-301.
30. Ughi N, Crotti C, Ingegnoli F. Effectiveness and safety of oxycodone/naloxone in the management of chronic pain in patients with systemic sclerosis with recurrent digital ulcers: two case reports. Clin Interv Aging. 2016 Mar 14;11:307-11. doi: 10.2147/ CIA.S102577.
31. Netsch D. Calcinosis cutis: WOC nurse management. J Wound Ostomy Continence Nurs. 2018 Jan/Feb;45(1):83-86. doi: 10.1097/ WON.0000000000000403.
32. Palmieri GM, Sebes JI, Aelion JA, et al. Treatment of calcinosis with diltiazem. Arthritis Rheum. 1995 Nov;38(11):1646-54.
33. Dolan AL, Kassimos D, Gibson T, Kings-ley GH. Diltiazem induces remission of calcinosis in scleroderma. Br J Rheumatol. 1995 Jun;34(6):576-8.
34. Farah MJ, Palmieri GM, Sebes JI, Cremer MA, Massie JD, Pinals RS. The effect of diltiazem on calcinosis in a patient with the CREST syndrome. Arthritis Rheum. 1990 Aug;33(8):1287-93.
35. Balin SJ, Wetter DA, Andersen LK, Davis MD. Calcinosis cutis occurring in association with autoimmune connective tissue disease: the Mayo Clinic experience with 78 patients, 1996-2009. Arch Dermatol. 2012 Apr;148(4):455-62. doi: 10.1001/archder-matol.2011.2052.
36. Vayssairat M, Hidouche D, Abdoucheli-Baudot N, Gaitz JP. Clinical significance of subcutaneous calcinosis in patients with systemic sclerosis: does diltiazem induce its regression? Ann Rheum Dis. 1998 Apr;57(4):252-4. doi: 10.1136/ard.57.4.252.
37. Li G, Adachi JD, Cheng J, et al. Relationship between calcium channel blockers and skin fibrosis in patients with systemic sclerosis. Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 106(4):56-60.
38. Dima A, Balanescu P, Baicus C. Pharmacological treatment in calcinosis cutis associated with con-
nective-tissue diseases. Rom J Intern Med. 2014 Apr-Jun;52(2):55-67.
39. Palaniappan P, Lionel AP, Kumar S. Successful treatment of calcinosis cutis in juvenile dermatomyositis with Pamidronate. J Clin Rheumatol. 2014 Dec;20(8):454-5. doi: 10.1097/ RHU.0000000000000199.
40. Canas CA, Bonilla-Abadia F, Mejia M, To-bon GJ. Recovery of severe muscular and fascial calcinosis after treatment with bisphosphonates in a child with juvenile dermatomyositis. J Clin Rheumatol. 2015 Aug;21(5):267-9. doi: 10.1097/ RHU.0000000000000264.
41. Saini I, Kalaivani M, Kabra SK. Calcinosis in juvenile dermatomyositis: frequency, risk factors and outcome. Rheumatol Int. 2016 Jul;36(7):961-5. doi: 10.1007/s00296-016-3467-6.
42. Fujii N, Hamano T, Isaka Y, Ito T, Imai E. Risedronate: a possible treatment for extraosseous calcification. Clin Calcium. 2005 Sep;15 Suppl 1:758; discussion 78-9. doi: CliCa05S-17579.
43. Cukierman T, Elinav E, Korem M, Chajek-Shaul T. Low dose warfarin treatment for calcinosis in patients with systemic sclerosis. Ann Rheum Dis. 2004 0ct;63(10):1341-3. doi: 10.1136/ard.2003.014431.
44. Berger RG, Featherstone GL, Raasch RH, McCartney WH, Hadler NM. Treatment of calcinosis universalis with low-dose warfarin. Am J Med. 1987 Jul;83(1):72-6.
45. Lassoued K, Saiag P, Anglade MC, Roujeau JC, Touraine RL. Failure of warfarin in treatment of calcinosis universalis. Am J Med. 1988 Apr;84(4):795-6.
46. Bair B, Fivenson D. A novel treatment for ulcerative calcinosis cutis. J Drugs Dermatol. 2011 Sep;10(9):1042-4.
47. Del Barrio-Diaz P, Moll-Manzur C, Älvarez-Veliz S, Vera-Kellet C. Topical sodium metabisulfite for the treatment of calcinosis cutis: a promising new therapy. Br J Dermatol. 2016 Sep;175(3):608-11. doi: 10.1111/bjd.14412.
48. Goossens J, Courbebaisse M, Caudron E, et al. Efficacy of intralesional sodium thiosulfate injections for disabling tumoral calcinosis: two cases. Semin Arthritis Rheum. 2017 Dec;47(3):451-455. doi: 10.1016/j.semarthrit.2017.05.013.
49. Baumgartner-Nielsen J, Olesen AB. Treatment of skin calcifications with intralesional injection of sodium thiosulphate: a case series. Acta Derm Venereol. 2016 Feb;96(2):257-8. doi: 10.2340/000155552206.
50. Mageau A, Guigonis V, Ratzimbasafy V, et al. Intravenous sodium thiosulfate for treating tumoral calcinosis associated with systemic disorders: report of four cases. Joint Bone Spine. 2017 May;84(3):341-344. doi: 10.1016/j.jbspin.2016.10.009.
51. Tosounidou S, MacDonald H, Situnayake D. Successful treatment of calcinosis with infliximab in a patient with systemic sclerosis/myositis overlap syn-
drome. Rheumatology (Oxford). 2014 May;53(5):960-1. doi: 10.1093/rheumatology/ket365.
52. de Paula DR, Klem FB, Lorencetti PG, Muller C, Azevedo VF. Rituximab-induced regression of CREST-related calcinosis. Clin Rheumatol. 2013 Feb;32(2):281-3. doi: 10.1007/s10067-012-2124-z.
53. Giuggioli D, Lumetti F, Colaci M, Fallahi P, Antonelli A, Ferri C. Rituximab in the treatment of patients with systemic sclerosis: our experience and review of the literature. Autoimmun Rev. 2015 Nov;14(11): 1072-8. doi: 10.1016/j. autrev.2015.07.008.
54. Hurabielle C, Allanore Y, Kahan A, Avouac J. Flare of calcinosis despite rituximab therapy. Semin Arthritis Rheum. 2014 Oct;44(2):e5-6. doi: 10.1016/j. semarthrit.2014.04.007.
55. Dubos M, Ly K, Martel C, Fauchais AL. Is rituximab an effective treatment of refractory calcinosis? BMJ Case Rep. 2016 May 31;2016. pii: bcr2015213179. doi: 10.1136/bcr-2015-213179.
56. Robertson LP, Marshall RW, Hickling P. Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis. 2003 Mar;62(3):267-9. doi: 10.1136/ard.62.3.267.
57. Reiter N, El-Shabrawi L, Leinweber B, Ab-erer E. Subcutaneous morphea with dystrophic calcification with response to ceftriaxone treatment. J Am Acad Dermatol. 2010 Aug;63(2):e53-5. doi: 10.1016/j.jaad.2009.11.016.
58. Hudson PM, Jones PE, Robinson TW, Dent CE. Extensive calcinosis with minimal scleroderma: treatment of ectopic calcification with aluminum hydroxide. Proc R Soc Med. 1974 Nov;67(11):1166-8.
59. Hazen PG, Walker AE, Carney JF, Stewart JJ. Cutaneous calcinosis of scleroderma: successful treatment with intralesional adrenal steroids. Arch Dermatol. 1982 May;118(5):366-7.
60. Fuchs D, Fruchter L, Fishel B, Holtzman M, Yaron M. Colchicine suppression of local inflammation due to calcinosis in dermatomyositis
and progressive systemic sclerosis. Clin Rheumatol. 1986 Dec;5(4):527-30.
61. Schanz S, Ulmer A, Fierlbeck G. Response of dystrophic calcification to intravenous immunoglobulin. Arch Derma-tol. 2008 May;144(5):585-7. doi: 10.1001/arch-derm.144.5.585.
62. Hsu VM, Chung L, Hummers LK, et al. Risk Factors for Mortality and Cardiopulmonary Hospi-talization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry. J Rheumatol. 2019 Feb;46(2):176-183. doi: 10.3899/ jrheum.180018.
63. Sultan-Bichat N, Menard J, Perceau
G, Staerman F, Bernard P, Reguiai' Z. Treatment of calcinosis cutis by extracorporeal shock-wave lithotripsy. J Am Acad Dermatol. 2012 Mar;66(3):424-9. doi: 10.1016/j.jaad.2010.12.035.
64. Blumhardt S, Frey DP, Toniolo M, Alkadhi
H, Held U, Distler O. Safety and efficacy of extracorporeal shock wave therapy (ESWT) in calcinosis cutis associated with systemic sclerosis. Clin Exp Rheumatol. 2016 Sep-Oct;34 Suppl 100(5):177-180.
65. Chamberlain AJ, Walker NP. Successful palliation and significant remission of cutaneous calcinosis in CREST syndrome with carbon dioxide laser. Dermatol Surg. 2003 Sep;29(9):968-70.
66. Saddic N, Miller JJ, Miller OF 3rd, Clarke JT. Surgical debridement of painful fingertip calcinosis cutis in CREST syndrome. Arch Dermatol. 2009 Feb;145(2):212-3. doi: 10.1001/archderm.145.2.212-b.
67. Lapner MA, Goetz TJ. High-speed burr deb-ulking of digital calcinosis cutis in scleroderma patients. J Hand Surg Am. 2014 Mar;39(3):503-10. doi: 10.1016/j.jhsa.2013.12.003.
Received 02.05.2019 Revised 20.05.2019 Accepted 22.05.2019
Information about authors
I.Yu. Golovach, MD, PhD in medicine, professor, Head of the Center of rheumatology, Clinical Hospital "Feofaniya" of the Agency of State Aff airs, Kyiv, Ukraine, e-mail: [email protected]; phone: +38 (050) 654-21-88; ORCID iD: https://orcid.org/0000-0002-6930-354X
Ye.D. Yehudina, MD, PhD in medicine, associate professor, State Institution"Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine', Dnipro, Ukraine, e-mail: [email protected]; phone: +38 (099) 059-54-75; ORCID iD: https://orcid.org/0000-0001-8702-5638
£гуд'ша €.Д.', Головач 1.Ю.2
'Державний заклад «Дн'тропетровська державна медична академ'я М'ш'ктерства охорони здоров'я УкраУни», м. Дн'тро, УкраУна
2Кл'ш'1чналкарня «Феофаня Державногоуправлння справами, м. КиУв, УкраУна
Кальциноз при системнш склеродермм: поширенкть, клшша, менеджмент, ускладнення
Резюме. У даному литературному оглядi пщсумовано сучасш даш щодо ешдемюлоги, патофiзюлоril, дiагностики та лжу-вання шюрного кальцинозу у пащенйв i3 системною склеро-
дермieю (ССД). Проведено аналiз обсервацшних дослщжень, що описують частоту кальцинозу при ССД i асоцшованих з ним клшчних ознак; молекулярних дослщжень, що вивча-
ють потенцiйнi патогенетичнi механiзми; наведенi клшчт випадки, що описують новi дiагностичнi шдходи i методи ль кування кальцинозу. Шк1рний кальциноз — це вщкладення нерозчинного кальцiю в шкiрi i пiIдшкiрних тканинах. Кальциноз — одна з основних, погано керованих клшчних проблем у пащенпв iз ССД, яка зачшае щонайменше одну чет-верту частину хворих. Кальциноз асоцiйований з бшьшою тривалiстю хвороби, дигiтальними виразками, акроостеоль зом, позитивними антицентромерними i антитопоiзомераз-ними антитiлами. Хоча патогенез кальцинозу остаточно не-вщомий, е докази, що пщтверджують роль мсцево! хротч-
но! травматизацй, хронiчного запалення, судинно! гшокси i дисрегуляцй бiлкiв кюткового матриксу як потенцiйних меха-нiзмiв розвитку цього патологiчного стану у пащенпв iз ССД. Дiагноз може бути встановлений на основi клшчних даних або за допомогою стандартно! рентгенографй. Кшька фарма-кологiчних методiв лiкуБання були застосованi у пащенпв iз кальцинозом зi змiнними i не такими значущими результатами, у свою чергу, хiрургiчне видалення депозитiв кальцiю за-лишаеться основним методом лшування. Ключовi слова: кальцифшацш; кальциноз шк1ри; системна склеродермы; патофiзiологiя; клiнiка; менеджмент; огляд
Егудина Е.Д.1, Головач И.Ю.2
1Государственное учреждение «Днепропетровская медицинская академия Министерства здравоохранения Украины», г. Днепр, Украина
2Клиническая больница «Феофания» Государственного управления делами, г. Киев, Украина
Кальциноз при системной склеродермии: распространенность, клиника,
менеджмент, осложнения
Резюме. В данном литературном обзоре проанализированы современные данные, касающиеся эпидемиологии, патофизиологии, диагностики и лечения кожного кальциноза у пациентов с системной склеродермией (ССД). Проведен анализ обсервационных исследований, описывающих частоту кальциноза при ССД и ассоциированных клинических признаков; молекулярных исследований, изучающих потенциальные патогенетические механизмы; представлены клинические случаи, описывающие новые диагностические подходы и методы лечения кальциноза. Кожный кальциноз — это отложение нерастворимого кальция в коже и подкожных тканях. Кальциноз — одна из основных, трудно управляемых клинических проблем у пациентов с ССД, затрагивающая по крайней мере одну четвертую часть больных. Кальциноз ассоциирован с большей продолжительностью болезни, диги-тальными язвами, акроостеолизом, положительными анти-
центромерными и антитопоизомеразными антителами. Хотя патогенез кальциноза до конца неизвестен, есть доказательства, подтверждающие роль местной хронической трав-матизации, хронического воспаления, сосудистой гипоксии и дисрегуляции белков костного матрикса как потенциальных механизмов развития этого патологического состояния у пациентов с ССД. Диагноз может быть поставлен на основе клинических данных или с помощью обычной рентгенографии. Несколько фармакологических методов лечения были применены у пациентов с кальцинозом с переменными и не столь значительными результатами, в свою очередь, хирургическое удаление депозитов кальция остается основным методом лечения.
Ключевые слова: кальцификации; кальциноз кожи; системная склеродермия; патофизиология; клиника; менеджмент; обзор
