Calcinosis in Systemic Sclerosis

Abstract

Purpose of Review:

To provide updated information on the prevalence, pathogenesis, diagnostics, and therapeutics of calcinosis cutis associated with systemic sclerosis (SSc).

Recent findings:

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.

Summary:

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.

INTRODUCTION

Calcinosis cutis is defined as the accumulation of insoluble calcium salts in the skin and subcutaneous tissues. Systemic sclerosis (SSc) is a heterogeneous disorder primarily characterized by fibrosis of skin and internal organs as well as vascular dysfunction. SSc is prone to dystrophic calcification which occurs in areas of damage associated with normal serum calcium and phosphorus levels. X-ray diffraction studies of draining calcinotic material in SSc patients confirm that the main inorganic component is hydroxyapatite, similar to that of bone [1]. Calcinosis can affect up to 20-40% of SSc patients [2]. The prevalence may vary depending on ethnicity, geographic location, and diagnostic approach. Based on physical examination or clinically indicated x-rays, it is more common in Caucasians (up to 38%) compared to Asian ethnicity (9%) [2,3]. It has a prevalence of 10% in North Africa [4], 29% in the Middle East [5] and 24% in Japan [6]. However, subclinical calcinosis detected on imaging studies was found to be present in up to 50% of patients within 4 years of disease onset in Japan [7*]. Calcinosis decreases quality of life for SSc patients due to pain, decreased hand function, ulceration, infection, and occasionally nerve compression. There are currently no effective medical therapies for calcinosis.

LOCATION AND ITS IMPACT

Calcinosis most commonly affects the hands, particularly the distal phalanges of the thumb and index fingers, which are prone to repetitive trauma [8] (See Figures 1 and 2). In addition to reduced hand mobility [9**], calcinosis in the hands and wrists can also lead to peripheral neuropathy [10*,11,12]. An ultrasound study showed that peritendinous calcifications are frequently associated with hand contractures in SSc patients [13]. Other common locations include the forearms, elbows, and extensor surface of the knees [14]. Unusual locations like the spine or face are reported in some studies [15–18]. Spinal calcinosis, which was found to occur commonly in association with acral calcinosis [21], can lead to radiculopathy, spinal stenosis, or cord compression [15–18,21].

Figure 1-.

Calcinotic material extruding from the index finger of a 45-year-old female with systemic sclerosis.

Figure 2-.

Calcinotic lesion with surrounding erythema in the thumb of 50-year-old female with systemic sclerosis.

ASSOCIATED DISEASE CHARACTERSTICS AND PATHOGENESIS

The exact pathogenesis of calcinosis is largely unknown, but there are some clinical and serological associations. Distinct antibody profiles, including anti-centromere [23] and anti-PM/Scl (Polymyositis/Scleroderma) [24] have been reported to be associated with calcinosis in some, but not all, studies [25]. Long disease duration is clearly associated with calcinosis development [24], and this may be representative of prolonged exposure to an inflammatory milieu. Inflammation has broad actions on several processes involved in calcinosis, including vascular dysfunction, bone metabolism, and phosphate metabolism, as discussed below.

Vascular dysfunction and hypoxia

Many studies have established that calcinosis in SSc is associated with features of vascular dysfunction including loss of digital pulp, acro-osteolysis and presence of digital pitting scars [2, 6, 8, 21, 23,26–30]. A Japanese cross-sectional study showed that calcinosis in the facial region is commonly associated with multiple external root resorption which is akin to loss of digital pulp in the hands [19]. Hypoxia is likely the link between vascular dysfunction and calcinosis in SSc. Vascular dysfunction combined with defective angiogenesis causes hypoxia in tissues [24], with markers of hypoxia, including keratinocyte GLUT-1 (glucose transporter), as well as advanced glycation/lipoperoxidation end products (AGEs) and their receptors (RAGE), present within the endothelium and the papillary dermis in SSc patients with calcinosis [31].

A pilot study with 20 SSc patients showed reduced perfusion in the superficial skin layers involving calcinotic areas compared to non-calcinotic areas [32]. Ulnar artery occlusion was found to be highly associated with radiograph-confirmed calcinosis in 43 SSc patients [33*]. Repetitive episodes of ischemia-reperfusion injury due to vascular dysfunction can lead to hypoxia and increase products from oxidative stress [31,34]. Further, areas prone to repetitive trauma are commonly involved sites for calcinosis. Injury to collagen, elastin or subcutaneous fat combined with hypoxia can lead to tissue necrosis, releasing denatured proteins which promotes calcification [35]. Cellular organelles like mitochondria can accumulate high amounts of calcium and phosphorus under prolonged inflammatory conditions and be released during muscle damage as demonstrated in in vivo murine models, thereby acting as nucleation sites for calcinosis [36,37].

Medications may also contribute to promotion of a hypoxic environment and subsequent development of calcinosis. Proton Pump Inhibitors (PPIs), medications frequently used to treat gastro-esophageal reflux disease (GERD) in patients with SSc, may promote atherogenic pathways and calcification through inhibition of dimethylarginine dimethylaminohydrolase [38**]. A retrospective cohort study of 199 SSc patients established a dose-response relationship between PPI use and calcinosis. This was further validated in a prospective cohort of 200 SSc patients who demonstrated an increase in odds of calcinosis of 4% with every 1 additional year on PPI therapy.

Mechanical stress or repetitive trauma

Calcinosis occurs most frequently in areas prone to repetitive trauma [8]. Mesenchymal Stem Cells (MSCs) showed osteogenic transformation when treated in vitro with blister fluid (rich in IL-31 or Th2 pathway) from the skin of SSc patients on stiff matrices, supporting the hypothesis that mechanical stress plays an important role in calcinosis [39].

Dysregulation in bone metabolism

The composition of calcinotic material in SSc is similar to that of bone, and dysregulation of bone metabolism has been implicated in calcinosis development [1]. A retrospective analysis of 5218 SSc patients from a multicenter international cohort showed that osteoporosis was associated with calcinosis [40]. It is likely that bone resorption, as occurs in acro-osteolysis and osteoporosis, releases inorganic phosphate which promotes osteoblastic differentiation of dermal fibroblasts [1]. Consistent with this interpretation, MSCs underwent osteogenic transformation upon in vitro exposure to appropriate osteogenic media consisting of beta-glycerophosphate [41].

Dysregulation in phosphate metabolism

Inorganic pyrophosphate (PPi), which is derived largely from ATP, is an inhibitor of mineralization. Alterations in the PPi pathway, leading to reduced levels, can promote calcification. Several genes involved in maintaining PPi levels, including ABCC6 (ATP binding cassette), ENPP1 (ectonucleotide pyrophosphatase phosphodiesterase 1) and NT5E (ecto- 5’ nucleotidase), have been implicated in other ectopic mineralization disorders [14,42]. The ENPP1 pathway may also be inhibited by inflammatory cytokines, in particular IL-1β [41]. PPi levels are reduced in ectopic mineralization disorders such as Pseudoxanthoma Elasticum. A recent study found plasma PPi levels were also reduced in SSc patients as compared to healthy controls, but there was no significant difference between those with and without calcinosis [43**]. Additional studies are necessary to further investigate the role of PPi and dysregulated phosphate metabolism in the pathogenesis of calcinosis.

FGF-23 (fibroblast growth factor 23) signals through its co-receptor KLOTHO in the proximal tubule of the kidney to downregulate sodium-phosphate cotransporters, leading to phosphaturia [44]. This pathway is disrupted in familial pseudotumoral calcinosis leading to hyperphosphatemic calcinosis. Although dystrophic calcification in SSc is associated with normal serum phosphate levels, it is nevertheless noteworthy that high levels of serum FGF-23 levels [45] have been associated with calcinosis in SSc. Thus, this pathway may be involved in SSc-related calcinosis.

GENETIC ASSOCIATIONS

The HLA-DRB1*04 allele is associated with subcutaneous calcinosis in SSc [46]. Polymorphisms of matrix metalloproteinase-encoding genes are also associated with calcinosis in SSc [47]. Genetic studies in 1142 SSc patients showed some association of TNFSF4 polymorphisms (Tumor necrosis factor ligand superfamily member 4) with calcinosis, thus implicating the importance of inflammation [48]. Genetic studies exploring genes involved in phosphate metabolism in SSc patients with a severe calcinosis phenotype are currently underway.

CLINICAL PRESENTATION

Calcinosis cutis lesions can present as subcutaneous nodules (circumscripta) which is the most common form in SSc patients. Other presentations include ‘sheet-like’ along the myofascial planes (calcinosis universalis) or extensive deposits covering larger surface areas (exoskeleton) [49–51]. While pseudotumoral calcinosis has been reported in up to 3% of SSc patients [52], giant calcinosis can occur in patients with dermatomyositis and SSc overlap syndrome [53]. Based on the shape and consistency on palpation, the lesions can be further classified into mousse (soft with chalky-like liquid under the skin), net (diffuse thin network), plate (large uniform agglomerate) or stone (palpable as a single or multiple stones of hard consistency) [14,54].

DIAGNOSTIC MODALITIES

Plain radiography of affected areas is the most common imaging modality used to detect calcinosis (Figure 3). A validated radiographic scoring system for longitudinal assessment of calcinosis, with excellent inter-rater and intra-rater reliability, was developed by Chung et al [26**]. Ultrasound can be used at the point of care (Figure 4) and has specificity close to 95-100% for detecting calcinosis compared to X-ray [55].

Figure 3-.

Calcinosis deposits in the fingers as detected on a plain radiograph

Figure 4-.

An aggregate of calcinosis detected by ultrasound on the volar aspect of the finger near the proximal interphalangeal joint

Although Computed tomography (CT) is more sensitive than X-rays and provides information on surrounding structures such as neurovascular bundles [56*], radiographic estimation of calcinosis volume seems to correlate well with that of CT [57]. Artificial Intelligence is being applied to dual energy CT scans in SSc patients with calcinosis of the fingers to more accurately estimate calcinotic burden, but further validation studies are necessary [58,59]. Novel 3D-cinematic picturization through CT scan is also being evaluated in detection of calcinosis universalis [60].

MANAGEMENT

As the pathogenesis behind calcinosis is still being unraveled, and outcome measures to use in clinical trials are still being validated, thus far, we have no effective treatment options.

General measures

As longstanding hypoxia and trauma play a crucial role in the development of calcinosis, avoidance of trauma can help prevent new lesions. Appropriate wound care and anti-microbial treatment are needed for non-healing and infected ulcers, respectively. Pain management is critical in the treatment of calcinosis, particularly for lesions involving pressure points or causing nerve compression.

Local and Non-invasive therapies

Herbal therapies like Holoil (neem oil and Hypericum perforatum) employed in wound care facilitated complete healing in 45% of calcinotic lesions (involving the hands) in 21 SSc patients over a mean duration of 40 days. It softens the lesions and facilitates easy excision of the calcinotic material. Although it needs to be validated in a larger cohort, it proved to be safe in this pilot study [54].

Topical sodium thiosulfate (STS) helps in clearing calcinotic lesions by acting as a calcium chelating agent. In addition to individual case reports, a retrospective study showed improvement in 68% of those treated with 25% sodium thiosulfate in zinc oxide [61, 62]. Topical sodium thiosulfate is generally dispensed through compounding pharmacies. A recent systematic review found improvement in 81% (39 of 48 patients) of patients over a mean duration of 4.9 months [63*]. Side effects included skin irritation, allergy to zinc, and occasionally pain with application.

Local and Minimally-invasive therapies

Intralesional sodium thiosulfate (1ml/cm^2) injected monthly into calcinotic plaques of a patient with diffuse cutaneous SSc resulted in nearly complete resolution in 3 months [64]. A case series of 6 patients (including 5 SSc patients) with calcinosis treated with intralesional injection every week (12.5 mg to 150 mg each dose) for 4 weeks, showed significant improvement in 100% of the SSc patients [65] .Intradermal or local anesthesia is often employed with this procedure, despite which burning pain at the site of injection is reported by many patients.

Extra-corporeal shockwave therapy is a minimally invasive procedure that is proving to help with pain relief (through nerve decompression) associated with recalcitrant calcinotic lesions that are not amenable for surgery. A prospective study reported analgesic improvement in 2 of 3 patients with 3 sessions done at 3-week intervals [66]. A 12-week study involving four SSc patients, resulted in significant pain relief in two of them [67]. CO2 laser also showed significant pain improvement in 6 of 9 patients. Common side effects include scarring, hyperkeratosis and ulcer recurrence [63].

Medical therapies

Table 1 outlines the various systemic medications that have been in use for calcinosis along with their typical dosing and common adverse effects.

Table 1-.

Systemic medical therapies for calcinosis in systemic sclerosis

Drug class	Mechanism of action	Drug (dosage)	Efficacy	References	Common adverse effects
Calcium channel blockers	Vasodilation by blocking voltage sensitive Ca2+ channels on vascular smooth muscle and decrease calcium efflux.	Diltiazem (oral 60mg TID) X 6.5 years	3/12- PR	Vayssairat et al (69)	Hypotension, peripheral edema, heart blocks.
		Diltiazem (oral up to 480mg/day)	9/17- PR	SJ Balin et al (68)
		Amlodipine (oral 10mg OD)	1/1- PR	SJ Balin et al (68)
Bisphosphonates	Reduce macrophage activity and bone turnover.	Pamidronate (IV 70-75mg every 12 weeks) X 8.6 cycles	5/7- non-progression	Rauch L et al (71)	Osteonecrosis of jaw, Flu like illness
Tetracyclines	Anti-microbial and inhibit MMPs	Minocycline 50-100mg (oral OD) X 4.8 months	8/9- PR	Robertson LP et al (73)	Dizziness, bluish discoloration of calcinotic lesions
		Minocycline 50-200mg (OD)X 6-12 weeks	34/78- PR	Carmen Fonseca et al (72)
Prostacyclin agonist	Vasodilation	Treprostinil (oral 0.125mg TID and increase as tolerated) X 1 year	4/12- Non progression	Chung M et al (74)	Gastrointestinal intolerance, headache
B-cell depletion	Monoclonal antibody against CD20 antigen of B lymphocytes	Rituximab (IV 375mg/m2 every 4-week) X 2 courses	1/1- PR	Daoussis et al (75)	Secondary infections
		Rituximab (IV 1g every 2 week) X3.1 cycles	4/8- pain improvement 2/8- PR	Narvaez J et al (76)
Leflunomide	Inhibit pyrimidine synthesis, anti-inflammatory	Leflunomide (20mg oral OD) X 12 months	1/1- PR	Lee SY et al (77)	Liver enzyme elevation.
TNF- alpha inhibitors	Suppress TNF-alpha	Infliximab (IV 3mg/kg at 0, 2, 6 weeks and then every 8 weeks) X 41 months	1/1- CR	Tosounidou S et al (78)	Secondary infection, allergic reactions
PDE4 inhibitor	Inhibits IL-17, IL-23 and TNF-alpha	Apremilast (oral 30mg BID) X3 months	1/1- PR	Qiblawi SH et al (79)	Secondary infections
Intravenous immunoglobulin (IVIG)	Suppress macrophage and complement pathway	IVIG (2g/kg/month) X 3 months	1/1- PR	Schanz et al (80)	Headache, nausea, dizziness, small increase in risk of thrombosis
JAK inhibitors	Inhibit macrophage and complement pathway	Tofacitinib (5mg oral BID) X 3 months	3/3- PR	Shneyderman M et al (81)	Increased risk of thrombosis, malignancy, secondary infections
Intravenous Sodium thiosulfate	Increase solubility of the calcium by compounding and help clearing	12.5g-25g sodium thiosulfate three times a week		Badawi AH et al(83) Mageau A et al(84) Song P et al(85)	Fatigue, nausea, vomiting, metabolic acidosis not requiring treatment

OD- once a day, BID- twice a day, TID- thrice a day, PR- partial response only, CR- complete response, IV- intravenous, MMPs- matrixmetalloproteinases, TNF- tumour necrosis factor, IL- interleukin, JAK- Janus Kinase

Calcium channel blockers (CCBs)

Calcium channel blockers are frequently prescribed for calcinosis and thought to inhibit calcium efflux into tissues, in addition to vasodilation. A retrospective analysis done in a cohort of 78 patients with calcinosis showed that 10 of 18 treated patients had partial response [68]. However, a case series of 12 SSc patients treated with diltiazem 60 mg three times a day, showed only a slight radiographic improvement in calcinosis in 3 patients over a mean duration of 8 years [69].

Bisphosphonates

Bisphosphonates have shown some benefit in calcinosis associated with juvenile dermatomyositis [70], but large-scale studies in SSc are lacking. They combat calcinosis by decreasing macrophage activation and reducing bone turnover. A retrospective analysis of 7 patients treated with IV pamidronate (including 2 patients with SSc) showed improvement in pain and non-progression of severe calcinosis cutis in 5 out of 7 patients (71%) including 1 SSc patient. It was given at a dose of 70-75 mg every 12 weeks for a mean duration of 24 months. Osteonecrosis of the jaw occurred in one patient [71].

Minocycline

Minocycline, with its combined anti-microbial and anti-inflammatory properties, is commonly used for calcinosis. Robertson et al described clinical improvement in 8 of 9 treated patients in an open-label study with a dose of 50-100 mg daily over a mean duration of 4.8 months [72].

A large observational study showed clinical improvement in 34 of 78 patients (43.6%) with multiple courses of 50-200 mg minocycline for 6-12 weeks [73].

Treprostinil

A pilot study of oral treprostinil, a prostacyclin analogue and powerful vasodilator, showed non-progression of SSc-associated calcinosis radiographically in 4 out of 5 patients who completed the trial [74**].

Rituximab

Rituximab is a monoclonal antibody directed against the CD20 antigen of B lymphocytes, thereby causing B-cell depletion. A patient with extensive calcinosis showed improvement with 2 courses of rituximab given at a dose of 375 mg/m^2 4 weeks apart [75]. An observational study consisting of 8 SSc patients with refractory calcinosis showed that a mean number of 3.12 rituximab cycles (1g every 2 weeks) showed significant improvement in 4 patients (50%) with regards to pain, and 2 of these had near complete radiographic resolution in calcinosis [76]. No serious infections were reported in this study.

Other immunosuppressants

There are a few independent case reports showing some beneficial effect from leflunomide [77], infliximab [78], apremilast [79] and intravenous immunoglobulins [80]. The JAK inhibitor tofacitinib has proven beneficial in calcinosis associated with dermatomyositis but has not yet been evaluated in SSc-associated calcinosis [81].

Intravenous Sodium Thiosulfate

Intravenous sodium thiosulfate has been a popular treatment for calciphylaxis associated with end stage renal disease [82,83] and similarly has been employed for recalcitrant calcinotic lesions associated with dermatomyositis. Several case reports showed improvement in pain and reduction in size of the calcinotic lesion [84–86]. This treatment is being explored for calcinosis in SSc patients as well.

Surgical treatments

Surgical excision of calcinotic lesions is an effective approach, particularly for periarticular lesions in the hands causing nerve compression [87*] and/or severe physical discomfort. Spinal canal stenosis causing radiculopathy treated with decompressive laminectomy results in symptom alleviation [18]. A retrospective analysis done at a single center showed significant improvement in analgesia in 6 of 39 patients who underwent elective surgical debulking of calcinosis. The most common complications included recurrence of calcinosis (15%), delayed wound healing (13%), and wound infection (10%).

CONCLUSION

Although a significant contributor to disease morbidity, very little is known about the origins of calcinosis in SSc. Several studies have established a strong association of calcinosis with long disease duration and features of vascular dysfunction. Further studies are necessary to better understand the role of bone metabolism and inflammation in the pathogenesis of calcinosis. Surgical excision when feasible is the most effective treatment. Topical therapies can be employed for uncomplicated small calcinotic lesions but will require long term adherence to show mild benefit. Systemic medical therapies like minocycline can be useful in treating the inflammation associated with calcinosis, but immunosuppressants should be used cautiously given the sparsity of evidence supporting their efficacy. Validated outcome measures and larger clinical trials are much needed to establish strong treatment recommendations for this debilitating condition.

KEY-POINTS.

• Biochemical studies support the association of calcinosis with prolonged vascular dysfunction, inflammation, and dysregulated phosphate metabolism in systemic sclerosis.

• Low level of evidence supports medical therapies like topical sodium thiosulfate and oral minocycline for SSc-related calcinosis.

• When lesions are accessible, surgical removal is the most effective treatment option for SSc-related calcinosis.