Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in children, affecting 2-4 children per million per year (1). Children typically present with proximal muscle weakness and pathognomonic rashes, notably Gottron’s sign and heliotrope (2). Despite improvements in mortality, significant morbidity associated with JDM remains. Calcinosis, which is the intracellular deposition of insoluble calcium salts in the skin, subcutaneous tissue, fascia, tendons, and muscles, affects approximately 40% of patients and can lead to skin ulcers and recurrent infection, joint contractures, and nerve entrapment. Calcinosis in JDM is dystrophic, occurring secondary to injury and in the setting of otherwise normal calcium and phosphate (3). Figure 1 shows calcinosis in the fingers of a child with JDM, and Figure 2 is a radiograph of calcinosis in the subcutaneous tissues near the knee. Prior studies have suggested that risk factors include delay in JDM diagnosis and prolonged disease activity, implying that early and aggressive treatment may minimize calcinosis risk (4). There remains a lack of consensus on appropriate treatment of calcinosis in JDM, likely due to an unclear understanding of its pathogenesis, disease rarity, and reliance on expert opinion via case reports and case series. This article is a review of literature published in the past 5 years regarding calcinosis in JDM, addressing updates in pathogenesis and treatment.

A 2022 review by Davuluri et al. (5) summarizes potential pathogenic mechanisms of calcinosis in JDM, including the process of mitochondrial calcification (3) which is driven primarily by reactive oxygen species (ROS) produced secondary to inflammation. Calcified mitochondria have been found in skeletal muscle cells of JDM patients (6), and once calcified, the mitochondria perpetuate inflammation by secreting inflammatory cytokines like IL-1β and upregulating type I interferon-regulated genes (7). Additionally, patients with JDM had increased cell-free mitochondrial DNA in their peripheral blood, with even higher levels noted in patients with calcinosis. Autoantibodies directed against mitochondrial antigens (AMA) were present in 40% of JDM patients and were significantly associated with calcinosis (odds ratio = 6.1). Interestingly, AMA became elevated prior to the clinical diagnosis of calcinosis and may have prognostic potential (8).

The role of neutrophils in JDM is also being explored, though they are not typically found in muscle biopsies. Investigators identified neutrophils in damaged muscle tissue via electron microscopy and showed that those neutrophils had phagocytized calcium crystals. The crystals induced neutrophil extracellular traps (NETs), leading to local tissue damage and inflammation. Macrophages were also shown to phagocytize calcium crystals (9).

Reported rates of calcinosis and associated risk factors vary. Recent North American reviews described calcinosis in 2-5% of patients at JDM diagnosis and in 13-25% overall (10–13). International cohort studies have shown higher rates ranging from 9 to 11% at diagnosis and 20 to 40% developing calcinosis over the disease course (14–21). A multinational, multicenter study of patients with the myositis-specific antibody (MSA) anti-nuclear matrix protein 2 (NXP2) described calcinosis in 15% at diagnosis and 42% overall (22). In other cohorts tested for MSA, rates of calcinosis by MSA were rarely significant, with the exception of one that showed 75% of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies developed calcinosis (16). Risk factors for initial development (and in some cases recurrence) of calcinosis included prolonged duration of disease prior to treatment (10, 12, 14), nailfold abnormalities at baseline (11), chronic disease course (11), lipodystrophy (12), joint contractures (12), longer time to regain full muscle strength (15), higher muscle biopsy score (16), and disease onset prior to age 6 years (16). In one cohort, 77% of calcinosis resolved in an average of 5.6 months, though 25% had recurrence at the original site in an average of 5 years. For those patients whose calcinosis never resolved, 71% had calcinosis at diagnosis and presented with longer disease duration (10). A review of 49 adult patients (median age 24 years) sought to characterize long-term outcomes, and at a median of 11.5 years post diagnosis, 55% had calcinosis. For each additional year of disease, the odds of calcinosis increased 12%, whereas for each additional year of age at diagnosis, the odds of calcinosis decreased 19% (23).

A review from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry compared the mean UV index in the month prior to symptom onset in a cohort of over 500 patients. The results showed an association between mean UV index and development of calcinosis, though this was dependent on race; there was a correlation in non-African American patients between higher UV exposure and development of calcinosis (24). In another study from the CARRA registry, African American patients had twofold increased odds of calcinosis compared to other patients (25). These studies suggest there are both genetic and environmental factors in the development of calcinosis.

A variation in presentation of JDM is clinically amyopathic disease (CAJDM). A retrospective review comparing patients with CAJDM to patients with muscle involvement found that none of the CAJDM patients developed calcinosis during a median follow-up of 2.9 years. This was compared to 33% of the JDM patients, suggesting that calcinosis may be a less frequent comorbidity in CAJDM (26).

Treatment guidelines for calcinosis in JDM are largely lacking. In 2017, the SHARE committee (Single Hub and Access point for pediatric Rheumatology in Europe) published treatment recommendations for JDM, but declined to give a specific recommendation for calcinosis due to lack of evidence. The SHARE committee suggested that the following treatments may be beneficial in patients with calcinosis: bisphosphonates, infliximab, abatacept, diltiazem, probenecid, intravenous immunoglobulin (IVIG), intralesional steroids, or surgical resection (27). Similarly, a CARRA 2017 consensus treatment plan for JDM with persistent skin rash excluded those patients with more than “mild” calcinosis (per opinion of the treating physician) (28).

A survey of over 100 pediatric rheumatologists on their current practice of assessing and treating calcinosis in JDM found a variety of immunomodulators are used in clinical practice, the most common being: IVIG, systemic glucocorticoids, methotrexate, mycophenolate mofetil (MMF), and colchicine. By far, the most commonly used alternative agent was bisphosphonates, followed by calcium channel blockers and topical sodium thiosulfate (STS). Experienced physicians, defined as having seen more than 10 cases of calcinosis, were significantly more likely to use these alternative agents compared to physicians who had seen fewer cases (29). A 2017 survey of pediatric rheumatologists found that 52.5% of physicians felt that the use of biologics would reduce calcinosis (30). The current literature regarding treatment is summarized below by medication and medication class.

Despite a growing body of literature, knowledge gaps remain in our understanding of the pathogenesis, risk factors, and most effective treatments for calcinosis in JDM. In a review of 563 patients with JDM from the CARRA registry, 39% of patient global activity scores were at least 2 points different than the corresponding physician global activity scores. Among these patients, 10% had calcinosis, and in multivariable analysis, calcinosis was an independent predictor of discordance in patient and provider global disease activity scores. This finding suggests that calcinosis has important impacts on the perception of JDM disease activity for both physicians and patients and should possibly be a research priority (54).

The lack of clear treatment guidelines is the result of many factors, including the rarity of JDM and the variability in reported rates of JDM-related calcinosis. A survey of practicing pediatric rheumatologists indicated that only 17% had treated more than 20 cases (29). Another factor is that most of the current literature is limited to anecdotal case reports and case series, which make it difficult to differentiate correlation and causation. The case reports and case series are also highly variable in underlying therapies, duration of treatment, duration of follow-up, and ultimately outcomes. For example, though high dose glucocorticoids have been the mainstay of treatment for JDM, and thus the prevention of calcinosis, Orandi et al. reported a retrospective review of 31 patients treated with lower dose and shorter duration glucocorticoids. The incidence and prevalence of calcinosis in the cohort was comparable to published literature, suggesting such high dose glucocorticoids may not be required to prevent sequelae like calcinosis (55).

Though there have been randomized controlled trials (RCTs) conducted in adult patients with DM, adult and juvenile DM are known to have key variations in presentation, complications, and outcomes, and so findings from these studies cannot be directly applied to pediatric patients (56). Additionally, true comparative studies are difficult without better objective measures of calcinosis; the majority of the current literature defines a presence or absence of calcinosis, making it difficult to quantify improvement on a given therapy.

Additional areas of future research should include the phenotype and specificity of MSA profiles. A recent case study described three patients, all with seronegative polyarthritis, who tested positive for anti-NXP2 antibodies, suggesting that they may not be specific for dermatomyositis (57). Additionally, a case series of patients with anti-NXP2 antibodies reported four patients who tested positive for multiple MSA, including anti-MDA5 and anti-Mi2 (22). While a false positive is certainly possible, further investigation is warranted.

Ultimately, despite the advancement in understanding of certain risk factors for calcinosis in JDM, particularly that early and aggressive treatment can help prevent development, questions about best treatment options remain. While RCTs are considered the most robust, they may not be feasible given the rarity of JDM and JDM-related calcinosis. Future research with more innovative comparative effectiveness approaches and standardized assessment tools for calcinosis are needed to define the most efficacious diagnostic and treatment for calcinosis in JDM.

EW, LC, and CP: conceptualization. CP: investigation and writing—original draft preparation. CP, LC, JD, and EW: writing—review and editing. All authors read and agreed to the published version of the manuscript.