Clinical course and potential associated factors of progressive calcinosis cutis in early systemic sclerosis: a cohort study

Abstract

Background

Calcinosis cutis of hands can progress and impair hand function in systemic sclerosis (SSc). Understanding the natural disease and comprehensive management is crucial.

Objective

To examine clinical course and identify risk factors associated with progressive calcinosis cutis in early SSc.

Methods

Dual time-point hand radiography was performed at initial and after diagnosis at median interval (range 2.9 ± 0.4 years) in 53 recruited patients with early SSc. Progressive calcinosis cutis defined as the worsening of severity according to simple soring scoring system (no, mild, moderate, severe) comparing to previous hand radiography. Odds ratio (OR) and their 95%CI were used to evaluate associated factors and calcinosis cutis progression.

Results

A total of 35 cases (155 per 100 person-year), showed progressive calcinosis cutis with the incidence of 22.6 per 100-person-years (95%CI 16.2–31.4). The most common area of progressive calcinosis cutis was at right distal phalanx, 12 of 35 (22.6%). Although statistically not significant by logistic regression analysis, elderly patients, Raynaud’s phenomenon, ischemic ulcer, telangiectasia, and salt-pepper tended to be more frequent in progressive calcinosis cutis than those who had no progression. Around one-quarter of those who had no calcinosis cutis experienced worsening across more than one level of severity.

Conclusion

Progression of calcinosis cutis in early SSc increased over time, particularly within 3 years after the first evaluation. Elderly patients and those with vasculopathy were found more frequently. Further study with a larger cohort is needed to support these findings.

Introduction

Systemic sclerosis (SSc) is an autoimmune disease of the connective tissues of the skin and various internal organs resulting from abnormalities of blood vessels, and fibrotic changes. Calcinosis cutis, characterized by the calcium deposits in the skin and subcutaneous tissue, manifesting in approximately 18–49% of SSc patients, most prominently affecting the hands [1–3]. Its natural history is unclear, and it can be present as early or late manifestation of the disease [2,4].

Diagnosis of calcinosis cutis could be done by physical examinations, and plain radiography serves as a very sensitive and effective tool for diagnosis and initial imaging evaluation [5,6]. The severity of the condition can directly affect the patient’s quality of life and necessitates comprehensive clinical management. Currently, there are limited researches on the natural history, potential risk factors associated, and the standardized measurement to determine the progression and the severity of calcinosis cutis.

The objective of the study is to explore the clinical course and identify factors associated with progressive calcinosis cutis using a simple standard scoring system in patients with early SSc, in whom internal organ involvement commonly occurred.

Methods

This retro-prospective cohort study examined hand radiographs and clinical characteristics of SSc patients who were seen at the Scleroderma Clinic, Srinagarind Hospital, Khon Kaen University, Thailand, from April 2020 to March 2023 [7].

Subject group

This study included SSc patients aged 18 and older who met the following criteria: a) They satisfied the 2013 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) Classification Criteria for SSc [8]. b) They were in the early stage of SSc, defined as having a time span of less than 4 years from the onset of SSc to their first hand radiographic examination. c) They had undergone hand radiography at least twice, with a minimum interval of 2 years between examinations, as part of routine evaluations for new or progressive acro-osteolysis. Patients with overlap syndrome or those with a history of hand trauma or previous hand surgery were excluded from the study [7].

Patient variables

We carried out an evaluation of these patients at two separate times: first at the initial hand radiographic examination and again at the subsequent radiographic assessment. The data collected included the patients’ age, gender, SSc subsets (diffuse cutaneous SSc [dcSSc]or limited cutaneous SSc [lcSSc]), the presence of anti-topoisomerase I (anti-topo I) antibodies, SSc clinical features, and the severity of skin thickness as assessed by the modified Rodnan skin score (mRSS) [7].

Hand radiographs

All eligible patients received hand radiographs in two positions: posteroanterior and oblique views using a standard radiography system (Hitachi, Radnext 80, 50 kVp, 1 mAs) at both the initial and follow-up evaluation times [7].

Operational definitions

SSc is categorized into diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) groups according to the criteria outlined by LeRoy et al. in 1988 [9]. The onset of SSc was defined as the time of the initial manifestation of the first non-Raynaud SSc symptom reported by the patient. Ischemic ulcer was a painful, denuded area with well demarcated borders located on the volar aspect of the fingers and was not associated with calcinosis cutis. Pulmonary hypertension is defined by a mean pulmonary arterial pressure >20 mmHg confirmed by right heart catheterization [10].

Interpretation of radiographs

All hand radiographs were reviewed using the Picture Archive and Communication Systems (PACS). Radiographic examination for calcinosis cutis was interpreted by two 10-years-experienced musculoskeletal radiologists. Radiologists were blinded to the time points of the radiograph. Any discrepancy was given in a consensus.

Calcinosis cutis was defined as radio-opaque (white) deposition in any area within soft tissues. A scale for the density of calcium is defined as

1. less than trabecular bone

2. similar to trabecular bone

3. similar to or denser than bone cortex

Radiograph were divided into 22 areas on each hand by anatomical region to locate the calcinosis cutis (Figure 1).

Figure 1.

The location of the occurrence (percentage) of calcinosis cutis of the second radiograph.

The overall information is scaled as the Simple Scoring System that proposed by Johnstone et al. [11] as follows (Figure 2):

Figure 2.

Progressive calcinosis classified by the Simple Scoring System. The second radiograph of right hand (partial-cut) (A) demonstrated progressive calcainosis cutis at area 5 to moderate degree from mild degree comparted to the first radiograph (B) by criteria of changing of the single site of low to high density calcium (arrow).

1. mild: single or more sites of low-density calcinosis

2. moderate: medium density calcinosis at one or more sites or single site of high density

3. severe: more than one site of high density or mix density

Criteria for SSc with and without progressive calcinosis cutis

Progressive calcinosis cutis is diagnosed when the severity increased in the second radiographic evaluation compared to the first radiographic examination using the Simple Scoring System; for example, a transition from no to mild, mild to moderate or moderate to severe calcinosis.

Statistical analysis

Continuous variables were presented as mean (± standard deviation) or median (± interquartile range [IQR]), as appropriate. Categorical variables were expressed as numbers and percentages. The incidence rate of progressive calcinosis cutis and its 95% confidence interval (95%CI) were assessed. Odds ratio (OR) and their 95%CI between associated factors and calcinosis cutis progression were determined. Student’s t-test or Wilcoxon rank-sum test was used to evaluate the difference in mean and median, respectively. All statistical tests were two-tailed. A P-value of < 0.05 was considered statistically significant. Data analyses were conducted using STATA version 16.0 (StatCorp., College Station, TX, US) [7].

Ethical consideration

This study was conceptualized by the authors and received an approval from the Human Research Ethics Committee of Khon Kaen University, granted the approval number HE651426. The study adhered to the principles outlined in the Helsinki Declaration and the Good Clinical Practice Guidelines. Prior to enrollment, all eligible patients provided a written informed consent as a prerequisite for participation in this study.

Results

Evaluation of clinical features

A total of 53 SSc patients were involved, with 33 (62.2%) being females. The average age at the 1st and 2nd radiographic evaluations was 57.6 ± 10.0 and 60.4 ± 9.8 years, respectively. At the time of the 2nd radiographic evaluation, the mean disease duration was 4.3 ± 1.2 years. The average interval time between the 1st and 2nd radiographic evaluations was 2.9 ± 0.4 years. At the 1st radiographic evaluation, calcinosis was detected in 27 out of 53 cases (50.9%). During follow-up (2nd radiographic evaluation), calcinosis cutis was identified in 45 cases (84.9%). Among those with calcinosis cutis at baseline, 17 cases showed no progression. The overall clinical characteristics of SSc patients with/without progressive calcinosis cutis are shown in Table 1.

Table 1.

Factors association with progressive calcinosis cutis based on simple scoring system by univariate analysis.

Data	Overall N = 53(%)	Without progressive calcinosis cutis N = 18	With progressive calcinosis cutis N = 35	OR (95%CI)	P-value
Female; n (%)	33 (62.2)	10 (55.6)	23 (65.7)	1.53 (0.48–4.90)	0.47
Diffuse cutaneous systemic sclerosis; n (%)	39 (75)	14 (77.8)	25 (73.5)	0.79 (0.21–3.01)	0.74
Age at the 1st radiographic evaluation; years (mean ± SD)	57.6 ± 10.0	50.9 ± 7.0	60.9 ± 9.8	–	<0.001*
Age at the 2nd radiographic evaluation; years (mean ± SD)	60.4 ± 9.8	54.4 ± 6.9	63.4 ± 9.7	–	0.001*
Duration of disease at 2nd radiographic evaluation; years (mean ± SD)	4.3 ± 1.2	4.1 ± 1.4	4.4 ± 1.1	–	0.49
Interval between the 1st and the 2nd radiographic evaluation; years (mean ± SD)	2.9 ± 0.4	2.9 ± 0.5	3.0 ± 0.3	–	0.48
Anti-topoisomerase I antibody positive; n (%)	37 (84)	13 (86.7)	24 (82.7)	0.74 (0.13–4.35)	0.74
Clinical features at the 2nd radiographic evaluation
Raynaud’s phenomenon; n (%)	23 (44.2)	3 (30)	20 (47.6)	2.00(0.61–6.56)	0.25
Ischemic ulcer; n (%)	6 (11.5)	0	6 (14.3)	NA	NA
Digital gangrene; n (%)	0	0	0	NA	NA
Telangiectasia; n (%)	22 (42.3)	3 (30)	19 (45.2)	1.78(0.54–5.83)	0.34
Salt and pepper skin; n (%)	27 (51.9)	4 (40)	23 (54.8)	1.58 (0.50–5.00)	0.43
Edematous skin; n (%)	2 (3.9)	1 (10)	1 (2.4)	0.52 (0.03–8.75)	0.65
Tendon friction rub; n (%)	6 (11.5)	2 (20)	4 (9.5)	1.07 (0.18–6.47)	0.94
Hand deformities; n (%)	16 (30.8)	3 (30)	13 (31.0)	1.24 (0.35–4.37)	0.73
Synovitis; n (%)	1 (1.9)	0	1 (2.4)	NA	NA
Muscle weakness; n (%)	1 (1.9)	0	1 (2.4)	NA	NA
mRSS; points (median (IQR))	2 (0–10)	2 (0–9)	3.5 (0–10)	–	0.91
Weight loss; n (%)	11 (21.2)	4 (22.2)	7 (20.5)	0.91 (0.23–3.63)	0.89
Pulmonary fibrosis; n (%)	27 (51.9)	5 (50)	22 (52.4)	1.13(0.34–3.53)	0.84
Pulmonary hypertension; n (%)	6 (11.8)	1 (10)	5 (12.2)	0.50 (0.09–2.78)	0.43
Clinical features at the 1st radiographic evaluation
Raynaud’s phenomenon; n (%)	13 (26.5)	5 (31.3)	8 (24.2)	0.86 (0.19–3.83)	0.84
Ischemic ulcer; n (%)	5 (10.2)	1 (6.2)	4 (12.1)	4.74 (0.54–41.47)	0.16
Digital gangrene; n (%)	1 (2.0)	0	1 (6.3)	NA	NA
Telangiectasia; n (%)	11 (22.5)	2 (12.5)	9 (27.3)	1.08(0.24–4.87)	0.92
Salt and pepper skin; n (%)	27 (55.1)	9 (56.3)	18 (54.6)	1.19(0.35–4.05)	0.78
Edematous skin; n (%)	7 (14.3)	3 (18.8)	4 (12.1)	0.80 (0.23–2.80)	0.73
Tendon friction rub; n (%)	6 (12.2)	3 (18.8)	3 (9.1)	1.10 (0.31–3.89)	0.88
Hand deformities; n (%)	22 (44.9)	6 (37.5)	16 (48.5)	2.59(0.49–13.64)	0.26
Synovitis; n (%)	1 (2.0)	0	1 (3.0)	5.54(0.64–47.92)	0.12
mRSS; points (median (IQR))	11(7–19)	11(3–19)	11.5(8.5–20)	–	0.43
Muscle weakness; n (%)	2 (4.1)	0	2 (6.1)	0.97(0.16–5.89)	0.97
Weight loss; n (%)	12 (24.5)	5 (31.2)	7 (21.2)	1.50 (0.48–4.71)	0.49
Pulmonary fibrosis; n (%)	13 (27.7)	4 (25.0)	9 (29.0)	0.88(0.14–5.54)	0.89
Pulmonary hypertension; n (%)	3 (6.4)	1 (6.2)	2 (6.5)	NA	NA

OR odds ratio, 95%CI 95% confidence interval, SD standard deviation, IQR interquartile range, mRSS modified Rodnan skin score, NA data not available due to statistical limitation.

Progression rate of calcinosis cutis with SSc

Among a total of 155 per 100 person-year, 35 cases were defined as having progressive calcinosis cutis with the incidence of 22.6 per 100-person-years (95%CI 16.2–31.4).

The location of the occurrence (percentage) of calcinosis cutis

In the right hand, out of the 22 areas examined, the occurrence of calcinosis cutis was highest at the 1^st distal phalanx (area 6: 22.6%), followed by distal radius-ulna (area 1: 20.8%), the 2^nd distal phalanx (area 10: 18.9%), the 5^th metacarpal (area 19: 17%), and the proximal carpal row (area 2: 15.1%) in order as shown in Figure 1.

In the left hand, out of the 22 areas examined, the highest occurrence of calcinosis cutis was at the 3^rd distal phalanx (area 14: 18.9%), followed by the proximal carpal row (area 2: 18.9%). The third occurrence of 15. 1% was equally seen in distal radius-ulna (area 1), the 1st distal phalanx (area 6), the 2nd distal phalanx (area 10), and the 5th middle phalanx (area 21).

Progression patterns of calcinosis cutis using the Simple Scoring System

At the 1st radiographic evaluation, 26 of 53 early SSc patients were identified to be negative of calcinosis cutis, while 12 have mild, 14 moderate, and 1 severe calcinosis cutis. During the follow-up period, 18 of 26 cases of calcinosis cutis-negative SSc patients developed calcinosis cutis; 4 cases developed mild calcinosis cutis, 13 cases moderate, and 1 case developed severe calcinosis cutis. Among 12 cases with mild calcinosis cutis at the 1^st radiographic evaluation, 10 cases progressed to moderate calcinosis cutis, and 1 case of moderate calcinosis cutis at the first evaluation progressed to severe calcinosis cutis by the 2nd radiographic evaluation. The progression patterns of the severity of calcinosis cutis are shown in Figure 3.

Figure 3.

Progression patterns of calcinosis cutis using the Simple Scoring System.

Potential predictors of progressive calcinosis cutis

Among various clinical parameters, elderly patients, female patients, those having telangiectasia, ischemic ulcer, salt and pepper skin, and Raynaud’s phenomenon at the 2nd radiographic evaluation were more frequently observed among patients with progressive calcinosis cutis than those without progressive calcinosis cutis, although those differences were statistically not significant by univariate analysis (Table 1).

When the occurrence of at least one new area of calcium deposit was used as the criterion of the progression of calcinosis cutis, 42 out of 53 SSc patients (79.2%) were classified to have progressive calcinosis cutis. By this classification, clinical features of SSc patients with and without progressive calcinosis cutis were compared and the results are given in Supplementary Table 1. Apparently, the results were essentially the same as those seen in the evaluation of the clinical features of SSc with/without progressive calcinosis cutis defined by the Simple Scoring System (Table 1).

Discussion

The aim of this study is to identify the progression of calcinosis among early SSc through a systematic evaluation using the Simple Scoring System [8] based on radiographic examination at two different time points. The incidence of progressive calcinosis cutis was 22.6 per 100 person-years with the median time of having progressive calcinosis cutis of 3.5 years. The incidence is comparable to the study of Avouac et al. [12]. They revealed that 27 of 103 SSc from a single cohort study (26%) showed radiographic progression of calcinosis, defined as at least one new calcification, or increase in size of at least one calcification at median interval of 5 years [12]. However, the incidence of our study is lower than another multi-center cohort study of Yehudina and Golovach, in that the authors reported that about 40% of 39 SSc patients experienced progression of calcinosis [1]. The variances of the incidence of the calcinosis cutis progression are possibly explained by the different study population, variety of methods and the criteria to assess calcinosis cutis progression. In the cohort study of Valenzuela et al. [3], they used the newly proposed radiographic scoring system based on the calcinosis scoring system (percentage area coverage and the average density score) and a 5-point Likert scale, which defined progressive calcinosis cutis as an increase in their radiological score >25% from the baseline at 1 year, while in this study, we used the simple scoring system, which defined the progressive calcinosis as having transition from no to mild, mild to moderate or moderate to severe calcinosis. In addition, when we used the presence of at least one new area of calcium deposit as the criteria for progressive calcinosis cutis, the criteria comparable to Avouac et al. [12], the incidence of progressive calcinosis went up to 79% (Supplementary Table 1).

In the present study, approximately two-thirds of the patients with early SSc had calcinosis cutis progression. The average interval between the 1^st and 2^nd radiographic evaluation was almost 3 years. These findings indicate that some may experience calcinosis cutis progression within 3 years after 1^st radiographic evaluation, while others may not show progression, and the calcinosis cutis remained stable during that time. For the patients who had calcinosis cutis progression during follow-up, we did not have information as to when the progression occurred. It might have happened within 3 years after the 1^st evaluation. Initially, we hypothesized that radiographic progression might be slow and might not occurred within 1–2 year after the 1^st evaluation. Until now, different from the scheduled radiographic evaluation for rheumatoid arthritis, there is no official guideline for the interval of hand radiographic evaluation in SSc. Thus, we set the interval of radiographic evaluation to be >2 years after 1^st evaluation to obtain sufficient number of patients with calcinosis cutis progression. Accordingly, we did not have data of the calcinosis cutis progression at 1, 1.5, 2, and 2.5 years after the 1^st radiographic evaluation. Even so, at the three-year follow-up, there was a noticeable increase in the number of patients with progression. From this perspective, we recommend using the hand radiograph within three years after initial radiographic evaluation to determine and monitor the severity of the disease in the following-up of calcinosis cutis.

Throughout the follow-up period, we observed that progressive calcinosis cutis can be accelerated and worsens across more than one level of severity. In fact, 13 out of 26 patients who had no calcinosis cutis previously developed moderate calcinosis cutis during the follow-up period, and one patient developed severe calcinosis cutis. These findings indicate that even patients had normal hand radiography at the baseline, they may experience rapid progression of calcinosis cutis within a short period. Previous studies showed that digital ulcers are the independent predictor of the progression of acro-osteolysis and calcinosis cutis [1,12], and the loss of digital pulp is a predictor of progressive calcinosis cutis [4]. From our observation, elderly patients and those with vasculopathy (Raynaud’s phenomenon, ischemic digital ulcer) tended to be at risk of progressive calcinosis cutis during follow-up. Although this finding is a tendency but statistically not significant, the results might guide attending physicians to be aware of calcinosis cutis development among those at risk of progression. We suggest conducting Further research on larger cohort of early SSc patients should be conducted in the near future.

Calcium deposit was commonly found at the tips of fingers, wrists and along the ulnar-side of hands by our observation. In addition, our data showed that calcinosis cutis progression appeared predominantly at the 1^st, 2^ndand 3^rd digits in dominant and non-dominant hands, which are the three most important functional fingers. These findings are similar to the previous reports [1,13,14] in that calcinosis cutis commonly developed at the distal fingers, particularly at the thumbs. Local trauma, chronic inflammation, and vascular hypoxia have been proposed as potential pathological mechanisms of the calcinosis cutis [1,5]. Although we could not identify any statistically significant clinical predictors for progressive calcinosis cutis in early SSc patients, ischemic digital ulcer and the presence of Raynaud’s phenomenon during the 2nd radiographic evaluation was more frequent in patients with progressive calcinosis cutis compared to those without progression. None of our patients had either infection at the tips of the finger or infected digital ulcer at the 2^nd radiographic evaluation (data not shown), providing confidence that local tissue inflammation was not a major cause of the progression of calcinosis cutis in hands and fingers of our patients. Considering the common occurrence of calcinosis cutis on the important functional fingers, local care of tissue in those area, avoiding trauma, and prevention of infection and/or inflammation, in combination with appropriate treatment of vasculopathy might help to prevent the progression of calcinosis cutis in those areas and maintain the function of patient’s hands in the future.

Some limitations in this study are; 1) the progressive calcinosis cutis analyzed in the traditional method using the Simple Scoring System, not using the Complex Scoring system, 2) no data was provided regarding the calcinosis cutis at baseline in different anatomical locations, 3) the absence of nailfold capillary study data and autoantibody data, other than anti-topoisomerase I, which is related to the low prevalence of these antibodies in previous reports among Thai SSc patients [15], could be potential factors influencing the progression of calcinosis cutis and likely warrants further investigation in future studies, 4) small sample population in the study may attribute to the statistical method’s limited power, likely stemming from the low number of events and a small sample size, 5) the methodology designed as minimum interval of 2 years between the first and the second radiographic examinations, which cannot explore development of calcinosis cutis before this period and 6) because this is a single center study, the findings might not be generalized.

The strengths of our study are the initial report of a longitudinal radiographic follow-up for early SSc patients. The findings enhance our comprehension of calcinosis cutis progression in early SSc patients, currently in the process of planning, an extended long-term follow-up for individuals who experienced progressive calcinosis cutis to gain more comprehensive understanding of the disease’s nature and its prolonged outcomes.

Conclusion

Calcinosis cutis in early SSc patients can progress during follow-up. The progression has increased over time, particularly within 3 years after the first evaluation. Around one-quarter of those who had no calcinosis cutis previously experienced acceleration and worsening across more than one level of severity. Elderly patients and those with vasculopathy were found more frequently; however, further study with a larger cohort is needed to support these findings.

Funding Statement

The authors received a grant supported from the Research of Khon Kaen University, Thailand.

Author contributions

Conception and design: Foocharoen C. Data collection: Kanjanajarurat V; Foocharoen C. Investigation: Kanjanajarurat V; Thammaroj P; Chowchuen P. Analysis and interpretation of data: Thammaroj P; Foocharoen C. Drafting the article: Kanjanajarurat V; Thammaroj P. Revising for intellectual content: Kanjanajarurat V; Thammaroj P; Foocharoen C. Final approval of the completed article: Kanjanajarurat V; Chowchuen P; Thammaroj P; Foocharoen C.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and material

Data and materials are available upon requestby contact to corresponding author.