Presence of Thrombocytopenia at Onset Is Associated with Severe Disease Course in Juvenile Dermatomyositis: An Experience from a Tertiary Care Centre in North India

Abstract

Objectives:

To analyse the clinical profile of children with Juvenile Dermatomyositis (JDMS) who had thrombocytopenia (<150 × 10⁹/L) at disease onset and compare them with patients who had normal platelet counts.

Methods:

Children diagnosed to have JDMS based on modified Bohan and Peter criteria and being followed up in a tertiary care referral hospital in North India were analysed. Collected data included clinical profile, laboratory investigations, treatment details, and outcome.

Results:

We analysed 131 patients with JDMS. Fourteen amongst these (10.7%) had thrombocytopenia at initial diagnosis. None of them had evidence of sepsis, overlap syndrome or macrophage activation syndrome. Median time for improvement of thrombocytopenia was 1.4 months (IQR: 0.4–6 months). Patients with thrombocytopenia had late onset of disease (9.9 vs. 6 years, P = .008). Amongst the cutaneous manifestations, periorbital swelling [10 vs. 49, P = .047] and anasarca [3 vs. 2, P = .009] were seen more with thrombocytopenic patients.

The number of patients with severe muscle disease (28 vs. 48, P = .001), respiratory muscle weakness [5 vs. 6, P = .002], pharyngeal weakness [9 vs. 40, P = .040], and gastrointestinal vasculopathy [5 vs. 1, P = .001] was high in the thrombocytopenic group. Median time required to achieve remission was longer in the thrombocytopenic group (8 vs. 4.5 months, P = .011). Mortality rate was also high in the thrombocytopenic group [3 (21.45%) vs. 7 (5.9%)].

Conclusion:

Children with thrombocytopenia at onset in JDMS showed severe disease activity, high rates of relapse, and mortality. Thrombocytopenia at disease onset in JDMS could be considered as a potential laboratory marker to predict a severe disease course and outcome.

Keywords

Autoimmunity antiplatelet antibodies haemophagocytosis outcomes immunosuppressive therapy

Introduction

Juvenile Dermatomyositis (JDMS) is a multisystem autoimmune vasculopathy characterised by symmetric skeletal muscle weakness, typical skin changes, and variable internal organ involvement.¹ Clinical features at initial presentation are heterogeneous and vary from mild rash and weakness to severe life-threatening muscle weakness, skin ulceration and systemic vasculopathy.² Predictive factors for a more severe disease course in JDMS have not been well defined.²

The disease course in JDMS can be categorised into three groups: monocyclic course, relapsing-remitting polycyclic course, and chronic continuous course.^3,4 While some children with JDMS have a mild clinical course, others can develop severe muscle weakness and systemic disease requiring high doses and prolonged duration of immunosuppressive therapy.² Hence, there is a need to identify predictors for severe disease course at initial diagnosis. Stringer et al. reported that the presence of persistent Gottron papules at 3 months and nailfold abnormalities at 6 months predicted a longer duration to remission.² Thrombocytopenia is not a common feature seen at the initial presentation of JDMS. However, anecdotal reports suggest that thrombocytopenia in JDMS is probably associated with severe disease.^5–7

Herein, we report the clinical profile of children with JDMS who had thrombocytopenia at disease onset. Clinical features, laboratory investigations, and complications in patients with thrombocytopenia were compared with those of patients of JDMS who had normal platelet counts.

Materials and Methods

Medical records of children diagnosed with JDMS over the past 28 years at the Allergy Immunology Unit, Advanced Paediatrics Centre, Post Graduate Institute of Medical Education and Research [PGIMER], Chandigarh, were retrieved and analysed. The informed consent was waived by the Departmental Review Board, Advanced Paediatrics Centre, PGIMER, as this retrospective study used medical record data. The Departmental Review Board of Department of Paediatrics, PGIMER, had approved the study, approval number: 101–21, dated 3 August 2021.

Diagnosis of JDMS was based on modified Bohan and Peter criteria,⁸ including magnetic resonance imaging (MRI) as a diagnostic method for JDMS, analogous to Robinson et al.⁹ The collected data included age at symptom onset, age at diagnosis, delay in diagnosis, involved muscle groups and severity of weakness at diagnosis, cutaneous manifestations and presence of systemic involvement. Severity of muscle weakness was evaluated using the manual muscle testing scale, assessing eight muscle groups (MMT-8 score, range: 0–80) after 2012.¹⁰ Complications of JDMS, such as calcinosis, lipodystrophy, interstitial lung disease (ILD), severe gastrointestinal (GI) involvement, and other systemic vasculopathy features were also recorded.

Laboratory investigations, including complete blood count, platelet count, muscle enzymes (creatinine phosphokinase [CPK], lactate dehydrogenase [LDH], aspartate aminotransferase [AST], and alanine aminotransferase [ALT]), myositis-specific and associated antibody immunoblot (MSA and MAA) assay, were included for data analysis. Records of available electromyogram (EMG) and muscle biopsy details were also included. Before 2002, patients were often subjected to a muscle biopsy or EMG for confirmation of diagnosis. However, with MRI being readily available in the institute, this was no longer considered necessary. MRI of thigh muscles or, at times, whole-body MRI was carried out depending upon clinical requirements. Short tau inversion recovery and fat-suppressed sequences were obtained.

Treatment details, response to therapy, and outcomes were also entered in the datasheet. Analysis was done comparing the clinical, laboratory, and outcome variables between patients who had thrombocytopenia (<150 × 10⁹/L) and patients with normal platelets at the time of diagnosis of JDMS.

Statistical Analysis

Statistical analysis was performed by the SPSS programme (version 23). Descriptive statistics such as medians and ranges were utilised for continuous variables, and counts and percentages for categorical variables. The Mann-Whitney U test was used to compare continuous variables between groups. Categorical variables were compared by using the Chi-square test or Fisher’s exact test, wherever needed. The log-rank Mantel-Cox test was used to estimate the probability of overall survival. All P values were 2-sided, and a P value of <.05 was considered significant.

Results

We analysed case records of 131 patients with JDMS. The median age at onset of symptoms and diagnosis was 6.5 years (Interquartile range, IQR: 3–9.8 years) and 7 years (IQR: 4–11), respectively. Median delay in establishing diagnosis was 6 months (IQR: 2–12 months) in our cohort.

Fourteen patients (10.7%) with JDMS were found to have thrombocytopenia at the time of diagnosis. Median platelet counts in the thrombocytopenic group were 1.02 × 10⁹/L (IQR: 0.66–1.26 × 10⁹/L, range: 0.4–1.4 × 10⁹/L). Significant affection of other cell lines (leukopenia, severe anaemia) was not seen in any of them. None underwent bone marrow examination as the platelet counts recovered following glucocorticoid therapy. The median time for improvement of platelet count was 1.4 months (IQR: 0.4–6 months). Patients who had thrombocytopenia at disease onset did not have clinical or laboratory manifestations suggestive of macrophage activation syndrome (MAS) such as hepatosplenomegaly, high-grade fever, deranged coagulogram, hyperferritinaemia, and hypertriglyceridemia. Clinical or immunological features of systemic lupus erythematosus (SLE) were also not seen in any of them. Serological studies also did not reveal any autoantibodies for SLE. None had evidence of bacterial or fungal sepsis at the time of diagnosis.

Patients with thrombocytopenia had a later age of onset of symptoms and diagnosis (9.9 vs. 6 years, P = .008; 10.1 vs. 7 years, P = .031). However, the median delay in diagnosis was less in the thrombocytopenia group (4.5 vs. 6 years, P = .016). Number of patients with heliotrope rash (9 vs. 80, P = .767), other rash (10 vs. 76, P = .770), Gottron papules (12 vs. 93, P = .735); and calcinosis (1 vs. 32, P = .188) were comparable between both groups (Table 1). Periorbital swelling [10 (71%) vs. 49 (41.8%), P = .047] was seen more commonly in patients with thrombocytopenia. Moreover, a higher proportion of patients in the thrombocytopenic group had anasarca at presentation [3 patients (21.4%) vs. 2 patients (1.7%), P = .009].

Respiratory muscle weakness [5 (35.7%) vs. 6 (5%), P = .002] and pharyngeal muscle weakness [9 (64.2%) vs. 40 (34.1%), P = .040] were more common in the thrombocytopenic group compared to the non-thrombocytopenic group. Though the number of patients with proximal muscle weakness was comparable, the MMT-8 score was lower in the thrombocytopenic group (28 vs. 48, P = .001). GI vasculopathy (hematemesis, melena) was seen frequently in the thrombocytopenic group [5 (35.7%) vs. 1 (0.8%), P = .001] (Table 1).

Table 1.

Comparison of Basic Demographics and Clinical Features at Diagnosis Between Patients with Thrombocytopenia and Patients with Normal Platelet Counts.

Variable	Total Cohort (n = 131)	Patients with Low Platelet Count (n = 14)	Patients with Normal Platelet Count (n = 117)	P Value
Median age at onset of symptoms (years)^a	6.5 (3–9.8)	9.9 (6.9–11.4)	6 (3–9)	.008
Median age at diagnosis (years)^a	7 (4–11)	10.1 (7.4–12)	7 (4–10)	.031
Median follow-up (years)^a	5.5 (2–9.5)	7.5 (3.3–11)	3.4 (2–9)	.105
Median delay in diagnosis (months)^a	6 (2–12)	4.5 (2–9.5)	6 (2–12)	.016
No of patients with fever^b	60	10	50	.050
No of patients with organomegaly^b	10	3	7	.075
No of patients with arthritis^b	18	0	18	.209
No of patients with oral ulcers^b	6	0	6	1.000
No of patients with Gottron papules^b	102	12	93	.735
No of patients with proximal muscle weakness^b	119	14	105	.361
Median MMT-8 at onset of illness^b	44 (30–56)	28 (25.5–35)	48 (39–56)	.001
No of patients with neck muscle weakness^b	65	10	55	.097
No of patients with periorbital swelling^b	59	10	49	.047
No of patients with heliotrope rash^b	89	9	80	.767
No of patients with inverse Gottron papules^b	19	2	17	1.000
No of patients with rash^b	85	10	79	.770
No of patients with cutaneous ulcers^b	24	2	22	1.000
No of patients with respiratory muscle weakness^b	11	5	6	.002
No of patients with pharyngeal muscle weakness^b	49	9	40	.040
No of patients with calcinosis^b	33	1	32	.188
No of patients with renal involvement^b	6	1	5	.500
No of patients with alopecia^b	8	1	7	1.000
No of patients with anasarca^b	5	3	2	.009
No of patients with lymphadenopathy^b	6	1	5	.500
No of patients with ILD^b	14	1	13	1.000
No of patients with overlap features^b	25	3	22	.730
No of patients with CNS vasculopathy^b	2	1	1	.203
No of patients with GI vasculopathy^b	6	5	1	.001

Notes n: Number of patients, MMT: Manual muscle testing, CNS: Central nervous system, GI: Gastrointestinal, ILD: Interstitial lung disease. ^aMann–Whitney U test. ^bChi-square test.

Median levels of serum AST (90 vs. 60 U/L, P = .032), ALT (73.5 vs. 44 U/L, P = .002), LDH (1489 vs. 691 U/L, P = .001), and CPK (460 vs. 193 U/L, P = .108) were elevated in the thrombocytopenic group (Table 2) (Figure 1A-1D). Five patients in the thrombocytopenic group underwent myositis-specific antibody (MSA) immunoblot assay; two amongst these had positive MSA [anti-transcription intermediary factor 1–γ (TIF1–γ) and antinuclear matrix protein (NXP-2) in one patient each] (Table 3).

The proportion of patients who received intravenous pulse methylprednisolone (n = 13 vs. n = 80; P = .066), methotrexate (n = 12 vs. n = 70; P = .247), and mycophenolate mofetil (n = 3 vs. n = 11, P = .170) was comparable between thrombocytopenic and non-thrombocytopenic groups (Table 2). A significantly high proportion of patients in the thrombocytopenic group required cyclophosphamide pulse therapy (n = 6 [42.8%] vs. n = 17 [14.5%], P = .018) and intravenous immunoglobulin (IVIg) (n = 6 [42.8%] vs. n = 18 [15.3%], P = .022) for achievement of remission (Table 2). Two patients in the thrombocytopenic group were also treated with rituximab due to severe disease. Children in the thrombocytopenic group took a longer time to achieve remission (8 vs. 4.5 months, P = .011).

Table 2.

Laboratory Characteristics, Treatment Details, and Outcome of Patients with Thrombocytopenia and Patients with Normal Platelet Counts.

Variable	Total Cohort (n = 131)	Patients with Low Platelet Count (n = 14)	Patients with Normal Platelet Count (n = 117)	P Value
Median haemoglobin value (g/L)^a (N: 0–10)	11.2 (10.1–12.4)	11 (9.5–11.7)	11.3 (10.1–12.6)	.247
Median TLC (×10⁹/L)^a (N: 4–11 × 10⁹/L)	8.93 (6.76–12.2)	10.9 (6.65–13.87)	8.8 (6.6–11.9)	.300
Median serum LDH level (U/L)^a (N: 0–10)	747 (451–1326)	1489 (885–2829)	691 (403–1235)	.001
Median serum CPK level (U/L)^a (N: 0–10)	210 (75–1039)	460 (172–1171)	193 (73–972)	.108
Median serum AST level (U/L)^a (N: 0–10)	65 (35–112)	90 (60.7–202.7)	60 (35–104)	.032
Median serum ALT level (U/L)^a (N: 0–10)	47 (28–99)	73.5 (55.7–233.7)	44 (24–96)	.002
Median level of ESR (mm/1st hour)^a (N: 0–10)	25.5 (17–43)	28 (17.2–46.7)	25.5 (17–42)	.568
Median level of CRP (mg/L)^a (N: 0–10)	1.75 (0.5–3.55)	3.6 (2–11.8)	1.2 (0.5–3)	.004
No of patients with positive ANA^b	57	6	51	1.000
No of patients received Methotrexate^b	81	12	70	.247
No of patients received Pulse steroids^b	93	13	80	.066
No of patients received Cyclophosphamide^b	23	6	17	.018
No of patients received IVIg^b	24	6	18	.022
No of patients received MMF^b	14	3	11	.170
Median time to remission (months)^a	6 (5–10)	8 (6–10.5)	4.5 (2–9)	.011
No of patients with relapse^b	24	6	18	.033
No of patients with mortality^b	10	3	7	.262
No of patients with monocyclic course^b	62	7	54	.186
No of patients with polycyclic course^b	13	2	11	.017
No of patients with chronic continuous course^b	9	0	8	.601

Notes: n: Number of patients, MMT: Manual muscle testing, IVIg: Intravenous immunoglobulin, MMF: Mycophenolate mofetil, LDH: Lactate dehydrogenase, CPK: Creatinine phosphokinase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, ANA: Antinuclear antibodies. ^aMann–Whitney U test. ^bChi-square test.

Proportion of patients who had disease relapse was higher in the thrombocytopenic group (n = 6, 42.8%) than the non-thrombocytopenic group (n = 18, 15.3%) (P = .033). A higher proportion of patients in the thrombocytopenic group had a polycyclic course (Table 2).

Three patients (21.4%) in the thrombocytopenic group (Pt. 3, Pt. 6, and Pt. 8) succumbed to the illness compared to seven in the non-thrombocytopenic group (6.2%) (Table 3). Survival curve analysis showed a poor outcome in the thrombocytopenia group; however, it was not statistically significant (P = .089) (Figure 1E).

Figure 1.

Comparison Between Levels of Aspartate Aminotransferase (A), Alanine Aminotransferase (B), Lactate Dehydrogenase (C), and Creatinine Phosphokinase (D) Between Patients with Thrombocytopenia (Labelled as 1) and Patients with Normal Platelet Counts (Labelled as 2). (E) Kaplan–Meier Survival Curve Between Thrombocytopenic Group and Normal Platelet Group (P = .089).

Table 3.

Clinical and Laboratory Features of Patients with JDMS and Thrombocytopenia.

Pt. No.	Age at Onset	Age at Diagnosis	Systemic Features	Skin Manifestations	Muscle Involvement	Laboratory Investigations at Initial Diagnosis	Treatment	Outcome	Time Taken for Platelet Improvement	Follow-up (Years)
1	1.5 years	2 years	Fever; Hepato-megaly	Periorbital oedema; Heliotrope rash; Gottron’s papules; Malar rash	Symmetric proximal muscle weakness; Neck flexor weakness; Pharyngeal weakness	Hb: 93 g/L; TLC: 3.05 × 10⁹/L; Plt: 123 × 10⁹/L; ESR: 47 mm/hr; MSA immunoblot: TIFγ: 3+	IVMP × 5 days; IV Cyclophosphamide; Methotrexate SC	Improved; Polycyclic course	4 months	2
2	8.9 years	9.1 years	Fever; Anasarca; Hematemesis	Periorbital oedema; Heliotrope rash; Malar rash; Skin ulcers	Symmetric proximal muscle weakness; Neck flexor weakness; Respiratory muscle weakness; Pharyngeal weakness; MMT8:28	Hb: 96 g/L; TLC: 8.7 × 10⁹/L; Plt: 140 × 10⁹/L; ESR: 45 mm/hr; ANA: 2+ speckled; UGI endoscopy: duodenal erosions	IVMP × 5 days; Methotrexate SC	Improved; Polycyclic course	3 weeks	10
3	3.9 years	4 years	Lower GI bleed	Heliotrope rash; Gottron’s papules	Symmetric proximal muscle weakness; Respiratory muscle weakness	Hb: 119 g/L; TLC: 8.7 × 10⁹/L; Plt: 40 × 10⁹/L; ESR: 46 mm/hr; ANA: Negative.	IVMP × 8 days; IVIg × thrice; IV Cyclophosphamide; Mechanical ventilation; Rituximab	Died due to respiratory weakness, failure and pneumonia	2 weeks	–
4	8 years	9 years		Gottron’s papules; Malar rash	Symmetric proximal muscle weakness; Neck flexor weakness; Pharyngeal weakness	Hb: 11 g/L; TLC: 11 × 10⁹/L; Plt: 55 × 10⁹/L; ESR: 59 mm/hr; ANA: Negative	IVMP × 5 days; Methotrexate SC	Improved; Monocyclic course	2 weeks	20
5	7 years	7.9 years	Fever	Periorbital oedema; Heliotrope rash; Malar rash; Gottron’s papules	Symmetric proximal muscle weakness; MMT8:44	Hb: 87 g/L; TLC: 12.2 × 10⁹/L; Plt: 57 × 10⁹/L; ESR: 67 mm/hr; ANA: 2+ multinucleated dots; Positive antids-DNA	Oral steroids; Methotrexate SC; Azathioprine	Improved; Monocyclic course	2 months	8.5
6	7.5 years	7.6 years	Fever; Hemat-emesis	Periorbital oedema; Gottron’s papules; Malar rash	Symmetric proximal muscle weakness; Neck flexor weakness; Respiratory muscle weakness and failure	Hb: 122 g/L; TLC: 10.2 × 10⁹/L; Plt: 120 × 10⁹/L; ANA: Negative	IVMP × 5 days; Methotrexate SC; IVIg; Mechanical ventilation	Relapse and succumbed due to respiratory weakness, failure and pneumonia	3 months	3
7	11.2 years	12 years	Hepato-megaly	Periorbital oedema; Heliotrope rash; Malar rash; Gottron’s papules; Calcinosis	Symmetric proximal muscle weakness; MMT8:44	Hb: 108 g/L; TLC: 34 × 10⁹/L; Plt: 100 × 10⁹/L; ESR: 24 mm/hr; ANA: Negative	IVMP × 5 days; Methotrexate SC	Improved; Monocyclic course	3 years	14
8	10.9 years	11.2 years	Fever; GI bleed; CNS vasculopathy	Periorbital oedema; Heliotrope rash; Gottron’s papules	Symmetric proximal muscle weakness; Neck flexor weakness; Respiratory muscle weakness; ILD; Pharyngeal weakness; MMT8:26	Hb: 123 g/L; TLC: 14.4 × 10⁹/L; Plt: 113 × 10⁹/L; ESR: 18 mm/hr; Serum TGL: 304 mg/dl; Normal coagulogram; ANA: 2+ nucleolar; Myositis Immunoblot: Neg	IVMP × 13 days; Methotrexate SC; IV Cyclophosphamide; IVIg; Rituximab; Mechanical ventilation; MMF	Polycyclic course; Succumbed due to relapse with pneumonia and respiratory failure	1 week	2.5
9	6.7 years	6.9 years	Fever; Anasarca	Periorbital oedema; Heliotrope rash; Malar rash; Gottron’s papules	Symmetric proximal muscle weakness; Pharyngeal weakness; MMT8:28	Hb: 97 g/L; TLC: 6.8 × 10⁹/L; Plt: 92 × 10⁹/L; ANA: Negative	IVMP × 5 days; Methotrexate SC	Improved; Monocyclic course	2 weeks	6
10	11.9 years	12 years	Fever	Periorbital oedema; Malar rash; Gottron’s papules; Alopecia	Symmetric proximal muscle weakness; Neck flexor weakness; MMT8:28; lipodystrophy	Hb: 116 g/L; TLC: 6.1 × 10⁹/L; Plt: 125 × 10⁹/L; ESR: 15 mm/hr; ANA: 1+ speckled	IVMP × 5 days; Methotrexate SC	Improved; Monocyclic course	1 months	9
11	11.8 years	12 years	Fever; Anasarca	Periorbital oedema; Heliotrope rash	Symmetric proximal muscle weakness; Neck flexor weakness; Respiratory muscle weakness; Pharyngeal weakness; MMT8:10; lipodystrophy; IgA nephropathy; Raynaud phenomenon +	Hb: 92 g/L; TLC: 10.9 × 10⁹/L; Plt: 70 × 10⁹/L; ESR: 18 mm/hr; ANA: 3+ speckled	IVMP × 5 days; Methotrexate SC; IV Cyclophosphamide; IVIg; MMF	Improved; Polycyclic course	1 week	5.5
12	11 years	11.2 years	Fever; GI bleed; Anasarca	Periorbital oedema; Heliotrope rash; Gottron’s papules; Oral ulcers; Skin ulcers	Symmetric proximal muscle weakness; Neck flexor weakness; Pharyngeal weakness; MMT8:28	Hb: 132 g/L; TLC: 14.89 × 10⁹/L; Plt: 77 × 10⁹/L; ESR: 17 mm/hr; ANA: 1+ speckled; Anti-dsDNA: Neg; APLA: Neg; Myositis Immunoblot: Neg	IVMP × 5 days; IV Cyclophosphamide; IVIg; MMF	Improved; Polycyclic course	1 week	3.4
13	11.2 years	11.6 years	Lymph- adenopathy	Gottron’s papules	Symmetric proximal muscle weakness; Neck flexor weakness; MMT8:32	Hb: 112 g/L; TLC: 13.7 × 10⁹/L; Plt: 130 × 10⁹/L; ESR: 15 mm/hr; ANA: Negative; Anti-NXP2: 3+	IVMP × 5 days; Methotrexate SC	Improved; Monocyclic course	3 years	7
14	11.88 years	12 years	Fever	Gottron’s papules; Malar rash	Symmetric proximal muscle weakness; Neck flexor weakness; MMT8:24	Hb: 115 g/L; TLC: 12.7 × 10⁹/L; Plt: 130 × 10⁹/L; ESR: 32 mm/hr; ANA: 2+ speckled; Myositis Immunoblot: Neg;	IVMP × 5 days; Methotrexate SC; IV Cyclophosphamide monthly pulses × 9; IVIg; Azathioprine	Improved; Monocyclic course	1 years	8

Note: Hb: Haemoglobin, TLC: Total leucocyte count, Plt: Platelet, ESR: Erythrocyte sedimentation rate, MSA: Myositis-specific antibody immunoblot, IVMP: Intravenous methylprednisolone, ANA: Antinuclear antibodies, SC: Subcutaneous, MMT: Manual muscle testing, GI: Gastrointestinal, CNS: Central nervous system, IVIg: Intravenous immunoglobulin, MMF: Mycophenolate mofetil, ILD: Interstitial lung disease, TGL: Triglyceride, APLA: Antiphospholipid antibodies.

Multivariate analysis showed a significant association of mortality with respiratory weakness (P = .012), ILD (P = .023), and CNS vasculopathy (P = .001), which are all related to JDMS. The mortality was not associated with overlap syndrome (P = .341), thrombocytopenia (P = .453) or ANA positivity (P = .808).

Discussion

We compared clinical profile, laboratory features and outcome between patients with thrombocytopenia and patients with normal platelet counts. We report herein that thrombocytopenia is frequently associated with severe disease activity in JDMS. In addition, we also provide an overview of published literature on JDMS with thrombocytopenia (Table 4). To the best of our knowledge, ours is the largest series of patients with JDMS who had thrombocytopenia.

Table 4.

Published Reports of Patients with Juvenile Dermatomyositis and Thrombocytopenia.

S. No.	Author; Year; Country	Age At Onset (Years)	Clinical Features	Respiratory Weakness	Investigations	Platelet Counts	Treatment	Outcome
1	Cooper C et al.,⁵ 1986; UK	15	Gottron’s papules; facial oedema; Heliotrope rash; periungual erythema; symmetric proximal muscle weakness;	No	Hb: 131 g/L; TLC: 13 × 10⁹/L; ESR: 30 mm/h; Positive RA factor & ANA; Negative DCT; Positive PaIgG; Bone marrow biopsy: Increased megakaryocytes.	85 × 10⁹/L	Prednisolone	Platelets normalised & platelet-associated IgG became negative; Overall clinical course improved
2	Kobayashi I et al.,⁶ 2000; Japan	14	Arthralgia; Epistaxis; Heliotrope rash; Gottron’s papules; Ulcers; symmetric proximal muscle weakness; ILD	ILD	Hb: 139 g/L; TLC: 14.2 × 10⁹/L; Positive PaIgG; ESR: 3 mm/h; Negative ANA; Bone marrow biopsy: phagocytosis of platelet with normal cellularity	7 × 10⁹/L	Resistant to Corticosteroids; IVIg; Cyclosporine.	Platelets normalised, and the overall clinical course improved
3	Kobayashi I et al.,⁷ 2004; Japan (n = 2)	10	Fever; progressive muscle weakness; Heliotrope rash; Gottron’s papules; Interstitial pneumonia;	Interstitial pneumonia	Hb: 146 g/L; TLC: 2.7 × 10⁹/L; Positive ANA; Bone marrow biopsy: phagocytosis; Negative PaIgG;	119 × 10⁹/L	Corticosteroid responsive; Cyclosporine.	Platelets normalised and overall clinical course improved
3	Kobayashi I et al.,⁷ 2004; Japan (n = 2)	14	Fever; Arthralgia; Skin rash; Epistaxis; BOOP;	BOOP	Hb: 131 g/L; TLC: 11.5 × 10⁹/L; CMV positivity; Positive PaIgG; Negative ANA; Bone marrow biopsy: Reduced nucleated cells, no phagocytosis	8 × 10⁹/L	Poorly responsive to corticosteroids; two courses of IV methylprednisolone; IVIg; Cyclosporine;	Platelets normalised and overall clinical course improved

Note: Hb: Haemoglobin, TLC: Total leucocyte count, ESR: Erythrocyte sedimentation rate, RA factor: Rheumatoid arthritis factor, ANA: Antinuclear antibodies, DCT: Direct Coombs test, CMV: Cytomegalovirus, IV: Intravenous, IVIg: Intravenous immunoglobulin, ILD: Interstitial lung disease, PaIgG: Platelet-associated IgG, BOOP: Bronchiolitis obliterans organising pneumonia.

JDMS is a chronic multisystem autoimmune illness primarily affecting skin and muscles, with variable internal organ involvement. The heterogeneous clinical presentation and variable clinical course in JDMS necessitate the identification of patients who are likely to have a severe disease course.² Previous studies on probable predictors of outcome in JDMS had identified the following variables for poor outcome: presence of persistent Gottron papules at 3 months; nailfold abnormalities at 6 months; and chronic course of disease (either polycyclic or chronic continuous course).^2,11

The usual age of symptom onset in JDMS in published reports is between 6.8 and 7 years, which was comparable to our total cohort (6.5 years). Further, the median age at symptom onset in the non-thrombocytopenic group (6 years) was also comparable to other reports.^12,13 However, children who had thrombocytopenia at the time of diagnosis had an older age of onset of disease (9.9 years) in our study. Cooper et al. and Kobayashi et al. have also reported a later age of disease onset in children with JDMS who had early-onset thrombocytopenia.^5,7 However, patients in the thrombocytopenic group had a significantly lesser delay in diagnosis. This could be attributed to the severe muscle disease, which is evident from the lower MMT-8 score.

Severe muscle disease was more prevalent in the thrombocytopenic group, which was evident from the lower MMT-8 score and a significant difference in levels of muscle enzymes in the thrombocytopenic group. These children also had an increased incidence of respiratory muscle involvement requiring mechanical ventilation, pharyngeal weakness, and GI vasculopathy. Except for periorbital swelling and anasarca, which were proportionately higher in the thrombocytopenic group, the rest of the cutaneous features were comparable in both groups. Several reports showed a severe disease in patients with JDMS who presented with generalised oedema/ anasarca at initial diagnosis.^14,15 Our study also reports a higher incidence of anasarca in thrombocytopenic patients.

Kobayashi et al. had shown parenchymal lung involvement in three children who had thrombocytopenia in the early course of illness.⁷ In our cohort, one child had features of subacute ILD following rituximab. Two had features of aspiration pneumonia in computed tomography imaging. However, JDMS-related ILD has not been seen. Median time required to achieve remission in the thrombocytopenic group was significantly higher than in the non-thrombocytopenic group. Relapses were more frequent, and the mortality rate was also higher in patients who had thrombocytopenia at onset.

Possible reasons for the development of thrombocytopenia in JDMS include autoimmune thrombocytopenia, associated viral infections, MAS or drug-induced. Kobayashi et al. have previously demonstrated the presence of antiplatelet IgG antibodies and bone marrow haemophagocytosis in children with JDMS who had thrombocytopenia.⁷ Further, authors have also shown elevated serum levels of neopterin and soluble interleukin-2 receptor in patients with thrombocytopenia, reflecting a possible role of activated T cells in the pathophysiology of thrombocytopenia.⁷ Moreover, improvement of platelet counts with immunosuppressive therapy suggests probable autoimmune aetiology for thrombocytopenia. Our study did not find obvious evidence of concomitant infections or associated MAS or other cytopenias at the time of thrombocytopenia. Similar to the previous reports, we have also documented improvement with immunosuppressive therapy administered in our cohort.

To the best of our knowledge, ours is the first study to document a definite association of thrombocytopenia with severe disease course and outcome of children with JDMS. However, ours is a single-centre study, and the results must be validated in an independent or larger multicentric cohort for deriving firm conclusions. Laboratory evaluation for possible viral aetiologies was not carried out as the thrombocytopenia was not persistent. Moreover, we could not perform antiplatelet antibody and bone marrow examination in children with thrombocytopenia, which would have provided insight regarding the aetiology of thrombocytopenia.

To conclude, thrombocytopenia could be considered a potential laboratory marker in patients with JDMS to predict the clinical course, response to therapy, relapse, and outcome.

Footnotes

Authors’ Contribution

MS, GA, NJ: Data Collection, Data analysis, writing of initial draft of manuscript, editing and revision of manuscript at all stages of its production, review of literature.

PV: Inception of idea, Data analysis, evaluation, management and follow-up of the patient and editing of manuscript, critical revision of the manuscript at all stages of production and final approval.

AJ, DS, AR, AG, SS: Evaluation and management of the patient, follow-up of the patient, data analysis, intellectual input, editing and approval of the manuscript.

Data Availability Statement

Data analysed during the study are included in this article. Original data is available with the corresponding author and shall be made available on reasonable request.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Prof. Surjit Singh and Dr Pandiarajan Vignesh are National Editorial Board Members of the Indian Journal of Rheumatology and were not involved in the decision-making process related to this manuscript.

Ethical Approval

The Departmental Review Board of the Department of Paediatrics, PGIMER, had approved the study, approval number: 101–21, dated 3 August 2021.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Patient Consent

The informed consent was not applicable as this study was retrospective assessment of medical record data.

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