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Journal of Scleroderma and Related Disorders logoLink to Journal of Scleroderma and Related Disorders
. 2022 May 1;7(3):204–216. doi: 10.1177/23971983221090857

Severe digital ischemia as an unrecognized manifestation in patients with antisynthetase autoantibodies: Case series and systematic literature review

Akira Yoshida 1, Takahisa Gono 1,2, Yuka Okazaki 1, Yuichiro Shirai 1,2, Mitsuhiro Takeno 1,3, Masataka Kuwana 1,2,✉
PMCID: PMC9537703  PMID: 36211206

Abstract

Objective:

Severe digital ischemia, including digital ulcers and gangrene, is considered rare in patients with antisynthetase antibodies. This study aimed to elucidate the clinical features of antisynthetase-positive patients complicated with digital ulcers and/or gangrene using a systematic literature review and case series in a single-center cohort.

Methods:

A systematic literature review was conducted to identify reports describing antisynthetase-positive cases with digital ulcers and/or gangrene. Our cohort of consecutive patients with antisynthetase antibodies was stratified by the history of severe digital ischemia. Demographic and clinical features and outcomes in patients with severe digital ischemia identified in the systematic literature review and our cohort were compared with those in patients without severe digital ischemia in our cohort.

Results:

The systematic literature review revealed 12 antisynthetase-positive patients with severe digital ischemia from one case series and eight case reports. Seven (7%) of 100 patients with antisynthetase antibodies in our cohort had a record of severe digital ischemia. Severe digital ischemia was often found at presentation and was associated with the classification of systemic sclerosis with or without myositis overlap. Clinical features associated with severe digital ischemia in antisynthetase-positive patients included Raynaud’s phenomenon (p < 0.001), digital pitting scars (p = 0.001), and nailfold capillary abnormality (p = 0.02). Outcomes of severe digital ischemia were generally favorable with vasodilators.

Conclusion:

Severe digital ischemia is an overlooked complication in antisynthetase-positive patients. Antisynthetase antibodies should be measured in patients presenting with digital ulcers or gangrene, especially in those with systemic sclerosis phenotype and features associated with antisynthetase antibodies in the absence of systemic sclerosis-specific autoantibodies.

Keywords: Antisynthetase syndrome, antiaminoacyl-tRNA synthetase antibody, digital ulcer, digital gangrene, myositis

Introduction

Autoantibodies against aminoacyl-tRNA synthetase, or antisynthetase antibodies, are common myositis-specific autoantibodies, appearing in 25%–35% of patients with idiopathic inflammatory myopathies (IIMs).1,2 Patients with antisynthetase antibodies are generally classified as having polymyositis (PM) or dermatomyositis (DM) but can also be classified as having other connective tissue diseases such as systemic sclerosis (SSc) or interstitial lung disease (ILD) without apparent PM/DM features, the latter of which is often classified as interstitial pneumonia with autoimmune features (IPAF). 3 On the contrary, a disease entity called antisynthetase syndrome has been proposed for patients with antisynthetase antibodies who present with a combination of ILD, myositis, arthritis, Raynaud’s phenomenon (RP), unexplained fever, and mechanic’s hands.4–6 In fact, patients with antisynthetase antibodies have a distinct histological pattern in muscle biopsy characterized by perifascicular necrosis and perimysial fragmentation with alkaline phosphatase activity,7,8 as well as a unique high-resolution CT (HRCT) pattern with overlapping nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP). 9

RP is recognized as one of the clinical features of patients with antisynthetase antibodies, and the reported frequency of RP in antisynthetase-positive patients ranges from 38% to 51%.10,11 Nailfold capillary abnormalities are also common. Sebastiani and colleagues reported that 62% of patients with antisynthetase antibodies had nailfold capillary abnormalities, including 35% with an SSc-like pattern. 12 On the contrary, severe digital ischemia presenting with digital ulcers and/or gangrene is considered uncommon in antisynthetase-positive patients. 4 Nevertheless, we have recently observed several patients with antisynthetase antibodies who developed severe digital ischemia, including a case already reported in the literature. 13 The prevalence, associated clinical features, and outcomes of severe digital ischemia in antisynthetase-positive patients remain unclear. Therefore, we investigated clinical features of patients with antisynthetase antibodies accompanied by severe digital ischemia through a comprehensive literature review and case series in our single-center cohort.

Methods

Systematic literature review

A systematic literature review (SLR) was conducted to retrieve articles describing patients with antisynthetase antibodies and severe digital ischemia according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for Individual Patient Data systematic reviews (PRISMA-IPD) statement. 14 PubMed, Scopus, and Web of Science were subjected to a search for English language literature with the following terms: “amino acyl-tRNA synthetases,” “anti-synthetase,” “tRNA synthetases,” “Jo-1,” “PL-7,” “PL-12,” “EJ,” “OJ,” “KS,” “skin ulcer,” “necrosis,” “cyanosis,” “gangrene,” and “ischemia.” The latest search was conducted on 30 August 2021. The detailed searching strategy is provided in Supplemental Table S1. After the removal of duplicates, titles and abstracts were screened by two independent reviewers (AY and TG). Then, full texts were subsequently assessed for eligibility, and the articles dealing with antisynthetase-positive cases accompanied by severe digital ischemia, that is, digital ulcers and/or gangrene, were selected. In addition, the references cited in each article were reviewed manually, and any articles relevant to the target topic were included in the analysis. The methodological quality of observational studies was assessed by the reviewers independently using the Newcastle-Ottawa Scale, which consisted of three items (selection, comparability, and outcome), and the final score (range 0–9) was calculated by a sum of individual scoring. 15

Patients

This study enrolled 100 consecutive patients with antisynthetase antibodies, who were selected from a patient registry of Scleroderma/Myositis Center of Excellence (SMCE), Nippon Medical School Hospital launched in August 2014, regardless of their clinical diagnosis. Serum samples were obtained from all patients at the first visit and were subjected to comprehensive autoantibody testing, including RNA immunoprecipitation (IP) assay using HeLa cell extracts, 16 at the autoantibody laboratory at Nippon Medical School Hospital. A patient was judged positive for antisynthetase antibody if the patient’s serum precipitated RNA components identical to those precipitated by the prototype sera positive for anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, or anti-KS antibody.17–21 Other myositis-specific autoantibodies and SSc-specific autoantibodies were also identified by commercially available immunoassays and/or in-house IP assays.1,22,23 Anti-SS-A/Ro and anti-SS-B/La were identified by RNA-IP assay, and anti-DNA antibodies were detected by commercially available Farr assay. This study was approved by the Ethics Committee of Nippon Medical School Hospital (27-07-462), and written informed consent was obtained from all patients.

Clinical features

Demographic and clinical information was recorded from the retrieved articles (for SLR cases) or clinical charts (for cohort cases). Classification of PM/DM was based on the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IIMs. 24 Classification of SSc was based on the 2013 ACR/EULAR classification criteria. 25 PM/DM-SSc overlap was defined as fulfilling PM/DM and SSc classification criteria together. The proposed criteria for IPAF 3 were applied to patients who were not classified by the criteria above.

The clinical findings obtained included heliotrope rash, Gottron’s papules/sign, muscle weakness, ILD, arthralgia/arthritis, 26 unexplained fever, mechanic’s hands, RP, puffy fingers, sclerodactyly, proximal scleroderma, digital pitting scars, telangiectasia, SSc-pattern nailfold capillary abnormality, 27 and classic risk factors of atherosclerosis (smoking history, hypertension, diabetes, and dyslipidemia). The definition of ILD was parenchymal lung disease detected by HRCT without known causes such as environmental or drug-related disorders. 28 The presence or absence of ILD and the HRCT pattern of ILD were evaluated by a pulmonologist with more than 20 years of experience in clinical practice. Unexplained fever was defined as a body temperature above 38°C on three or more occasions and no accompanying diagnosis with investigations during three outpatient visits or three inpatient days. 29 In patients classified as having PM/DM, disease activity at the onset of severe digital ischemia was assessed with the myositis intention-to-treat activity index (MITAX), and the results were shown as MITAX score, which was calculated by dividing MITAX sum score by the total score of 63 points. 30 In cases classified as having SSc, modified Rodnan total skin thickness score (mRSS) was recorded with the standardized method. 31 Livedo, palpable purpura, and mononeuritis multiplex were also recorded as signs suggestive of vasculitis. 32 In this study, digital ulcers and gangrene were regarded as severe digital ischemia. The definition of a digital ulcer was a skin ulcer located distal to or at the proximal interphalangeal (PIP) joint and not due to trauma. 25 A skin ulcer was defined as loss of epidermal covering with a break in the basement membrane, excluding scars, abrasions, incisions, lacerations, and fissures, as proposed by the World Scleroderma Foundation. 33 Gangrene was defined as necrosis of tissues caused by a total lack of blood supply with a dry, shrunken, and intensely black appearance. 34 In addition, detailed information regarding severe digital ischemia was recorded, including the distribution (fingers or toes), imaging (conventional angiography or CT angiography), treatment (vasodilators, antiplatelets/anticoagulants, and immunosuppressants), outcomes (healing, demarcation, autoamputation, and surgical amputation), and recurrence.

Statistical analysis

All continuous variables are shown as the median and interquartile range (IQR). Unpaired comparisons of continuous variables were made using the Mann–Whitney U-test. Categorical variables were compared using Fisher’s exact test. A two-sided p value < 0.05 was considered statistically significant. Statistical analyses were performed using the software program EZR (ver. 1.35, Saitama Medical Center, Jichi Medical University, Saitama, Japan). 35

Results

Cases identified by SLR

Figure 1 illustrates a flowchart of SLR. After removing duplicates, 401 studies were retrieved from PubMed, Scopus, and Web of Science. Title and abstract screening led to the inclusion of 10 articles for full-text assessment. Among those, one case series including 4 patients, and 6 case reports fulfilled the inclusion criteria. One case was previously reported by our institution, 13 thus was excluded from SLR cases and included in the cohort cases. Three additional case reports were identified from the reference lists. Finally, 12 cases with antisynthetase antibodies and severe digital ischemia were identified from one case series and eight case reports, and were included in the analysis36–44. The risk of bias by the Newcastle-Ottawa Scale was assessed as intermediate (total score: 4/9) for an article of case series 43 (Supplemental Table S2).

Figure 1.

Figure 1.

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A flowchart of the systematic literature review.

The clinical features of 12 patients described in the retrieved articles are summarized in Supplemental Table S3. Digital ulcers and gangrene were found in six and nine patients, respectively, including four having both complications. Except for case S2, all the ischemic legions appeared on fingers. It was of note that severe digital ischemia was one of the initial presentations of the disease in nine cases (S2, S3, S5, S6, S7, S8, S10, S11, and S12). Conventional angiography was conducted in four reported cases (S2, S5, S8, and S11). Occlusion of the proper palmar digital arteries was the common finding in two cases complicating digital gangrene (S5 and S11), and occlusion of the radial and the ulnar artery was detected in the case of S8 with multiple digital ulcers and gangrene. In only one case with gangrene on toes (S2), the peroneal and posterior tibial arteries were occluded with minimal collaterals. Pathological examination was not conducted in any of the cases.

Case series of the SMCE cohort

The autoantigenic specificity of antisynthetase antibodies in 100 patients in the SMCE cohort included anti-Jo-1 in 25, anti-PL-7 in 16, anti-PL-12 in 11, anti-EJ in 26, anti-OJ in 5, and anti-KS in 18. One patient had anti-Jo-1 and anti-EJ antibodies together. Of these patients, 7 (7%) had severe digital ischemia during the course of the disease. The detailed clinical characteristics of individual patients are summarized in Supplemental Table S4, and are described briefly below.

Case C1: anti-PL-7

This case has been reported previously. 13 A 60-year-old male patient was admitted to an emergency room because of rapidly progressive ILD and multiple digital gangrenes. The possibility that low cardiac output or severe hypoxia played as provoking factors for severe digital ischemia could not be excluded. Physical examination showed mechanic’s hands and nailfold capillary abnormalities. Angiography showed multiple occlusions in the proper palmar digital arteries distal to the bilateral second to fifth metacarpophalangeal (MCP) joints. Skin biopsy from the dorsal side of the left second finger revealed thrombosis with fibrin deposition along the arterial wall without cellular infiltration. Concomitant advanced gastric carcinoma was diagnosed by evaluation for gastrointestinal bleeding. Methylprednisolone (mPSL) pulse therapy followed by PSL (50 mg daily) and intravenous cyclophosphamide (IVCY) was introduced for rapidly progressive ILD, and heparinization was added for multiple digital gangrenes. He died of respiratory insufficiency due to ILD 1 month later. During the clinical course, the area of digital gangrene gradually enlarged and showed no sign of healing.

Case C2: anti-PL-7

A 47-year-old woman was referred to our center because of digital gangrene that had developed in the left third finger 1 month prior (Figure 2(a)). She had a 6-year history of RP. Physical examination showed puffy fingers, digital pitting scars, and SSc-like nailfold capillary abnormalities with no sclerodactyly, DM rashes, muscle weakness, or ILD. Treatment with calcium channel blocker (CCB), oral prostacyclin (PGI2) analog beraprost, and cilostazol resulted in the autoamputation of the gangrenous tissue with no recurrence during a 3-year follow-up.

Figure 2.

Figure 2.

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Severe digital ischemia at presentation: (a) Digital gangrene of the left third digit in case C2. (b) Digital gangrene of the left third digit in case C3. Mechanic’s hand is noted on the radial side of the second digit (arrows). (c) Digital ulcer and gangrene of the right second and third digits in case C6. (d) Digital gangrene of the left third digit in case C7.

Case C3: anti-PL-12

A 53-year-old woman was referred to our center due to refractory digital gangrene of the left third finger despite treatment with beraprost and cilostazol. She had been treated periodically with corticosteroids for unexplained fever for 6 years. She had a 3-year history of RP and showed Gottron’s sign and mechanic’s hands (Figure 2(b)) in addition to puffy fingers, digital pitting scars, nailfold capillary abnormalities, ILD, and lower esophageal dysmotility. Angiography of the left hand revealed narrowing at the superficial palmar arch and occlusions of the proper palmar digital arteries distal to MCP joints (Figure 3(a)). PSL (25 mg daily) and IVCY were introduced mainly for progressive ILD. The gangrene expanded despite treatment with a CCB and intravenous prostaglandin E1 (PGE1) analog. After the addition of sildenafil, expansion of the gangrene gradually halted, resulting in autoamputation.

Figure 3.

Figure 3.

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Vascular imaging of patients with severe digital ischemia: (a) Conventional angiography of the left hand in case C3. Arterial narrowing at the superficial palmar arch (arrowheads) and occlusion distal to the metacarpophalangeal joints (arrows). (b) CT angiography of the left hand in case C5. Arterial occlusions distal to the metacarpophalangeal joints in the left third and fourth digits (arrows). (c) CT angiography of the left forearm and hand in case C7. Occlusion of the distal ulnar artery with some collateral vessels (arrows), narrowing of the distal radial artery and palmar arch (arrowheads), and arterial occlusions at the metacarpophalangeal joints of the first to third digits (open arrows).

Case C4: anti-PL-12

A 50-year-old woman with a 6-year history of Sjögren’s syndrome was admitted to our hospital due to unexplained fever and a digital ulcer of the right third finger that had persisted for 1 month. She had a 6-year history of RP. On examination, Gottron’s papules, sclerodactyly, nailfold capillary abnormalities, arthritis of both hands, and ILD were noted. CT angiography of the right hand revealed no macrovascular abnormality. Hydroxychloroquine was initiated, along with a CCB, for the treatment of skin rash and arthritis. The digital ulcer gradually resolved and did not recur during the 2-year follow-up.

Case C5: anti-EJ

A 67-year-old woman was referred to our center 2 years ago due to recurrence of classic DM and ILD. She had a 6-year history of treatment with PSL and cyclosporine for ILD. The introduction of PSL (30 mg daily) and tacrolimus (TAC) resulted in improvement of ILD, muscle weakness, and DM rash. Two years later, this patient had another flare with fever, myositis, and progression of ILD, requiring treatment with PSL (30 mg daily) and IVCY. During the course of the flare, she had experienced acrocyanosis in the left fourth digit, leading to gangrene. CT angiography revealed occlusion of the proper palmar digital arteries distal to MCP joints in the left third and fourth digits (Figure 3(b)). The introduction of an intravenous PGE1 analog resulted in the resolution of gangrene in 3 weeks. Four months later, the patient died of respiratory failure due to acute exacerbation of ILD.

Case C6: anti-EJ

A 63-year-old man was referred to our center due to a digital ulcer and gangrene on the right second and third digits (Figure 2(c)). Four years before referral, he had received methotrexate (MTX) and low-dose PSL for arthritis in both hands, but later MTX was replaced with TAC because ILD was noted on a chest X-ray. On admission, muscle weakness and muscle enzyme elevation were noted, along with RP, sclerodactyly, digital pitting scars, and nailfold capillary abnormalities. Administration of a CCB and an IV PGE1 without intensification of immunosuppressive therapy resulted in autoamputation of the gangrene and resolution of the digital ulcer. Six months later, this patient experienced worsening myositis, which required treatment with PSL (30 mg daily) and azathioprine. Gangrene recurred in the right third finger 1 year later, resulting in autoamputation with no further episodes of recurrence.

Case C7: anti-EJ

A 53-year-old woman was admitted to our hospital due to a digital ulcer and gangrene of the left third digit, which had appeared 4 weeks prior (Figure 2(d)). She had a 1-year history of RP and had been treated with MTX and low-dose PSL for 18 years under a diagnosis of rheumatoid arthritis. Physical examination revealed Gottron’s sign, muscle weakness of the neck flexors, and muscle enzyme elevation, along with puffy fingers, skin thickening of the face, and telangiectasia. Hand X-ray revealed erosions and joint space narrowing consistent with rheumatoid arthritis. CT angiography of the left forearm revealed multiple occlusions in the distal ulnar artery with collaterals and in the proper palmar digital arteries of the first to third finger at MCP joints, as well as stenosis in the distal radial artery and superficial palmar arch (Figure 3(c)). There was no improvement in the digital ulcer or the gangrene despite treatment with a CCB, and an intravenous PGE1 analog in addition to hyperbaric oxygen therapy. The addition of sildenafil resulted in healing of the digital ulcer and autoamputation of the gangrenous tissue, and no recurrence was observed during the 1-year follow-up.

Among the cases of the SMCE cohort, digital ulcers and gangrene were found in four and six patients, respectively, including ulcers and gangrene together in three. All lesions were located on the fingers. All except case C5 were referred to our center because of severe digital ischemia. The median time interval from the first manifestation of any symptoms related to antisynthetase antibodies to the onset of severe digital ischemia was 5 years (IQR 2.5–5.5). Four patients developed severe digital ischemia under immunosuppressive therapy. Vascular imaging was conducted in six patients, including conventional angiography in three (C1, C3, and C6) and CT angiography in three (C4, C5, and C7). Arterial occlusion or stenosis was found in five patients, while one case (C4) showed no remarkable vascular findings on CT angiography. Narrowing of the superficial palmar arch and occlusion of the proper palmar digital arteries distal to MCP joints were common, and stenosis or occlusion of the radial and ulnar arteries were detected in two patients (C6 and C7). Collateral vessels were poorly developed in all patients except C7, who had occlusion of the ulnar artery.

Clinical characteristics of antisynthetase-positive patients with severe digital ischemia

Table 1 summarizes demographic and clinical features of antisynthetase-positive patients with severe digital ischemia who were identified in the SLR (n = 12) or SMCE cohort (n = 7). These patients were combined, and their clinical characteristics were compared with those of the patients without severe digital ischemia in the SMCE cohort (n = 93). Clinical characteristics were also compared between patients with and without severe digital ischemia within the SMCE cohort. There was no difference in the specificity of antisynthetase antibodies between patients with and without severe digital ischemia. On the contrary, the distribution of clinical classifications was different between patients with and without severe digital ischemia (p < 0.001); there was a higher prevalence of PM/DM-SSc overlap and SSc, and a lower prevalence of amyopathic DM and IPAF in patients with severe digital ischemia than in those without. The median MITAX score in five patients who were classified as having PM/(IMNM), DM, or ADM in the SMCE cohort was 0.14 (IQR 0.11–0.24) at the onset of severe digital ischemia. Of the clinical features associated with antisynthetase antibodies, RP was more prevalent in the patients with severe digital ischemia than in those without (p < 0.001 in the combined analysis and p = 0.004 in the SMCE cohort). Notably, SSc features were more common in general in patients with severe digital ischemia than in those without, and statistically significant difference was found for digital pitting scars (p = 0.001 in the combined analysis and p < 0.001 in the SMCE cohort), and nailfold capillary abnormality (p = 0.02 in the combined analysis and p = 0.01 in the SMCE cohort). Skin thickness was generally mild, and mRSS in all but one case with severe digital ischemia was ⩽4. Nailfold capillary abnormality was present in 12 (63%) of the 19 cases with severe digital ischemia; early and active patterns were observed in three and nine patients, respectively. Other clinical features that showed consistent trends toward the association with severe digital ischemia in both comparisons included younger age at diagnosis, a lower prevalence of muscle weakness, and a higher prevalence of arthralgia/arthritis and unexplained fever. ILD tended to be less prevalent in patients with severe digital ischemia than in those without. The HRCT patterns of ILD were variable in patients with severe digital ischemia, including usual interstitial pneumonia, NSIP, diffuse alveolar damage, and NSIP with the OP pattern. In contrast, there was no difference in the prevalence of atherosclerotic risk factors or signs suggestive of vasculitis. Only one patient with severe digital ischemia (S12) had concomitant anti-U1 ribonucleoprotein antibody, and additional SSc-specific or myositis-specific antibodies were not found in the remaining antisynthetase-positive cases with severe digital ischemia. Of patients in whom information on antiphospholipid antibody (aPL) measurement was available, only one of the eight patients in the SLR was positive, while all five patients in the SMCE cohort were negative.

Table 1.

Demographic and clinical features of antisynthetase-positive patients with and without severe digital ischemia.

Patients with severe digital ischemia Patients without severe digital ischemia (SMCE) (n = 93) p a (SMCE) p b (combined)
SLR (n = 12) SMCE (n = 7) Combined (n = 19)
Median age at diagnosis (IQR) 47 [37–69] 53 [52–62] 53 [42–65] 65 [53–71] 0.08 0.02
Female (%) 10 (83) 5 (71) 15 (79) 67 (72) 1.00 0.78
Observation period (years) (IQR) NA 4.6 [1.4–6.0] NA 3.9 [2.0–5.3] 0.89 NA
Antisynthetase antibodies, n (%) c
 Anti-Jo-1 5 (46) 0 5 (28) 25 (27) 0.14 0.08
 Anti-PL-7 1 (9.1) 2 (28) 3 (17) 14 (15)
 Anti-PL-12 3 (27) 2 (28) 5 (28) 9 (9.8)
 Anti-EJ 0 3 (43) 3 (17) 23 (25)
 Anti-OJ 2 (18) 0 2 (11) 5 (5.4)
 Anti-KS 0 0 0 18 (20)
Clinical classifications, n (%)
 DM 2 (17) 1 (14) 3 (16) 13 (14) <0.001 <0.001
 ADM 2 (17) 0 2 (10) 28 (30)
 PM (IMNM) 3 (25) 0 3 (16) 15 (16)
 PM/DM-SSc overlap 2 (17) 4 (57) 6 (32) 3 (3.2)
 SSc 2 (17) 1 (14) 3 (16) 3 (3.2)
 IPAF 1 (8.3) 1 (14) 2 (10) 30 (32)
 Unclassified 0 0 0 1 (1.1)
PM/DM features, n (%)
 Heliotrope rash 3 (25) 1 (14) 4 (21) 9 (9.7) 0.53 0.23
 Gottron’s papules/sign 4 (33) 4 (57) 8 (42) 39 (42) 0.46 1.00
 Muscle weakness 6 (50) 4 (67) (n = 6) 10 (56) (n = 18) 21 (23) (n = 92) 0.07 0.009
Clinical features associated with antisynthetase antibodies, n (%)
 ILD 11 (92) 5 (71) 16 (84) 88 (95) 0.08 0.13
 Arthralgia/arthritis 6 (50) 3 (43) 9 (47) 19 (20) 0.18 0.02
 Raynaud’s phenomenon 9 (75) 5 (83) (n = 6) 14 (78) (n = 18) 20 (22) 0.004 <0.001
 Unexplained fever 1 (8.3) 6 (86) 7 (37) 16 (17) <0.001 0.07
 Mechanic’s hands 2 (17) 6 (86) 8 (42) 39 (42) 0.04 1.00
SSc features, n (%)
 Puffy fingers 1 (8.3) 4 (57) 5 (26) 15 (16) 0.02 0.33
 Sclerodactyly 3 (25) 2 (28) 5 (26) 7 (7.5) 0.12 0.03
 Proximal scleroderma 2 (17) 1 (14) 3 (16) 5 (5.4) 0.36 0.13
 Digital pitting scars 1 (8.3) 3 (43) 4 (21) 0 <0.001 0.001
 Telangiectasia 0 1 (14) 1 (5.3) 0 0.07 0.17
 Nailfold capillary abnormality 6 (50) 6 (86) 12 (63) 31 (33) 0.01 0.02
Atherosclerotic risk factors, n (%)
 Smoking NA 5 (71) NA 39 (43) (n = 90) 0.24 NA
 Hypertension NA 2 (28) NA 25 (28) (n = 90) 1.00 NA
 Diabetes NA 2 (28) NA 18 (20) (n = 90) 0.63 NA
 Dyslipidemia NA 0 NA 23 (26) (n = 90) 0.19 NA
Signs suggestive of vasculitis, n (%)
 Livedo/palpable purpura/mononeuritis multiplex 0 0 0 2 (2.2) 1.00 1.00
Autoantibodies, n (%)
 Antitopoisomerase I 0 0 0 0 1.00 1.00
 Anti-RNA polymerase III 0 0 0 1 (1.1) 1.00 1.00
 Anticentromere 0 0 0 2 (2.2) 1.00 1.00
 Anti-U1 RNP 1 (8.3) 0 1 (5.3) 5 (5.4) 1.00 1.00
 Anti-U3 RNP NA 0 NA 0 1.00 NA
 Anti-U11/U12 RNP NA 0 NA 0 1.00 NA
 Anti-Th/To NA 0 NA 0 1.00 NA
 Anti-PM/Scl NA 0 NA 0 1.00 NA
 Anti-Ku NA 0 NA 0 1.00 NA
 Anti-RuvBL1/2 NA 0 NA 0 1.00 NA
 Anti-SS-A/Ro 3 (25) 3 (43) 6 (32) 15 (16) 0.11 0.19
 Anti-SS-B/La 1 (8.3) 1 (14) 2 (10) 2 (2.2) 0.20 0.13
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ADM: amyopathic dermatomyositis; DM: dermatomyositis; ILD: interstitial lung disease; IMNM: immune-mediated necrotizing myopathy; IPAF: interstitial pneumonia with autoimmune features; IQR: interquartile range; NA: data not available; PM: polymyositis; SMCE: Scleroderma/Myositis Center of Excellence; SLR: systematic literature review; SSc: systemic sclerosis.

a

Comparison between patients with and without severe digital ischemia in the SMCE cohort.

b

Comparison between patients with severe digital ischemia in the combined SLR and SMCE cohort and those without severe digital ischemia in the SMCE cohort.

c

The antigenic specificity of antisynthetase antibodies was not available in one case identified by the SLR. One patient positive for both anti-Jo-1 and anti-EJ antibodies in the SMCE cohort was excluded from the statistical analysis.

Ten of 19 antisynthetase antibody-positive cases with severe digital ischemia were not classified as having SSc by the 2013 ACR/EULAR classification criteria (Case S2, S5, S6, S8, S9, S10, S11, S12, C1, and C5). When clinical features were compared between patients with and without severe digital ischemia, RP was again more prevalent in the patients with severe digital ischemia compared to those without (p = 0.02; Supplemental Table S5).

Outcomes of severe digital ischemia

Information on treatment regimens was available for 18 patients (Table 2). Vasodilators, immunosuppressants, and antiplatelets/anticoagulants were used as the first-line treatment of severe digital ischemia in 11 (61%), 10 (56%), and 3 (17%), respectively. The outcome of severe digital ischemia was available in 17 patients. Severe digital ischemia responded to the first-line treatment in eight patients, and the second- or third-line treatment was successful in three additional patients. As a result, 11 patients (65%) had favorable outcomes, such as healing of ulcers, autoamputation, or demarcation of gangrene. Six patients experienced worsening digital ischemia (S2, S3, S7, S8, S11, and C1), and one required surgical amputation of the digits. It was of note that four of the six nonresponders initially received immunosuppressive therapy without vasodilators. Three patients experienced a recurrence of digital ulcers or gangrene during follow-up.

Table 2.

Treatment used for severe digital ischemia and outcomes.

Case [ref] Treatment for severe digital ischemia Outcome of severe digital ischemia
Vasodilators Immunosuppressants Others
S1 36 — GC — NA
S2 37 First-line — GC, MTX Heparin Progression: surgical amputation of the first to third digits of the right foot
Second-line IV PGI2 Warfarin
S3 38 CCB GC, IVCY Progression: ulcers relapsed every winter
S4 39 NA NA
S5 40 — GC, MMF — Improvement: demarcation of gangrene
S6 41 First-line IV PGE1 GC — Improvement: healing of ulcers and demarcation of gangrene
Recurrence on day 28
Second-line ERA IVCY — Improvement: healing of ulcers and demarcation of gangrene
S7 42 — GC — Progression: recurrence of gangrene
S8 43 IV PGE1 - — Progression: not described in detail
S9 43 — GC, AZA — Improvement: not described in detail
S10 43 — GC, IVCY — Improvement: not described in detail
S11 43 IV PGE1 GC, IVCY — Progression: not described in detail
S12 44 First-line IV PGE1 Progression: enlargement of gangrene
Second-line Oral PGI2, PDE5i GC, IVCY Clopidogrel Progression: gangrene persisted
Third-line Addition of IVIG Improvement: healing of ulcers and autoamputation of gangrene
No recurrence for 3 years
C1 13 — GC, IVCY Heparin Progression: enlargement of gangrene without healing tendency
C2 CCB, oral PGI2 Cilostazol Improvement: autoamputation of gangrene
No recurrence for 3 years
C3 First-line
Second-line		 CCB, IV PGE1
Addition of PDE5i		 GC, IVCY — Progression: gangrene persisted
Improvement: healing of ulcers and autoamputation of gangrene
No recurrence for 4 months
C4 CCB — — Improvement: healing of ulcer
No recurrence for 2 years
C5 IV PGE1 — — Improvement: demarcation of gangrene
No recurrence for 4 months
C6 CCB, IV PGE1 — — Improvement: healing of ulcers and autoamputation of gangrene
Recurrence of gangrene 1 year later
C7 First-line
Second-line		 CCB, IV PGE1
Addition of PDE5i		 — HBO Progression: ulcer and gangrene persisted
Improvement: healing of ulcer and autoamputation of gangrene
No recurrence for 1 year
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AZA: azathioprine; CCB: calcium channel blocker; ERA: endothelin receptor antagonist; GC: glucocorticoid; HBO: hyperbaric oxygen therapy; IV: intravenous; IVCY: intravenous cyclophosphamide; IVIG: intravenous immunoglobulin; MMF: mycophenolate mofetil; MTX: methotrexate; NA: data not available; PDE5i: phosphodiesterase-5 inhibitor; PGE1: prostaglandin E1; PGI2: prostacyclin.

Discussion

In this study, we identified a total of 19 patients with antisynthetase antibodies who were complicated with digital ulcers and/or gangrene in an SLR and a single-center cohort. Severe digital ischemia was often found at presentation and was associated with SSc features including RP, digital pitting scars, and nailfold capillary abnormality, in the context of features of antisynthetase syndrome, while antisynthetase-positive patients without SSc features also developed severe digital ischemia. RP was also found to be associated with severe digital ischemia even in antisynthetase-positive patients without SSc features. In general, severe digital ischemia responded favorably to vasodilators but not to immunosuppressive treatment, as reported for digital ulcers in SSc patients. 45

Severe digital ischemia is considered rare in antisynthetase-positive patients. 4 In fact, the SLR identified one case series and eight case reports of antisynthetase-positive patients with severe digital ischemia. On the contrary, in our single-center cohort of 100 patients with antisynthetase antibodies, the prevalence of severe digital ischemia was 7%. Since our center is unique in terms of its dual specialty in SSc and myositis, antisynthetase-positive patients with severe digital ischemia might have been preferentially referred to as patients suspected to have SSc. In addition, in our center, comprehensive autoantibody assays including RNA-IP assay are routinely conducted in all patients suspected to have SSc or myositis regardless of their clinical presentation or the results of routine autoantibody testing available in hospitals. This peculiarity of our center might have facilitated the discovery of antisynthetase-positive patients with severe digital ischemia. In a recent case series from another hospital in Japan, severe digital ischemia was observed in 8.7% of 46 patients with antisynthetase antibodies. 43 Routine measurement of antisynthetase antibodies using a convenient enzyme-linked immunosorbent assay is available in clinical practice in Japan. 46 These results suggest that antisynthetase antibody-positive patients with severe digital ischemia might be overlooked in routine clinical practice.

In many rheumatology centers, it is unlikely that antisynthetase antibodies are measured in patients who present with digital ulcers or gangrene. Thus, antisynthetase-positive patients with severe digital ischemia might go unnoticed simply because their antisynthetase antibodies are not measured. These patients might be classified as SSc patients without SSc-specific autoantibodies despite the presence of features associated with antisynthetase antibodies, including ILD, myositis, arthritis, unexplained fever, and mechanic’s hands, which are sometimes found in patients with SSc. In our SSc cohort, antisynthetase antibodies were detected by RNA-IP in 2.0% of 440 patients (unpublished observation). 47 Another recent study reported that antisynthetase antibodies were found in 7 (5.5%) of 128 SSc patients negative for antinuclear antibodies by indirect immunofluorescence. 48 Since none of the patients reported in this study had concomitant SSc-specific autoantibodies except anti-U1 RNP, we suggest that antisynthetase antibodies be measured in patients with SSc or very early diagnosis of SSc 49 presenting with digital ulcers or gangrene, especially in those with clinical features such as ILD, arthralgia/arthritis, unexplained fever, and mechanic’s hands, in the absence of SSc-specific autoantibodies. This might be clinically important, since some patients presenting initially with severe digital ischemia later experienced worsening complications associated with antisynthetase antibodies, including arthritis, myositis, and/or ILD, which required immunosuppressive treatment (i.e. cases C5 and C6). The MITAX score at the onset of severe digital ischemia in patients classified as having PM/DM was comparable to the score of patients with “active disease” reported in previous studies.50–53 Our findings stimulate further studies measuring antisynthetase antibodies in a large cohort of patients with severe digital ischemia regardless of underlying connective tissue diseases.

The underlying mechanisms of digital vasculopathy in antisynthetase-positive patients are largely unknown, and the contribution of SSc-related vascular remodeling, vasculitis, thromboembolisms, and comorbidities such as low cardiac output or severe hypoxia has been suggested in previous reports.13,36–44 This study suggests some similarities between severe digital ischemia observed in antisynthetase-positive patients and SSc patients. In antisynthetase-positive patients, severe digital ischemia was associated with SSc features and therapeutic response to vasodilators rather than immunosuppressive treatment. In addition, vascular imaging studies have revealed narrowing or occlusion of digital, radial, and ulnar arteries along with impaired collateral vessel formation; these features were shown to be a risk for the development of digital ulcers in SSc patients. 54 The predominant vascular remodeling in antisynthetase-positive patients with severe digital ischemia is supported by a lack of association between severe digital ischemia and traditional atherosclerosis risk factors or signs suggestive of vasculitis.

Some limitations should be noted. The selection bias was inevitable because this study used a single-center, retrospective cohort involving a small number of patients with severe digital ischemia. A large, prospective cohort study of patients with antisynthetase antibodies or severe digital ischemia is required to elucidate the incidence of severe digital ischemia as well as predictors for future development of digital ulcers or gangrene in antisynthetase-positive patients. In addition, it was difficult to evaluate the efficacy of individual treatment regimens due to the use of published case reports and the retrospective cohort study.

In conclusion, patients with antisynthetase antibodies occasionally show severe digital ischemia at presentation accompanied by clinical manifestations of SSc, although the exact incidence of this complication remains uncertain. Antisynthetase antibodies should be measured in patients presenting with digital ulcers or gangrene, especially in those with SSc phenotype and features of antisynthetase syndrome, in the absence of SSc-specific autoantibodies.

The Editor/Editorial Board Member of JSRD is an author of this article; therefore, the peer review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process.

Supplemental Material

sj-pdf-1-jso-10.1177_23971983221090857 – Supplemental material for Severe digital ischemia as an unrecognized manifestation in patients with antisynthetase autoantibodies: Case series and systematic literature review
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Supplemental material, sj-pdf-1-jso-10.1177_23971983221090857 for Severe digital ischemia as an unrecognized manifestation in patients with antisynthetase autoantibodies: Case series and systematic literature review by Akira Yoshida, Takahisa Gono, Yuka Okazaki, Yuichiro Shirai, Mitsuhiro Takeno and Masataka Kuwana in Journal of Scleroderma and Related Disorders

Acknowledgments

The authors thank Dr. Nobuhito Sasaki for evaluating HRCT findings.

Footnotes

Availability of data and materials: The data used in our current research are available from the corresponding author.

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare no conflicts of interest related to this work. Outside the submitted work, Y.A. and O.Y. have nothing to disclose. G.T., S.Y., T.M., and K.M. have relevant financial activities outside the submitted work as follows: G.T., speaking fees from Astellas, Asahi Kasei, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Janssen, Mitsubishi Tanabe, and Ono Pharmaceuticals; S.Y., speaking fees from Astellas, Boehringer Ingelheim, Bayer, Janssen, Mochida, and Nippon Shinyaku; T.M., consulting fees and speaking fees from Amgen; grants and speaking fees from AbbVie, Asahi Kasei, Chugai, Eisai, and Mitsubishi Tanabe; speaking fees from Astellas, Ayumi, Eli Lilly, Jansen, Kyorin, Nippon Shinyaku, Novartis, Ono Pharmaceuticals, and Takeda; K.M., grants and speaking fees from Boehringer Ingelheim, MBL, and Ono Pharmaceuticals; consulting fees from Corbus, Kissei, and Mochida; speaking fees from AbbVie, Asahi Kasei, Astellas, Bayer, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Nippon Shinyaku, and Pfizer.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the Japan Agency for Medical Research and Development (grant no. 21ek0109531h0001) and a research grant for intractable diseases from the Japanese Ministry of Health, Labor, and Welfare.

Supplemental material: Supplemental material for this article is available online.

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Supplementary Materials

sj-pdf-1-jso-10.1177_23971983221090857 – Supplemental material for Severe digital ischemia as an unrecognized manifestation in patients with antisynthetase autoantibodies: Case series and systematic literature review
Click here for additional data file. (368KB, pdf)

Supplemental material, sj-pdf-1-jso-10.1177_23971983221090857 for Severe digital ischemia as an unrecognized manifestation in patients with antisynthetase autoantibodies: Case series and systematic literature review by Akira Yoshida, Takahisa Gono, Yuka Okazaki, Yuichiro Shirai, Mitsuhiro Takeno and Masataka Kuwana in Journal of Scleroderma and Related Disorders

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