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Abstract

Objective

We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren’s syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5′-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients.

Methods

Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0–37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-).

Results

. IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group.

Interpretation

In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS.

myositis, inflammatory myopathies, dermatomyositis, polymyositis, inclusion body myositis, anti-synthetase syndrome, Sjögren’s syndrome, anti-cN1A

Rheumatology key messages

  • In myositis patients, Sjögren’s syndrome (SS) is associated with inclusion body myositis (IBM).

  • In myositis patients, SS is associated with anti-cN1A antibody, independently of the IBM diagnosis.

  • Consequently, anti-cN1A has limited specificity for IBM in myositis patients with SS.

Introduction

Myositis is a group of rare autoimmune diseases characterized by myopathy with evidence of inflammation-driven muscle lesions. They encompass a heterogeneous group of disorders that include, according to the 2017 EULAR/ACR classification, DM, PM, and inclusion body myositis (IBM) [1]. Several autoantibodies are useful to further classify myositis [2]. Identification of myositis subgroups is fundamental because each of these distinct disorders requires different management [3].

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease that primarily involves exocrine glands, but can potentially involve any organ [4]. SS is frequently associated with another connective tissue disorder [5].

We recently reported a 0.5% prevalence of IBM in SS patients [6], consistent with the 0.6% prevalence described by Kanellopoulos et al. [7]. IBM is a subgroup of myositis in which immunomodulating agents are not effective and may even increase the risk of progression toward disability [8].

Whether myositis patients with SS differ from myositis patients without SS in terms of the myositis characteristics is currently unknown. Indeed, the prevalence of SS in myositis has been reported to show very important variations (ranging from 0.8% to 18% [9, 10]) probably due to heterogeneous definitions of SS, myositis and its subgroups. The impact of SS in myositis patients in terms of organ involvement, myositis subtypes and response to treatment has never been specifically studied in a controlled study.

Here, we report the clinico-serological characteristics of a cohort covering the entire spectrum of myositis, with and without SS, assessed using the most up-to date criteria for these conditions.

Patients and methods

Patients

Myositis patients (with a probability ≥55%, corresponding at least to ‘possible myositis’ according to the EULAR/ACR 2017 criteria [1]) admitted between July 1993 and January 2019 to the University Hospital of Strasbourg and screened for SS using the 2016 ACR/EULAR criteria [11] were included. For all patients, the 2016 ACR/EULAR criteria for SS were applied as follows: i) the patient charts were systematically reviewed, ii) the archives of the Department of Pathology of the University Hospital of Strasbourg were interrogated to further identify the patients who underwent minor salivary gland biopsy, and iii) the archives of the Laboratory of Immunology were interrogated to further identify the patients who were tested for anti-SSA and anti-SSB. Patients for whom the 2016 ACR/EULAR criteria for SS were inconclusive due to missing data were not included.

The Strasbourg myositis cohort includes patients diagnosed with myositis at the public referral centre for rare autoimmune diseases hosted in Strasbourg University Hospital. The diagnostic work-up in the patients systematically included a neurologic evaluation at the public referral centre for neuromuscular disease (also hosted in Strasbourg University Hospital) when there was muscle involvement.

The public referral centre for rare autoimmune diseases registry database was used to collect clinical and serological data associated with myositis and SS during the follow-up. Immunomodulatory treatments were also recorded.

Myositis was first subclassified according to EULAR/ACR 2017 criteria [1] and the criteria suggested by Lloyd et al. were used to diagnose IBM, since these criteria have been shown to exhibit the best performance for the diagnosis of this disease [11].

The definitions of ‘interstitial lung disease’, ‘arthralgia’, ‘cutaneous involvement’, ‘cancer’, ‘peripheral nervous system involvement’, ‘diagnostic delay of myositis’, ‘improvement of the myopathy’ are available in Supplementary Data S1, available at Rheumatology online.

Sera were screened for the different autoantibodies at the time of diagnosis. Screening for antinuclear antibodies (ANAs) was performed by indirect immunofluorescence on HEp-2 cells (Zeus Scientific, USA). ANAs were defined as positive if ≥1/320e. The following autoantibodies were searched for: anti-SSA/Ro60 (anti-Ro52 specificity was not tested), -SSB/La, -Sm, -U1-RNP, -Scl70, -centromere, -Jo1, -PL7, -PL12, -EJ, -OJ, -KS, -Zo, -Ha, -Ku, -PM/Scl, -SRP (Alphadia, Belgium) -Mi2, -MDA5, -NXP2, -Tif-1γ, -SAE, -HMGCR (D-TEK, Belgium), -cN1A (EuroImmun, Germany [12]).

Statistical analysis

Data statistical analyses were performed using JMP software (version 7.0, SAS Institute Inc.). Categorical variables were compared between groups using Fisher’s exact test or χ2 test. Quantitative variables were compared using t test (normal distribution) or Mann–Whitney test (non-normal distribution). The normality of the distributions was verified with the Shapiro-Wilk test. Statistical significance was established at P value < 0.05. Myositis parameters significantly associated with SS were determined using a multivariate analysis (logistic regression). To this aim, myositis features displaying an association with SS with a P < 0.10 in the univariate analysis were included in the multivariable logistic regression analysis.

Ethics

The study was approved by the Ethics Committee of Strasbourg Hospital (no. CE-2019–69) in October 2019.

Results

Flowchart of the study is shown in Supplementary Fig. S1, available at Rheumatology online.

Patients were excluded (n = 318) due to the following lack of data required to diagnose SS: subjective sicca syndrome (n = 278), objective sicca syndrome (n = 308) and/or labial salivary gland biopsy focus score (n = 156).

Ninety-nine patients with myositis (according to EULAR/ACR 2017 criteria) and screened for SS (according to ACR/EULAR 2016 criteria) were included. Thirty-four (34%) had SS.

Sex ratio (female/male) was 4:1. The median age at myositis diagnosis was 53 years (range 16–77). The median follow-up was 71 months (range 12–450). Sixty-three patients (63%) had PM, 24 had DM (24%) and 12 IBM (12%).

Myositis patients with SS more frequently have IBM

Comparisons between myositis patients with SS (myositis/SS+) and myositis patients without SS (myositis/SS-) are shown in Table 1.

Table 1
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Characteristics of myositis patients with and without SS

Myositis/SS+ group
Myositis/SS- group
P values
P values
n = 34n = 65univariatemulti-variable
Demographic data
Female, n (%)31 (91)49 (75)0.0580.19
In DM/PM/IBM5 (100)/19 (90)/7 (88)17/19 (89)/30 (71)/2 (50)
Age at myositis onset, years [range]53.5 [21–74]53 [16–77]0.45–
In DM/PM/IBM47 [21–64]/59 [22–73]/50 [34–74]42 [17–76]/53 [16–77]/61.5 [54–76]
Diagnostic delay of myositis, months [range]6 [0–336]4 [0–122]0.0570.11
In DM/PM/IBM5 [2–13]/5.5 [0–336]/21 [0–144]3 [0–120]/4 [0–122]/25 [4–64]
Onset delay of SS in relation to myositis, months [range]0 [−383–87]//—
In DM/PM/IBM0 [−5–0]/0 [−232–87]/−1.5 [−383–11]
Duration of myositis follow-up, months [range]89.5 [12–343]57 [12–450]0.43—
In DM/PM/IBM20 [12–60]/103[12–270]/89 [18–343]63 [13–450]/52 [13–291]/ 107.5 [51–243]
Smoking history, n/N (%)11/28 (39)26 (52)0.28—
Muscle features
Type of myositis:
- DM, n (%)5 (14)19 (29)0.11—
- PM, n (%)21 (62)42 (65)0.78—
- IBM, n (%)8 (24)4 (6)0.0200.44
Highest CK rate, UI/l [range]430 [66–14 650]1259 [34–14 000]0.0460.53
In DM/PM/IBM1117 [347–14 650]/404 [68–7013]/ 547 [200–905]387 [71–11 000]/1361 [34–14 000]/ 1273 [514–3926]
Weakness at the last evaluation, n (%)11 (32)12 (18)0.14—
In DM/PM/IBM0/3 (14)/8 (100)3 (16)/5 (11)/4 (100)
Myositis systemic involvements, n (%)25 (73)53 (82)0.35—
In DM/PM/IBM5 (100)/18 (86)/2 (25)19 (100)/33 (79)/1 (25)
Skin involvement, n (%)15 (44)46 (71)0.015—
In DM/PM/IBM5 (100)/10 (47)/019 (100)/27 (64)/0
- DM rash, n (%)5 (15)19 (29)0.11—
In DM/PM/IBM5 (100)/0/019/0/0
- Sclerodactyly, n (%)4 (12)13 (20)0.40—
In DM/PM/IBM0/4 (19)/02 (11)/11 (26)/0
- Mechanic’s hands, n (%)5 (15)26 (40)0.0100.20
In DM/PM/IBM2/5 (40)/3 (14)/09 (47)/17 (40)/0
- Puffy fingers2 (6)4 (6)1.0—
In DM/PM/IBM0/2 (10)/01 (5)/3 (7)/0
Raynaud’s phenomenon, n (%)14 (41)32 (50)0.40—
In DM/PM/IBM2/5 (40)/11 (52)/1 (13)7 (37)/25 (60)/0
Interstitial lung disease, n (%)a8 (24)27 (42)0.0750.51
In DM/PM/IBM2/5 (40)/6 (29)/07/19 (37)/20 (48)/0
Arthralgia and/or arthritis, n (%)20 (59)32 (49)0.37—
In DM/PM/IBM3 (60)/15 (71)/2 (25)12 (63)/19 (45)/1 (25)
PNS involvement8 (24)5 (8)0.0280.62
In DM/PM/IBM0/5 (24)/3 (38)0/3 (7)/2 (50)
Cryoglobulinaemic vasculitis1 (3)00.34—
In DM/PM/IBM0/1 (5)/00/0/0
Glandular involvement
Subjective sicca syndrome, n (%)34 (100)16 (26)<0.n—
Schirmer test ≤5 mm, n/N (%)b26 (96)9 (31)<0.0001—
Salivary flow ≤0.1 ml/min, n/N (%)3/7 (43)2/10 (20)0.59—
≥1 focus/mm² in a labial salivary gland biopsy27/30 (90)1/25 (4)<0.0001—
Cancer during follow-up, n (%)7 (21)8 (12)0.28—
In DM/PM/IBM2 (40)/4 (19)/1 (13)1 (5)/6 (14)/1 (25)
Cancer onset ≤3 years in relation to myositis, n (%)2 (6)5 (8)1.0—
In DM/PM/IBM1 (20)/1 (5)/01 (5)/3 (8)/1 (25)
Lymphoma, n (%)2 (6)00.12—
In DM/PM/IBM0/1 (5)/1 (13)
Immunomodulatory treatment
Corticosteroids, n (%)b31 (91)58 (89)0.80—
In DM/PM/IBM5 (100)/19 (90)/7 (88)18 (95)/39 (93)/1 (25)
Synthetic conventional DMARDs, n (%)c31 (91)57 (88)0.60—
In DM/PM/IBM5 (100)/19 (90)/7 (88)19 (100)/36 (86)/2 (50)
- HCQ, n (%)13 (38)10 (16)0.012—
In DM/PM/IBM2 (40)/7 (33)/4 (50)9 (47)/1 (2)/0
Other immunomodulators, n (%)d15 (44)18 (29)0.10—
In DM/PM/IBM3 (60)/7 (33)/5 (63)2 (11)/14 (33)/2 (50)
Lines of immunomodulators, n [range]2 [0–6]2 [0–5]0.27—
In DM/PM/IBM2 [1–4]/2 [0–6]/3 [0–4]2 [1–5]/2 [0–4]/1.5 [0–5]
Serologic data
Myositis-specific antibodies, n (%)16/29 (55)45/60 (75)0.0590.93
In DM/PM/IBM3/4 (75)/13/19 (68)/0/614/19 (74)/31/38 (82)/0/3
- DM antibodies, n (%)e2/32 (6)8/63 (13)0.49—
- Antisynthetase antibodies, n (%)f9/29 (31)16/60 (27)0.67—
In DM/PM/IBM3 (75)/6 (33)/05 (26)/11 (31)/0
- Anti-U1-RNP , -PM/Scl, -Ku, -centromere antibodies, n (%)g7/34 (21)17/65 (26)0.54—
In DM/PM/IBM0/7 (41)/01 (6)/16 (43)/0
- IMNM antibodies, n (%)h0/30 05/60 (8)0.16—
In DM/PM/IBM0/0/00/5 (13)/0
Anti-SSA and/or -SSB, n (%)17/34 (50)6/59 (9)<0.0001—
− Anti-SSA17 (50)6 (9)
− Anti-SSBi8 (23)1 (1)
ANA positivityj22/28 (79)32/58 (55)0.06
Anti-cN1A, n/N (%)10/26 (38)3/54 (6)0.00050.021
In DM/PM/IBM2/3 (66)/4/17 (24)/4/6 (67)1/18 (6)/1/32 (3)/1/3 (33)
Myositis/SS+ group
Myositis/SS- group
P values
P values
n = 34n = 65univariatemulti-variable
Demographic data
Female, n (%)31 (91)49 (75)0.0580.19
In DM/PM/IBM5 (100)/19 (90)/7 (88)17/19 (89)/30 (71)/2 (50)
Age at myositis onset, years [range]53.5 [21–74]53 [16–77]0.45–
In DM/PM/IBM47 [21–64]/59 [22–73]/50 [34–74]42 [17–76]/53 [16–77]/61.5 [54–76]
Diagnostic delay of myositis, months [range]6 [0–336]4 [0–122]0.0570.11
In DM/PM/IBM5 [2–13]/5.5 [0–336]/21 [0–144]3 [0–120]/4 [0–122]/25 [4–64]
Onset delay of SS in relation to myositis, months [range]0 [−383–87]//—
In DM/PM/IBM0 [−5–0]/0 [−232–87]/−1.5 [−383–11]
Duration of myositis follow-up, months [range]89.5 [12–343]57 [12–450]0.43—
In DM/PM/IBM20 [12–60]/103[12–270]/89 [18–343]63 [13–450]/52 [13–291]/ 107.5 [51–243]
Smoking history, n/N (%)11/28 (39)26 (52)0.28—
Muscle features
Type of myositis:
- DM, n (%)5 (14)19 (29)0.11—
- PM, n (%)21 (62)42 (65)0.78—
- IBM, n (%)8 (24)4 (6)0.0200.44
Highest CK rate, UI/l [range]430 [66–14 650]1259 [34–14 000]0.0460.53
In DM/PM/IBM1117 [347–14 650]/404 [68–7013]/ 547 [200–905]387 [71–11 000]/1361 [34–14 000]/ 1273 [514–3926]
Weakness at the last evaluation, n (%)11 (32)12 (18)0.14—
In DM/PM/IBM0/3 (14)/8 (100)3 (16)/5 (11)/4 (100)
Myositis systemic involvements, n (%)25 (73)53 (82)0.35—
In DM/PM/IBM5 (100)/18 (86)/2 (25)19 (100)/33 (79)/1 (25)
Skin involvement, n (%)15 (44)46 (71)0.015—
In DM/PM/IBM5 (100)/10 (47)/019 (100)/27 (64)/0
- DM rash, n (%)5 (15)19 (29)0.11—
In DM/PM/IBM5 (100)/0/019/0/0
- Sclerodactyly, n (%)4 (12)13 (20)0.40—
In DM/PM/IBM0/4 (19)/02 (11)/11 (26)/0
- Mechanic’s hands, n (%)5 (15)26 (40)0.0100.20
In DM/PM/IBM2/5 (40)/3 (14)/09 (47)/17 (40)/0
- Puffy fingers2 (6)4 (6)1.0—
In DM/PM/IBM0/2 (10)/01 (5)/3 (7)/0
Raynaud’s phenomenon, n (%)14 (41)32 (50)0.40—
In DM/PM/IBM2/5 (40)/11 (52)/1 (13)7 (37)/25 (60)/0
Interstitial lung disease, n (%)a8 (24)27 (42)0.0750.51
In DM/PM/IBM2/5 (40)/6 (29)/07/19 (37)/20 (48)/0
Arthralgia and/or arthritis, n (%)20 (59)32 (49)0.37—
In DM/PM/IBM3 (60)/15 (71)/2 (25)12 (63)/19 (45)/1 (25)
PNS involvement8 (24)5 (8)0.0280.62
In DM/PM/IBM0/5 (24)/3 (38)0/3 (7)/2 (50)
Cryoglobulinaemic vasculitis1 (3)00.34—
In DM/PM/IBM0/1 (5)/00/0/0
Glandular involvement
Subjective sicca syndrome, n (%)34 (100)16 (26)<0.n—
Schirmer test ≤5 mm, n/N (%)b26 (96)9 (31)<0.0001—
Salivary flow ≤0.1 ml/min, n/N (%)3/7 (43)2/10 (20)0.59—
≥1 focus/mm² in a labial salivary gland biopsy27/30 (90)1/25 (4)<0.0001—
Cancer during follow-up, n (%)7 (21)8 (12)0.28—
In DM/PM/IBM2 (40)/4 (19)/1 (13)1 (5)/6 (14)/1 (25)
Cancer onset ≤3 years in relation to myositis, n (%)2 (6)5 (8)1.0—
In DM/PM/IBM1 (20)/1 (5)/01 (5)/3 (8)/1 (25)
Lymphoma, n (%)2 (6)00.12—
In DM/PM/IBM0/1 (5)/1 (13)
Immunomodulatory treatment
Corticosteroids, n (%)b31 (91)58 (89)0.80—
In DM/PM/IBM5 (100)/19 (90)/7 (88)18 (95)/39 (93)/1 (25)
Synthetic conventional DMARDs, n (%)c31 (91)57 (88)0.60—
In DM/PM/IBM5 (100)/19 (90)/7 (88)19 (100)/36 (86)/2 (50)
- HCQ, n (%)13 (38)10 (16)0.012—
In DM/PM/IBM2 (40)/7 (33)/4 (50)9 (47)/1 (2)/0
Other immunomodulators, n (%)d15 (44)18 (29)0.10—
In DM/PM/IBM3 (60)/7 (33)/5 (63)2 (11)/14 (33)/2 (50)
Lines of immunomodulators, n [range]2 [0–6]2 [0–5]0.27—
In DM/PM/IBM2 [1–4]/2 [0–6]/3 [0–4]2 [1–5]/2 [0–4]/1.5 [0–5]
Serologic data
Myositis-specific antibodies, n (%)16/29 (55)45/60 (75)0.0590.93
In DM/PM/IBM3/4 (75)/13/19 (68)/0/614/19 (74)/31/38 (82)/0/3
- DM antibodies, n (%)e2/32 (6)8/63 (13)0.49—
- Antisynthetase antibodies, n (%)f9/29 (31)16/60 (27)0.67—
In DM/PM/IBM3 (75)/6 (33)/05 (26)/11 (31)/0
- Anti-U1-RNP , -PM/Scl, -Ku, -centromere antibodies, n (%)g7/34 (21)17/65 (26)0.54—
In DM/PM/IBM0/7 (41)/01 (6)/16 (43)/0
- IMNM antibodies, n (%)h0/30 05/60 (8)0.16—
In DM/PM/IBM0/0/00/5 (13)/0
Anti-SSA and/or -SSB, n (%)17/34 (50)6/59 (9)<0.0001—
− Anti-SSA17 (50)6 (9)
− Anti-SSBi8 (23)1 (1)
ANA positivityj22/28 (79)32/58 (55)0.06
Anti-cN1A, n/N (%)10/26 (38)3/54 (6)0.00050.021
In DM/PM/IBM2/3 (66)/4/17 (24)/4/6 (67)1/18 (6)/1/32 (3)/1/3 (33)
a

Diffusing capacity for carbon monoxide in SS+ vs SS- was 70% [range 29–100] and 59% [25–100], respectively, P = 0.065; forced vital capacity was 85% (46–124) and 82% (47–122), P = 0.79. bLast corticosteroid dose was 0 [range 0–75] and 2 mg [range 0–90], P = 0.26, respectively. cComprising methotrexate, HCQ, MMF, AZA, ciclosporin, leflunomide, sulfasalazine, cyclophosphamide, rapamycin, colchicine. dComprising intravenous immunoglobulins, rituximab, plasma exchange, anti-TNFa, tocilizumab. eAnti-MDA5 was found in 2/23 (8%) vs 3/48 (6%) patients and anti-Mi2 in 0/24 vs 5/52 (10%), respectively. fAnti-Jo1 was found in 6/29 (21%) vs 10/62 (16%) patients. gAnti-PM/Scl was found in 3/27 (11%) vs 9/60 (15%) and anti-Ku in 3/26 (12%) vs 4/56 (7%), anti-U1-RNP in 1/33 (3%) vs 5/65 (8%), anti-centromere in 1/25 (4%) vs 0/55, no anti-Scl70 was found. hAnti-SRP was found in 0/27 vs 5/55 (9%) patients. iNo patient was positive for anti-SSB alone (without anti-SSA). jPatterns according to the international consensus were: AC1 (8% vs 17%), AC3 (4% vs 0%), AC4 (56% vs 13%), AC5 (4% vs 9%), AC6 (0% vs 4%), AC8 (26% vs 20%), AC9 (0% vs 2%), AC19 (4% vs 9%), AC20 (0% vs 13%) in patients with SS vs without SS. IBM: inclusion body myositis; IMNM: immune-mediated necrotizing myopathy; PNS: peripheral nerve system; ANA: antinuclear antibodies. Data with p-value < 0.05 are in bold.

Table 1
Open in new tab

Characteristics of myositis patients with and without SS

Myositis/SS+ group
Myositis/SS- group
P values
P values
n = 34n = 65univariatemulti-variable
Demographic data
Female, n (%)31 (91)49 (75)0.0580.19
In DM/PM/IBM5 (100)/19 (90)/7 (88)17/19 (89)/30 (71)/2 (50)
Age at myositis onset, years [range]53.5 [21–74]53 [16–77]0.45–
In DM/PM/IBM47 [21–64]/59 [22–73]/50 [34–74]42 [17–76]/53 [16–77]/61.5 [54–76]
Diagnostic delay of myositis, months [range]6 [0–336]4 [0–122]0.0570.11
In DM/PM/IBM5 [2–13]/5.5 [0–336]/21 [0–144]3 [0–120]/4 [0–122]/25 [4–64]
Onset delay of SS in relation to myositis, months [range]0 [−383–87]//—
In DM/PM/IBM0 [−5–0]/0 [−232–87]/−1.5 [−383–11]
Duration of myositis follow-up, months [range]89.5 [12–343]57 [12–450]0.43—
In DM/PM/IBM20 [12–60]/103[12–270]/89 [18–343]63 [13–450]/52 [13–291]/ 107.5 [51–243]
Smoking history, n/N (%)11/28 (39)26 (52)0.28—
Muscle features
Type of myositis:
- DM, n (%)5 (14)19 (29)0.11—
- PM, n (%)21 (62)42 (65)0.78—
- IBM, n (%)8 (24)4 (6)0.0200.44
Highest CK rate, UI/l [range]430 [66–14 650]1259 [34–14 000]0.0460.53
In DM/PM/IBM1117 [347–14 650]/404 [68–7013]/ 547 [200–905]387 [71–11 000]/1361 [34–14 000]/ 1273 [514–3926]
Weakness at the last evaluation, n (%)11 (32)12 (18)0.14—
In DM/PM/IBM0/3 (14)/8 (100)3 (16)/5 (11)/4 (100)
Myositis systemic involvements, n (%)25 (73)53 (82)0.35—
In DM/PM/IBM5 (100)/18 (86)/2 (25)19 (100)/33 (79)/1 (25)
Skin involvement, n (%)15 (44)46 (71)0.015—
In DM/PM/IBM5 (100)/10 (47)/019 (100)/27 (64)/0
- DM rash, n (%)5 (15)19 (29)0.11—
In DM/PM/IBM5 (100)/0/019/0/0
- Sclerodactyly, n (%)4 (12)13 (20)0.40—
In DM/PM/IBM0/4 (19)/02 (11)/11 (26)/0
- Mechanic’s hands, n (%)5 (15)26 (40)0.0100.20
In DM/PM/IBM2/5 (40)/3 (14)/09 (47)/17 (40)/0
- Puffy fingers2 (6)4 (6)1.0—
In DM/PM/IBM0/2 (10)/01 (5)/3 (7)/0
Raynaud’s phenomenon, n (%)14 (41)32 (50)0.40—
In DM/PM/IBM2/5 (40)/11 (52)/1 (13)7 (37)/25 (60)/0
Interstitial lung disease, n (%)a8 (24)27 (42)0.0750.51
In DM/PM/IBM2/5 (40)/6 (29)/07/19 (37)/20 (48)/0
Arthralgia and/or arthritis, n (%)20 (59)32 (49)0.37—
In DM/PM/IBM3 (60)/15 (71)/2 (25)12 (63)/19 (45)/1 (25)
PNS involvement8 (24)5 (8)0.0280.62
In DM/PM/IBM0/5 (24)/3 (38)0/3 (7)/2 (50)
Cryoglobulinaemic vasculitis1 (3)00.34—
In DM/PM/IBM0/1 (5)/00/0/0
Glandular involvement
Subjective sicca syndrome, n (%)34 (100)16 (26)<0.n—
Schirmer test ≤5 mm, n/N (%)b26 (96)9 (31)<0.0001—
Salivary flow ≤0.1 ml/min, n/N (%)3/7 (43)2/10 (20)0.59—
≥1 focus/mm² in a labial salivary gland biopsy27/30 (90)1/25 (4)<0.0001—
Cancer during follow-up, n (%)7 (21)8 (12)0.28—
In DM/PM/IBM2 (40)/4 (19)/1 (13)1 (5)/6 (14)/1 (25)
Cancer onset ≤3 years in relation to myositis, n (%)2 (6)5 (8)1.0—
In DM/PM/IBM1 (20)/1 (5)/01 (5)/3 (8)/1 (25)
Lymphoma, n (%)2 (6)00.12—
In DM/PM/IBM0/1 (5)/1 (13)
Immunomodulatory treatment
Corticosteroids, n (%)b31 (91)58 (89)0.80—
In DM/PM/IBM5 (100)/19 (90)/7 (88)18 (95)/39 (93)/1 (25)
Synthetic conventional DMARDs, n (%)c31 (91)57 (88)0.60—
In DM/PM/IBM5 (100)/19 (90)/7 (88)19 (100)/36 (86)/2 (50)
- HCQ, n (%)13 (38)10 (16)0.012—
In DM/PM/IBM2 (40)/7 (33)/4 (50)9 (47)/1 (2)/0
Other immunomodulators, n (%)d15 (44)18 (29)0.10—
In DM/PM/IBM3 (60)/7 (33)/5 (63)2 (11)/14 (33)/2 (50)
Lines of immunomodulators, n [range]2 [0–6]2 [0–5]0.27—
In DM/PM/IBM2 [1–4]/2 [0–6]/3 [0–4]2 [1–5]/2 [0–4]/1.5 [0–5]
Serologic data
Myositis-specific antibodies, n (%)16/29 (55)45/60 (75)0.0590.93
In DM/PM/IBM3/4 (75)/13/19 (68)/0/614/19 (74)/31/38 (82)/0/3
- DM antibodies, n (%)e2/32 (6)8/63 (13)0.49—
- Antisynthetase antibodies, n (%)f9/29 (31)16/60 (27)0.67—
In DM/PM/IBM3 (75)/6 (33)/05 (26)/11 (31)/0
- Anti-U1-RNP , -PM/Scl, -Ku, -centromere antibodies, n (%)g7/34 (21)17/65 (26)0.54—
In DM/PM/IBM0/7 (41)/01 (6)/16 (43)/0
- IMNM antibodies, n (%)h0/30 05/60 (8)0.16—
In DM/PM/IBM0/0/00/5 (13)/0
Anti-SSA and/or -SSB, n (%)17/34 (50)6/59 (9)<0.0001—
− Anti-SSA17 (50)6 (9)
− Anti-SSBi8 (23)1 (1)
ANA positivityj22/28 (79)32/58 (55)0.06
Anti-cN1A, n/N (%)10/26 (38)3/54 (6)0.00050.021
In DM/PM/IBM2/3 (66)/4/17 (24)/4/6 (67)1/18 (6)/1/32 (3)/1/3 (33)
Myositis/SS+ group
Myositis/SS- group
P values
P values
n = 34n = 65univariatemulti-variable
Demographic data
Female, n (%)31 (91)49 (75)0.0580.19
In DM/PM/IBM5 (100)/19 (90)/7 (88)17/19 (89)/30 (71)/2 (50)
Age at myositis onset, years [range]53.5 [21–74]53 [16–77]0.45–
In DM/PM/IBM47 [21–64]/59 [22–73]/50 [34–74]42 [17–76]/53 [16–77]/61.5 [54–76]
Diagnostic delay of myositis, months [range]6 [0–336]4 [0–122]0.0570.11
In DM/PM/IBM5 [2–13]/5.5 [0–336]/21 [0–144]3 [0–120]/4 [0–122]/25 [4–64]
Onset delay of SS in relation to myositis, months [range]0 [−383–87]//—
In DM/PM/IBM0 [−5–0]/0 [−232–87]/−1.5 [−383–11]
Duration of myositis follow-up, months [range]89.5 [12–343]57 [12–450]0.43—
In DM/PM/IBM20 [12–60]/103[12–270]/89 [18–343]63 [13–450]/52 [13–291]/ 107.5 [51–243]
Smoking history, n/N (%)11/28 (39)26 (52)0.28—
Muscle features
Type of myositis:
- DM, n (%)5 (14)19 (29)0.11—
- PM, n (%)21 (62)42 (65)0.78—
- IBM, n (%)8 (24)4 (6)0.0200.44
Highest CK rate, UI/l [range]430 [66–14 650]1259 [34–14 000]0.0460.53
In DM/PM/IBM1117 [347–14 650]/404 [68–7013]/ 547 [200–905]387 [71–11 000]/1361 [34–14 000]/ 1273 [514–3926]
Weakness at the last evaluation, n (%)11 (32)12 (18)0.14—
In DM/PM/IBM0/3 (14)/8 (100)3 (16)/5 (11)/4 (100)
Myositis systemic involvements, n (%)25 (73)53 (82)0.35—
In DM/PM/IBM5 (100)/18 (86)/2 (25)19 (100)/33 (79)/1 (25)
Skin involvement, n (%)15 (44)46 (71)0.015—
In DM/PM/IBM5 (100)/10 (47)/019 (100)/27 (64)/0
- DM rash, n (%)5 (15)19 (29)0.11—
In DM/PM/IBM5 (100)/0/019/0/0
- Sclerodactyly, n (%)4 (12)13 (20)0.40—
In DM/PM/IBM0/4 (19)/02 (11)/11 (26)/0
- Mechanic’s hands, n (%)5 (15)26 (40)0.0100.20
In DM/PM/IBM2/5 (40)/3 (14)/09 (47)/17 (40)/0
- Puffy fingers2 (6)4 (6)1.0—
In DM/PM/IBM0/2 (10)/01 (5)/3 (7)/0
Raynaud’s phenomenon, n (%)14 (41)32 (50)0.40—
In DM/PM/IBM2/5 (40)/11 (52)/1 (13)7 (37)/25 (60)/0
Interstitial lung disease, n (%)a8 (24)27 (42)0.0750.51
In DM/PM/IBM2/5 (40)/6 (29)/07/19 (37)/20 (48)/0
Arthralgia and/or arthritis, n (%)20 (59)32 (49)0.37—
In DM/PM/IBM3 (60)/15 (71)/2 (25)12 (63)/19 (45)/1 (25)
PNS involvement8 (24)5 (8)0.0280.62
In DM/PM/IBM0/5 (24)/3 (38)0/3 (7)/2 (50)
Cryoglobulinaemic vasculitis1 (3)00.34—
In DM/PM/IBM0/1 (5)/00/0/0
Glandular involvement
Subjective sicca syndrome, n (%)34 (100)16 (26)<0.n—
Schirmer test ≤5 mm, n/N (%)b26 (96)9 (31)<0.0001—
Salivary flow ≤0.1 ml/min, n/N (%)3/7 (43)2/10 (20)0.59—
≥1 focus/mm² in a labial salivary gland biopsy27/30 (90)1/25 (4)<0.0001—
Cancer during follow-up, n (%)7 (21)8 (12)0.28—
In DM/PM/IBM2 (40)/4 (19)/1 (13)1 (5)/6 (14)/1 (25)
Cancer onset ≤3 years in relation to myositis, n (%)2 (6)5 (8)1.0—
In DM/PM/IBM1 (20)/1 (5)/01 (5)/3 (8)/1 (25)
Lymphoma, n (%)2 (6)00.12—
In DM/PM/IBM0/1 (5)/1 (13)
Immunomodulatory treatment
Corticosteroids, n (%)b31 (91)58 (89)0.80—
In DM/PM/IBM5 (100)/19 (90)/7 (88)18 (95)/39 (93)/1 (25)
Synthetic conventional DMARDs, n (%)c31 (91)57 (88)0.60—
In DM/PM/IBM5 (100)/19 (90)/7 (88)19 (100)/36 (86)/2 (50)
- HCQ, n (%)13 (38)10 (16)0.012—
In DM/PM/IBM2 (40)/7 (33)/4 (50)9 (47)/1 (2)/0
Other immunomodulators, n (%)d15 (44)18 (29)0.10—
In DM/PM/IBM3 (60)/7 (33)/5 (63)2 (11)/14 (33)/2 (50)
Lines of immunomodulators, n [range]2 [0–6]2 [0–5]0.27—
In DM/PM/IBM2 [1–4]/2 [0–6]/3 [0–4]2 [1–5]/2 [0–4]/1.5 [0–5]
Serologic data
Myositis-specific antibodies, n (%)16/29 (55)45/60 (75)0.0590.93
In DM/PM/IBM3/4 (75)/13/19 (68)/0/614/19 (74)/31/38 (82)/0/3
- DM antibodies, n (%)e2/32 (6)8/63 (13)0.49—
- Antisynthetase antibodies, n (%)f9/29 (31)16/60 (27)0.67—
In DM/PM/IBM3 (75)/6 (33)/05 (26)/11 (31)/0
- Anti-U1-RNP , -PM/Scl, -Ku, -centromere antibodies, n (%)g7/34 (21)17/65 (26)0.54—
In DM/PM/IBM0/7 (41)/01 (6)/16 (43)/0
- IMNM antibodies, n (%)h0/30 05/60 (8)0.16—
In DM/PM/IBM0/0/00/5 (13)/0
Anti-SSA and/or -SSB, n (%)17/34 (50)6/59 (9)<0.0001—
− Anti-SSA17 (50)6 (9)
− Anti-SSBi8 (23)1 (1)
ANA positivityj22/28 (79)32/58 (55)0.06
Anti-cN1A, n/N (%)10/26 (38)3/54 (6)0.00050.021
In DM/PM/IBM2/3 (66)/4/17 (24)/4/6 (67)1/18 (6)/1/32 (3)/1/3 (33)
a

Diffusing capacity for carbon monoxide in SS+ vs SS- was 70% [range 29–100] and 59% [25–100], respectively, P = 0.065; forced vital capacity was 85% (46–124) and 82% (47–122), P = 0.79. bLast corticosteroid dose was 0 [range 0–75] and 2 mg [range 0–90], P = 0.26, respectively. cComprising methotrexate, HCQ, MMF, AZA, ciclosporin, leflunomide, sulfasalazine, cyclophosphamide, rapamycin, colchicine. dComprising intravenous immunoglobulins, rituximab, plasma exchange, anti-TNFa, tocilizumab. eAnti-MDA5 was found in 2/23 (8%) vs 3/48 (6%) patients and anti-Mi2 in 0/24 vs 5/52 (10%), respectively. fAnti-Jo1 was found in 6/29 (21%) vs 10/62 (16%) patients. gAnti-PM/Scl was found in 3/27 (11%) vs 9/60 (15%) and anti-Ku in 3/26 (12%) vs 4/56 (7%), anti-U1-RNP in 1/33 (3%) vs 5/65 (8%), anti-centromere in 1/25 (4%) vs 0/55, no anti-Scl70 was found. hAnti-SRP was found in 0/27 vs 5/55 (9%) patients. iNo patient was positive for anti-SSB alone (without anti-SSA). jPatterns according to the international consensus were: AC1 (8% vs 17%), AC3 (4% vs 0%), AC4 (56% vs 13%), AC5 (4% vs 9%), AC6 (0% vs 4%), AC8 (26% vs 20%), AC9 (0% vs 2%), AC19 (4% vs 9%), AC20 (0% vs 13%) in patients with SS vs without SS. IBM: inclusion body myositis; IMNM: immune-mediated necrotizing myopathy; PNS: peripheral nerve system; ANA: antinuclear antibodies. Data with p-value < 0.05 are in bold.

IBM was found in 24% of the myositis/SS+ patients vs 6% in the myositis/SS- group (P = 0.02). By contrast, the other myositis subgroups (DM and PM as defined by the EULAR/ACR 2017 criteria) and their related myositis-specific autoantibodies tended to be less prevalent in myositis/SS+ patients. Accordingly, skin (P = 0.015) and lung (P = 0.075) involvements (absent in all the IBM patients but frequent in the two other myositis subtypes) were less frequently seen in myositis/SS+. Myositis diagnosis tended to be delayed in patients with SS as compared with patients without SS [6 months (range 0–336) vs 4 (0–122), P = 0.057]. Peripheral nerve involvement, a manifestation of both IBM [13] and SS [14], was found in 24% of the myositis/SS+ patients vs 8% of their counterparts (P = 0.028). Finally, these differences between the two groups were not significant in multivariable analysis taking into account the higher prevalence of IBM in myositis/SS+.

Overall, the frequency of myositis-associated cancer was similar between patients with and without SS (6% vs 8%, P = 1.0). Lymphoma was diagnosed in 2 myositis/SS+ [6% (95% CI: 2, 20) vs none of the myositis/SS- patients; P = 0.12]. One patient had developed non-Hodgkin lymphoma diagnosed simultaneously with SS. The other had B diffuse large cell lymphoma of the parotid (associated with cryoglobulinaemic vasculitis type II), occurring 17 years after the SS diagnosis.

Aside from HCQ, which was more frequently given in myositis/SS+ patients (38% vs 16%, P = 0.012), no difference was observed in the treatment regimens among the different myositis subtypes. Importantly, 11/12 IBM patients received an immunomodulatory drug [median number of lines, besides steroids: 3 (range 1–5)] and none experienced muscle improvement, whether they had SS (n = 7) or not (n = 4).

Myositis patients with SS more frequently had anti-cN1A antibodies, independently of the IBM diagnosis

Anti-cytosolic 5′-nucleotidase 1 A (cN1A) antibody has previously been proposed as a specific biomarker of IBM, but is also highly prevalent in SS [15]. Positivity for anti-cN1A was found in 38% of myositis/SS+ vs 6% in the myositis/SS- group (P = 0.0005). Multivariable analysis revealed that the association between SS and anti-cN1A was independent of the higher prevalence of IBM in the SS group (P = 0.021).

As shown in Table 2, the specificity of anti-cN1A for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group.

Table 2
Open in new tab

Specificity and sensitivity of anti-cN1A antibody for IBM diagnosis

Overall cohortMyositis/SS+Myositis/SS-
Specificity0.890.700.96
(95% CI)(0.79, 0.94)(0.48, 0.85)(0.87, 0.99)
Sensitivity0.560.670.33
(95% CI)(0.27, 0.81)(0.30, 0.90)(0.06, 0.79)
Overall cohortMyositis/SS+Myositis/SS-
Specificity0.890.700.96
(95% CI)(0.79, 0.94)(0.48, 0.85)(0.87, 0.99)
Sensitivity0.560.670.33
(95% CI)(0.27, 0.81)(0.30, 0.90)(0.06, 0.79)

SS+: patients with Sjögren’s syndrome; SS-: patients without Sjögren’s syndrome.

Table 2
Open in new tab

Specificity and sensitivity of anti-cN1A antibody for IBM diagnosis

Overall cohortMyositis/SS+Myositis/SS-
Specificity0.890.700.96
(95% CI)(0.79, 0.94)(0.48, 0.85)(0.87, 0.99)
Sensitivity0.560.670.33
(95% CI)(0.27, 0.81)(0.30, 0.90)(0.06, 0.79)
Overall cohortMyositis/SS+Myositis/SS-
Specificity0.890.700.96
(95% CI)(0.79, 0.94)(0.48, 0.85)(0.87, 0.99)
Sensitivity0.560.670.33
(95% CI)(0.27, 0.81)(0.30, 0.90)(0.06, 0.79)

SS+: patients with Sjögren’s syndrome; SS-: patients without Sjögren’s syndrome.

Discussion

We here show that in myositis patients, SS is associated with IBM and with anti-cN1A antibody independently of the myositis subtype.

The present study demonstrates the association between IBM and SS that had been previously suspected from results in uncontrolled cohorts: we recently reported that 0.5% of SS patients developed IBM [6] and other authors described 10–12% of SS in IBM patients [10, 16]. This is the first study to ascertain this association based on a controlled cohort covering the entire spectrum of myositis. Interestingly, Lindvall et al. [17] found signs of IBM in 22% of muscle biopsies of asymptomatic SS patients, suggesting common pathophysiological mechanisms in these two conditions.

Although the cohort described is important bearing in mind the rarity of myositis, the statistical power remains small especially when subdividing the samples into each myositis subgroups. Another limitation of this work is its retrospective nature, but importantly, it allowed us to collect a myositis population with long follow-up.

Response to conventional immunomodulatory treatments of IBM/SS+ has been described only in case reports or in small (n ≤ 5) uncontrolled series, and was controversial. While some authors described a mild improvement after limited follow-up [18, 19], the others reported no improvement or a subsequent deterioration after longer follow-up [7, 10]. Limaye et al. reported a single IBM-SS patient [19] with a < 6% improvement at manual muscle testing (MMT) recorded <3 months after rituximab infusion (a brief interval considering the efficacy of this drug in myositis [20] and that was not maintained over time). None of our 3 IBM-SS patients who received rituximab experienced a significant improvement of the myositis as defined by the IMACS (≥15% increase in MMT, see Supplementary Data S1, available at Rheumatology online). In addition, two large randomized controlled trials testing rituximab in SS did not meet their primary endpoint [21]. Nevertheless, whether rituximab might be efficient in slowing down IBM progression in patients with SS remains to be explored.

T cell large granular lymphocytic leukaemia (T-LGLL) has been reported in both IBM and SS, indicating a shared pathophysiology between these two autoimmune diseases [19]. None of our 12 patients with IBM had suspected T-LGLL based on blood cell counts. No lymphocytosis was observed except in one IBM patient with lymphoma. Immunophenotyping of blood lymphocytes to check for this disease was not performed and so we cannot rule out the possibility that some had T-LGLL.

We report here the largest series of IBM associated with SS treated with immunomodulatory drugs, benefiting from a prolonged follow-up and a standardized definition of improvement. Importantly, like IBM patients without SS, none of these patients experienced muscle improvement. The high proportion of IBM patients treated with immunomodulators was related to the delayed diagnosis (a median of 21 months [range 0–144]).

Anti-cN1A antibody has been reported as useful for differentiating IBM from other forms of myositis and from other neuromuscular diseases. However, this autoantibody has also been reported in one third of SS patients [15]. Given the association between IBM and SS that we demonstrate here, the independence of the association between anti-cN1A and SS is a crucial issue. We here show that anti-cN1A, measured with a validated technique that is routinely available [12] is associated with SS independently of the IBM diagnosis. Most importantly, while the specificity of anti-cN1A for IBM was excellent in myositis/SS- patients, it was significantly altered in myositis/SS+ patients.

Accurate identification of IBM is fundamental. Unlike the other myositis subtypes, conventional immunomodulatory drugs are not effective in this disease and may even increase the risk of progression toward disability [8]. Thus, awareness of the high prevalence of IBM in myositis patients with SS and the poor specificity of anti-cN1A for IBM in this setting has important implications for care.

In conclusion, IBM is more frequently observed in myositis patients with SS than in myositis patients without SS. They also more frequently have anti-cN1A antibodies, independently of the IBM diagnosis.

Acknowledgements

We acknowledge the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). We also thank Ms Mary V.C. Pragnell for careful language reviewing of the manuscript.

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The authors have declared no conflicts of interest.

Data availability statement

Anonymized data not published within the article will be shared upon request from any qualified investigator. All data relevant to the study are included in the article or uploaded as supplementary information.

Supplementary data

Supplementary data are available at Rheumatology online.

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