Information from a total of 190 CRFs was extracted. Of them, 15 were excluded due to incomplete information or change in diagnosis at follow up. The cohort consisted of 175 patients, with a mean age of 40.9 years (± 12.6) and a female preponderance (F:M::3.3:1). Of the cohort 133/175(76%) were classifiable as definite/probable IIM as per Peter and Bohan criteria. They were sub-classified as DM 78(44.6%), OM 45 (25.7%), ASS 11(6.3%) and PM 25(14.3%) and a single case of NAM. In the subset with DM, 5 were CADM. Juvenile onset IIM were categorized into juvenile DM (12/15) and juvenile onset OM (3/15). The baseline demographics, disease subsets, autoantibody profile and muscle histopathology features are represented in Table 1.
Table 1
Baseline demographics, clinical phenotype, autoantibodies, treatment and mortality overview - IIM (overall and subsets).
|
Overall
|
DM
|
OM
|
PM
|
JM
|
ASS
|
N (%)
|
175
|
78(44.6)
|
45(25.7)
20/11/10/4(SSc,MCTD,UCTD,SLE)
|
25(14.3)
|
15(8.6)
|
11(6.3)
|
Median age in Years (IQR)
|
38(27.5,48.5)
|
39.5(30,50)
|
37(34,44)
|
45(29.5,50)
|
12.5(10,15)
|
46(43,55)
|
F:M
|
3.3:1
|
2.9: 1
|
6.5:1
|
3.2:1
|
2:1
|
1.2:1
|
Median(IQR) duration of illness(months)
|
4(1,7)
|
3(1,8)
|
4(1,5)
|
4(1,6)
|
2(1,6)
|
3(2,14.5)
|
Median MMT-8 (baseline) n = 133
|
61(49,69)
|
61(50,67)
|
61(49,72)
|
55(39,61)
|
61.5(45.5,71)
|
66(61.5,75)
|
MITAX (baseline) n = 75
|
12(7,16)
|
12.5(7,18)
|
12(6.75,12)
|
9(5,12)
|
13(8.5,15.5)
|
0
|
Dysphagia (%)
|
51 (29.1)
|
27(34.6)
|
14 (31.1)
|
6 (24)
|
3 (20)
|
0 *
|
Dysphonia (%)
|
14 (8)
|
5 (6.4)
|
4 (8.8)
|
2 (8)
|
2 (13.3)
|
0
|
Respiratory weakness(%)
|
6 (3.4)
|
2(2.5)
|
4 (8.8)
|
0
|
0
|
0
|
ILD (%)
|
24 (13.7)
|
6 (7.7)
|
10 (22.2)*
|
1 (2.4)
|
1 (6.6)
|
6(54.5)***
|
DM specific rash(%)
|
70 (40)
|
54 (69.2)
|
3 (6.6)
|
1 (2.4)
|
10 (66.6)
|
2(18.2)
|
Cardiac (%)
|
11 (6.3)
|
1 (1.3)
|
6 (13.3)*
|
0
|
1(6.6)
|
3(27.3)**
|
Calcinosis (%)
|
13 (7.4)
|
5 (6.4)
|
2 (4.4)
|
1(2.4)
|
3 (20)
|
2(18.2)
|
Malignancy (%)
|
7 (4)
|
6 (7.7)
|
0
|
1(2.4)
|
0
|
0
|
ANA (n = 154)(%)
|
98 (63.6)
|
28 (38.9)
|
34 (87)
|
10(41.6)
|
9 (60)
|
8 (80)
|
MSA (n = 111)(%)
Jo-1
Non Jo-1 ARS
MI-2(α&β)
SRP
|
12 (10.8)
8 (7.2)
10 (9)
3 (2.7)
|
2(4.4)
4 (8.8)
8 (17)
1 (2.2)
|
-
-
1 (4.3)
2 (8.6)
|
1(6.6)
1 (6.6)
-
-
|
1 (7.6)
-
1 (7.6)
-
|
8 (72.7)
3 (27.2)
-
-
|
MAA (n = 137) (%)
U1RNP
Ro-52
Ku
Pm-Scl
Scl 70
SSA
CENP
|
41 (29.9)
50 (36.5)
7 (6.3)
10 (9)
5 (3.6)
9 (6.5)
4 (2.9)
|
9 (16.3)
14 (25.4)
3 (5.4)
4 (7.2)
1 (1.8)
2 (3.6)
2 (3.6)
|
25 (62.5)**
22 (55)#
3 (7.5)
2 (5)
4 (10)
2 (5)
2 (5)
|
5 (26.3)
4 (21)
1 (5.2)
1 (5.2)
-
3 (15.7)
-
|
2 (15.4)
3 (23)
-
3 (23)
-
2 (15.4)
-
|
0
7 (63)**
-
−
−
−
−
|
Muscle Histopathology
|
n = 77
|
n = 34
|
n = 14
|
n = 14
|
n = 8
|
n = 4
|
PFA
Endomysial inflammation
Perivascular inflammation
Necrosis
No features of myositis
|
22
3
44
29
4
|
16
1
21
14
0
|
2
0
8
8
1
|
0
1
9
4
1
|
4
0
4
2
1
|
0
1
2
0
1
|
Treatment
Steroid
MP pulse
Immunosuppressants
Methotrexate
Azathioprine
Mycophenolate mofetil
Cyclophosphamide
Rituximab
HCQ
Tacrolimus
Leflunomide
IVIg
PLEX
|
165(94.2)
58(33)
90 (52)
52 (29.7)
33 (18.9)
12 (6.8)
19 (10.8)
28 (16)
7 (4)
4 (2.2)
4 (2.3)
2 (1.1)
|
75(96.1)
27(34.6)
40(51.2)
24 (30.7)
13(16.6)
5(6.4)
8(10.2)
13(16.6)
2(2.5)
1(1.2)
3(3.8)
1(1.2)
|
45(100)
13(28.8)
26(57.7)
17(37.7)
9(20)
4(8)
5(11)
9(20)
3(6.6)
2(4.4)
-
-
|
22(88)
8(32)
8(32)
8(32)
5(20)
1(4)
-
-
-
-
1(4)
1(4)
|
12(80)
5(33.3)
10(66.6)
2(13.3)
2(13.3)
-
1(6.6)
3(20)
1(6.6)
-
-
-
|
10(90.9)
5(45.4)
6(54.5)
1(9)
4(36.3)
2(18.2)
5(45.4)
3(27.2)
1(9)
1(9)
-
-
|
Death
|
24 (13.7)
|
15(19.2)
|
2(4.4)
|
4(16)
|
2(13.3)
|
1(9)
|
Statistically significant- *p = .03(ASS vs rest & OM vs rest); #-.01(OM vs rest); **p = .02(ASS vs rest & OM vs rest);*** p = .001(ASS vs rest). |
DM- Dermatomycosis, PM - polymyositis, OM - overlap myositis, SSc- systemic sclerosis, MCTD - Mixed connective tissue disease, UCTD - undifferentiated CTD, SLE - systemic lupus erythematosus, ASS- antisynthetase syndrome, JM- Juvenile Myositis, ILD- Interstitial Lung Disease, MMT8- Manual Muscle Testing, MITAX- myositis intention to treat activity index, PFA - Perifascicular atrophy, HCQ-Hydroxychloroquine, PLEX-Plasma Exchange, IVIg- Intravenous Immunoglobulin, MP- Methylprednisolone |
Myositis autoantibodies:
Antinuclear antibody was detected in 98(57.25%). MSAs were demonstrated in 26/111(23.4%), most commonly Jo-1 12/137(8.8%), Mi-2 10/111(9%), non Jo-1 ARS 8/111(7.2%) and SRP 3/111(2.7%). MAAs were detected in 81/137(59.1%) while 16(11.7%) were negative for both MSA & MAA. Multiple MSA positivity was seen in 6/111(5.4%), overlap of MSA and MAA was noted in 11/111 (9.9%). These have been detailed in Table 1.
Clinical response and functional outcome
Table 2
Outcome parameters at > 24 months of follow up in IIM subsets (n = 94)
|
Overall(94)
n(%)
|
DM(35)
n(%)
|
OM(33)
n(%)
|
PM(13)
n(%)
|
JM(8)
n(%)
|
ASS(5)
n(%)
|
Course
Monocyclic
Polycyclic
Chronic continuous
|
13(13.8)
35(37.2)
46(48.9)
|
4(10.8)
14(40)
17(45.9)
|
5(15.2)
11(33.3)
17(51.5)
|
3(23.07)
4(30.7)
6(46.1)
|
1(12.5)
4(50)
3(37.5)
|
0
2(40)
3(60)
|
Response
Complete Response on Rx
Complete Response off Rx
Partial
|
69(73.4)
13(13.8)
11(11.7)
|
28(80)
4(10.8)
3(8.6)
|
25(75.7)
5(15.2)
3(9.1)
|
7(53.8)
3(23.07
3(23.07)
|
5(62.5)
1(12.5)
2(24)
|
4(100)
0
0
|
Steroid (mg)/ day at last FU(n = 87)
0
≤ 7.5
> 7.5
|
35(40.2)
45(51.7)
7(0.08)
|
14(42.4)
18(51.5)
2(6.1)
|
13(43.3)
14(46.7)
3(10)
|
5(38.5)
6(53.8)
1(7.7)
|
3(42.8)
3(42.8)
1(14.3)
|
0
0
4(100)
|
HAQ(n = 79)
0
≤ 1
> 1
|
51(64.6)
24(30.4)
4(5)
|
19(65.5)
10(34.5)
0
|
18(64.3)
9(32.1)
1(3.6)
|
5(45.5)
4(36.4)
2(18.2)
|
6(100)
0
0
|
3(60)
1(20)
1(20)
|
MDI(n = 90)
0
1–2
> 2
|
38(42.7)
36(40.4)
16(17.7)
|
17(48.6)
13(37.1)
5(14.3)
|
11(34.4)
13(40.6)
8(25)
|
4(36.4)
6(54.5)
1(9.1)
|
4(50)
2(25)
2(25)
|
2(50)
2(50)
|
MRS (n = 84)
0–1
2
> 2
|
61(72.6)
19(22.6)
4(4.8)
|
26(72)
7(28)
0
|
19(65.5)
9(31)
1(3.5)
|
7(58.3)
3(25)
2(16.7)
|
6(100)
0
0
|
4(80)
0
1(20)
|
HAQ-Health Assessment questionnaire’s; MDI – Myositis Damage Index; MRS-Muscle Ranking Score; FU- Follow Up; Rx- Treatment |
Table 3
Prognostic factors for clinical response, steroids discontinuation and mortality
Prognostic factors for clinical response, steroid withdrawal and death
|
n
|
Odds ratio(95% CI)
|
P value
|
Adjusted odds
(95% CI)
|
P value
|
CR on or off Rx (n = 93)
|
No Relapses
|
93
|
4.9(1.2, 19.8)
|
0.02
|
12.9(0.9,188)
|
0.06
|
HAQ ≤ 1 at last f/u
|
76
|
10.9 (3.3, 160)
|
0.008
|
6.7(0.8,51.8)
|
0.06
|
MRS
|
90
|
3.2(1.4,7.3)
|
0.004
|
1.7(0.4,6.6)
|
0.4
|
MDI
|
90
|
1.7(1.1,2.7)
|
0.01
|
1.7(0.9,2.9)
|
0.07
|
Steroid withdrawal (n = 93)
|
Myositis associated antibody
|
67
|
5.7(1.8,17.4)
|
0.002
|
4.6(0.69,30.6)
|
0.14
|
Ro 52
|
69
|
3.2(1.1,9.5)
|
0.03
|
1(0.14,6.9)
|
0.9
|
Follow-up duration
|
93
|
0.9(0.96,0.99)
|
0.001
|
0.9(0.96,0.99)
|
0.02
|
HAQ < = 1 at last f/u
|
76
|
3.3(1.3,8.6)
|
0.01
|
1.8(0.2,14.7)
|
0.5
|
MRS at last f/u
|
80
|
1.7(1,3)
|
0.03
|
1.2(0.3,4.7)
|
0.7
|
Mortality (n = 175)
|
DM vs non DM
|
|
2.52(0.9,6.3)
|
0.052
|
|
|
Baseline MMT-8
|
131
|
0.97(0.93,1)
|
0.05
|
0.9(0.9,1.1)
|
0.1
|
Dysphagia
|
|
2.5(1.03,6.2)
|
0.04
|
1.5(0.3,6.8)
|
0.6
|
Dysphonia
|
|
5.3(1.6,17)
|
0.005
|
3.4(0.3,35.8)
|
0.3
|
Respiratory weakness
|
|
6.3(1.8,22)
|
0.004
|
2.5(0.2,28.3)
|
0.4
|
Malignancy
|
|
6(1.9,18.3)
|
0.002
|
1.5(0.2,10.5)
|
0.7
|
RNP/Sm positivity
|
140
|
0.12(0.02,0.9)
|
0.002
|
0.1(0.02,1.2)
|
0.07
|
Factors analysed in univariate analysis were age, sex, diagnosis, time to presentation, baseline MMT-8, oropharyngeal weakness, ILD, MSA positivity, MAA positivity, Ro-52positivity, RNP/Sm positivity, time to 0–15 mg/kg steroids, response at 6 months, relapsing disease, HAQ-DI ,MRS,MDI at last follow-up. Significant factors (p = < 0.05) only are represented in the table. |
DM- Dermatomycosis, MMT8- Manual Muscle Testing, MRS-Muscle Ranking Score, MITAX- myositis intention to treat activity index, HCQ-Hydroxychloroquine, CR-Complete Response |
Steroids were used in all patients except one, the majority [157(89.7%)] required high dose steroids, 58/175 (33.1%) required pulse steroids in addition. All patients received simultaneous steroid sparing agents. The distribution of steroid sparing immunomodulators are represented in Table 1. Median number of steroid sparing immunomodulators used in management of these patients were 1(1,2). Methotrexate was the most common immunomodulator prescribed in 91 (52%) of patients. Nineteen (10.9%) patients in this cohort required rituximab due to either relapse or lack of adequate response to steroids and or steroid sparing immunomodulators.
Follow up information of 24 months or more was available in 94 (54.9%) patients, the median (IQR) followup in this subset was 65(35,100.7) months. Of them, 13(13.8%) had monocyclic illness (treatment free remission), 37(38.5%) polycyclic and 46(47.9%) chronic continuous course. At the last follow up, 69(73.4%) were in complete clinical remission (CR) on medications, 11(11.7%) had partial response(PR). Overall, complete discontinuation of steroids could be achieved in 35(36.5%) and another 46(47.9%) were on low dose prednisolone < 7.5mg/day. Complete discontinuation of steroids[35(38.9%)] was associated with a longer follow-up duration(OR 0.9(0.96,0.99)), MAA positivity[OR 5.7(1.8,17.4)]), Ro-52 positivity [(3.2(1.1.9,5)] better HAQ-DI (OR 3.3(1.3,8.6)) and MRS[OR 1.7(1,3)]) scores as compared to those who were on some dose of steroids[52(61.1%)].
Complete clinical response on/off treatment at last follow-up[82(87.2%)] were less likely to have a relapse (OR 4.9(1.2,19.8), more likely to have HAQ-DI of 0 at last follow-up[OR 10.9(3.3,160)], better MRS [3.2(1.]4,7.3)), lesser MDI scores[1.7 (1.1,2.7)]) as compared to those who had partial response[11(11.7%)] at last follow-up. Treatment free remission was attained by 13(13.8%) individuals, after a median(IQR) of 60(36,89) months; they had a longer median duration of follow-up[OR 0.9(0.97,0.99)], were less likely to have dysphagia at presentation [OR 0.3(0.09,0.9)], were associated with Ro-52 positive [OR 8.5(1,70)]. They had a moderate severity at presentation [median(IQR)MMT 8 of 52.5(50,59)], other baseline factors and response and functional outcomes were not different from the rest of the cohort.
Median HAQ score (n = 79) recorded at last follow-up was 0(0,0.2) and was recorded 0 in 51(63.7%). Another 24(31.2%) patients had mild to moderate disability (HAQ > 0 ≤ 1) and only 4 reported moderate to severe (HAQ > 1) disability (Fig. 1). Correspondingly, MRS scores (84) were favorable in our cohort with median scores of 0(0,2) ; 61(70.4%) having no residual symptoms or no significant disability(score-0,1); 19(21.6%) having slight disability (score-2) and 4(5.7%) having moderate disability respectively. Median MDI scores of the cohort (n = 89) was 1(1,2).
In view of the majority having a favourable outcome, factors influencing outcome were not further explored. The common complications observed during followup included infections, metabolic and cardiovascular events. These are represented in supplementary table2.
Relapse:
Among patients who have followed up for longer than 6 months (n = 125), a single relapse has occurred in 45(36%) while more than one relapse has occurred in 21(16.8%). Median relapse free survival rate of our cohort is 121(CI 88–153) months. Survival curve based on relapse free survival is represented in Fig. 2. Factors such as IIM subtype, dysphagia, ILD, MAA, complete vs partial response at 6 months, median HAQ, median MRS and median MDI were not different in the subgroups who had at least one relapse versus those who had no relapse.
Malignancy:
Association with malignancy was noted in 7 patients (DM-5, CADM-1, PM-1). The median duration between diagnosis of malignancy and myositis was 2.5(0,5) months except for a single patient developing malignancy 59 months after diagnosis of myositis. Features of muscle disease / DM skin lesions persisted in 4 even after the treatment of malignancy, requiring steroids and immunomodulatory agents over long term. The malignancies noted were carcinoma of breast (2), papillary carcinoma of thyroid (1), lung carcinoma (2) and adenocarcinoma of ovary(2).
Mortality:
In our cohort, 24 (13.7%) patients have died. Disease specific mortality rate was 9.1%. One year, 5 years and 10 years cumulative survival rate of our cohort was 89.1%, 86.9% and 86.3% respectively. Majority of deaths (15/24) occurred during the initial 6 months of illness and were related to disease (45.8%) or infectious complications(16.6%). The median duration from diagnosis to death was 3.5 (1,10.5) months. The mean survival time of the cohort was 239 (CI 220,258) months(Fig. 3).
Acute coronary syndrome (ACS, n = 2) leading to deaths were attributed to IIM both were young (< 50 years) and had no other adverse cardiac risk factors. Of the 7 patients with malignancy, 4 have died during follow up. Two were directly related to malignancy and occurred soon after diagnosis itself. Survival curve based on the above data is depicted in Fig. 2. Univariate regression analysis of factors associated with mortality were baseline MMT-8[OR 0.97(0.9,1)], dysphonia[5.3(1.6,17)], dysphagia[2.5(1,6.2)], respiratory weakness[6.3(1.8,22)], malignancy[6(1.9,18.3)], and absence of RNP/Sm[0.1(0.02,0.9)], however none of the factors were found to be significant in multivariate analysis (Table 3).