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ORIGINAL ARTICLE
Ahead of print publication  

Intravenous immunoglobulin in the management of idiopathic inflammatory myositis: A single centre retrospective review


1 Arthritis Rheumatology Clinic, Vadodara, Gujarat, India
2 Department of Rheumatology and Clinical Immunology, Sir Ganga Ram Hospital, New Delhi, India
3 Department of Rehumatology, Private Medical College, Bathinda, Punjab, India

Correspondence Address:
Jeet Hemantkumar Patel,
202, Shyam Arena Complex, Sampatrao Colony, Alkapuri, Vadodara - 390 007, Gujarat
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_28_20

  Abstract 


Objective: Intravenous immunoglobulin (IVIG) has been used in the treatment of severe idiopathic inflammatory myositis (IIM) in the past. We conducted a retrospective analysis of IIM cases and compared patients who received IVIG with those who did not.
Methods: Electronic records from the year 2015–2019 were searched for myositis cases using the terms “myositis, inflammatory myositis, autoimmune myositis.” Cases with dermatomyositis, polymyositis, necrotizing autoimmune myositis, and connective tissue disease myositis/overlap myositis were included (n = 28) and those with infectious or granulomatous myositis were excluded (n = 7). Relevant data were noted. Participants were classified into cases and controls based on IVIG use for treatment. Results were expressed as median and interquartile range. Nonparametric testes were used for comparisons.
Results: Word search revealed 35 cases of myositis. Of them, 28 patients were included in the study. From these patients, ten patients had treatment with IVIG and 18 had not. The median age was 49.5 (39.5, 57) years, and disease duration 5.5 (2.5, 12) months. IVIG-treated patients had a more extended hospital stay and less arthritis (P < 0.05). A common indication of IVIG use was esophageal ± respiratory muscle weakness (n = 5/10). In the IVIG group, there was a higher rate of pulse glucocorticoids use (P = −0.02); however, the use of other drugs was similar. Sepsis, gastrointestinal complications, and pneumonia were higher in IVIG-treated patients (P < 0.05). IVIG-treated patients had a higher mortality rate and lower response compared to controls (P < 0.05).
Conclusion: IVIG is often the drug of choice for patients with infections in IIM in the Indian setting. Although the IVIG group suffered high mortality, confounding factors, and small sample size, limit conclusions on the usefulness of IVIG in IIM. However, this study showed that IVIG might not alleviate infections complicating IIM cases. Further studies are required.

Keywords: Idiopathic inflammatory myositis, infections, intravenous immunoglobulin



How to cite this URL:
Patel JH, Duggal L, Chaturvedi V, Jain N, Bhandari G, Gupta M. Intravenous immunoglobulin in the management of idiopathic inflammatory myositis: A single centre retrospective review. Indian J Rheumatol [Epub ahead of print] [cited 2020 Oct 29]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=289178




  Introduction Top


Idiopathic inflammatory myositis (IIMs) are a heterogeneous group of rare disorders.[1] Although the classical presentation of IIM is symmetric proximal muscle weakness, patients can present with features of connective tissue diseases (CTD), cardiopulmonary manifestations, skin lesions, arthritis, malignancy, and even infections.

IIM often leads to increased morbidity and, at times, even mortality. The mainstay of treatment is glucocorticoids (GC), with immunosuppressive agents (ISA) such as methotrexate (MTX), azathioprine (AZR), and mycophenolate mofetil (MMF).[2] Intravenous immunoglobulin (IVIG) and rituximab (RTX) are known treatment options for resistant and severe cases.[3] The usefulness of IVIG in various autoimmune disorders, including IIM, had been studied and later on evaluated in a few trials.[4]

No standard guidelines or evidence-based treatment protocols have been developed till date for IIM with unanimous agreement internationally. Individualized treatment is a more justifiable approach, which is based on the factors such as disease severity, previous treatments taken, presence of extra-muscular features, associated esophageal and/or respiratory muscle weakness, concurrent infections and contraindications to particular medications, etc. Nonresponse to treatment may be as high as 25%, and the relapse rate is also high.[5] Considering the cost of IVIG, nature of IIM (requiring days to months for improvement), and the presence of infections as a significant mortality factor, it is crucial to ascertain its utility in IIM patients. We, thus, investigated the usefulness of IVIG in the management of IIM patients.


  Methods Top


Ethics approval was taken from the Ethics Committee. The electronic database was searched for myositis patients admitted at the hospital from January 2015 to December 2019 using terms “myositis,” “inflammatory myositis,” and “autoimmune myositis.”

Thirty-five cases were obtained, of which those (n = 28) with a diagnosis of dermatomyositis (DM)/polymyositis (PM), necrotizing autoimmune myositis (NAM), and CTD myositis/overlap myositis (OM) were included and the rest (n = 7) excluded (e.g., viral myositis, sarcoid granulomatous myositis, pyomyositis, etc.). Cases of IIM were classified according to Bohan and Peter criteria for DM/PM.[6] Anti-signal recognition particle positive IIM patients and statin-induced myositis patients were classified as NAM. CTD patients with myositis fulfilling Bohan and Peter criteria were classified as CTD myositis and/or OM (if they met criteria for CTD and IIM both).

Patients' demographic data, history, clinical examination, and relevant laboratory investigation were recorded. Data related to testing of myositis-specific antibodies/myositis associated antibodies (MAA) performed by line immune assay (LIA) method were recorded. While in patients of CTD Myositis/OM, extractable nuclear antigens performed by LIA were documented.

IIM patients were classified into two groups: (1) cases (patients who received IVIG) and (2) controls (patients who did not). Severe disease was defined as patients having rapidly progressive muscle weakness, respiratory or esophageal muscle weakness, myocarditis, or rapidly worsening interstitial lung disease (ILD). Infections were identified as the presence of microorganism that was usually absent in the human host, presence of sepsis, or having pneumonia. Polymerase chain reaction (PCR), antigen, or antibody assay by enzyme-linked immunosorbent assay, blood culture, or other body fluid culture were laboratory methods used to detect microbes.

The outcome of patients was recorded as death, improved, and not improved/not worsened. The treatment response was determined by one or more of the following: clinical improvement in muscle weakness, improvement in muscle enzymes/extra-muscular manifestations, or the ability to taper the GC dose.

Data were exported to Microsoft Excel. Data were checked for normality using the Kolmogorov–Smirnov test. Since data were nonnormal, we have used nonparametric tests for reporting the data. Continuous variables were expressed as median with interquartile range (IQR) (Quartile [Q1] 1 and Quartile 3 [Q3]). Categorical variables were analyzed by frequency distribution and contingency tables. Data were assessed using EpiInfo 7 software (version 7.2.3.1, Centers for Disease Control and Prevention in Atlanta, Georgia, USA). Fisher's exact test was used for noncontinuous variables, while for continuous variables, the Mann–Whitney U-test was used for two-tailed P values. A P value of 0.05 was considered statistically significant.


  Results Top


Twenty-eight patients admitted under the Department of Rheumatology, Neurology, and Internal Medicine were included in the study. Of these 28 patients, ten patients were treated with IVIG and rest were treated without it. In the present study, indications for IVIG were as follows: esophageal muscle weakness, respiratory muscle weakness, associated cardio-respiratory system involvement, resistance to other ISA, bed-bound state of muscular weakness and/or associated infections where other ISA were contraindicated. The dose of IVIG was 2 g/kg body weight by intravenous route over 3–5 days and was repeated according to patients' disease and treatment response.

Demographic data and disease characteristics

Median age (IQR) was 49.5 (39.5, 57) years. Nine males and 19 females had a disease duration of 5.5 (2.5, 12) months and hospital stay of 6 (4.5, 14.5) days. Both groups were comparable on the basis of age and gender (P = 0.16 and P = 0.67, respectively). Male:female ratio was 1:1.5 and 1:2.6 in IVIG versus non-IVIG group. Duration of illness ranged from 7 days to 2 years in the IVIG group, while it was from 15 days to 3 years in the non-IVIG group. The subtypes of IIM and blood tests, as well as the treatment given in the patients of the two groups, are listed in [Table 1].
Table 1: Comparison between intravenous immunoglobulin and nonintravenous immunoglobulin group

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ANA was present in 64.29% (n = 18/28). Ro52 was present in 50% of patients (n = 14/28), and it was the common MAA in the present study. Serum ferritin level and erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) were raised in most of the cases in the IVIG group. Median serum ferritin (IQR) was 740 (481, 3450) mcg/L. Median ESR (IQR) and median CRP (IQR) was 54.5 (34, 78) mm/1st h and 76.5 (32, 103) mg/dl, respectively. GCs were used in all patients (dose 1 to 0.75 mg/kg/day); however, IV pulse GC was used in 11 patients only. MTX (n = 17/28) was the most common ISA used for IIM management, followed by AZR (n = 8/28) and MMF (n = 7/28). A most common indication for IVIG in the present study was esophageal ± respiratory muscle weakness (n = 5/10).

Infections

Infections were significantly higher in the IVIG group (P < 0.05). Infections were also the most common cause of death in this group. In the IVIG group, tests for microbes were positive in seven cases. No microorganism was found in the remaining three cases, although they had pneumonia and/or sepsis. Cytomegalovirus (CMV) and Klebsiella pneumonia were common organisms isolated. In the IVIG group, three patients with CMV infection died, while one had no response to treatment. Details on infections are given in [Table 2].
Table 2: Infections in intravenous immunoglobulin versus nonintravenous immunoglobulin groups

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The outcome of IIM cases

Among the ten patients treated with IVIG, seven patients received a single dose, two patients received two doses, and one patient received four doses (1 dose = 2 g/kg) of IVIG. Seven patients died and one patient did not respond to IVIG. Two of them responded to IVIG: one had marginal improvement and one had a full recovery [Figure 1]. In this group, all patients were treated with pulse GC, except three who were treated with septic dose of GC. All patients with esophageal and/or respiratory muscle involvement died. In the non-IVIG group, one patient of cancer-associated DM died due to sepsis, liver, and lung metastasis. Fifteen patients showed improvement to treatment in this group, which was statistically significant (P < 0.05).
Figure 1: One hundred percent stacked column chart showing outcome between intravenous immunoglobulin versus nonintravenous immunoglobulin group and infection versus noninfection

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  Discussion Top


This study is an attempt to assess the outcomes and management of IIM patients treated with IVIG. In this study, nonsevere cases responded well to GC and other ISA such as MTX and MMF. On the other hand, rapidly deteriorating severe IIM patients had a poor outcome. Infections are a significant cause of mortality and morbidity and inevitably affect the disease outcome. Despite treatment with all efficient agents, for example, IVIG and RTX, a large proportion of IIM patients with infections might suffer mortality in developing countries like India.

IVIG treated patients had more respiratory/esophageal muscle weakness, less arthritis and more NAM that denotes more severe disease compared to non-IVIG group. On the other hand, non-IVIG patients had more females, less severe disease, shorter hospital stay, more CTD/OM myositis subtype and more arthritis/arthralgia. Comparison between IVIG versus non-IVIG group is not explicit due to the presence of many confounding factors. Confounding factors like severity of the disease, esophageal ± respiratory muscle weakness, pulse GC use, infections, and other ISA, all are complexly inter related. It is difficult to measure the effects of individual factors on disease outcome as they are intertwined. Furthermore, IIM is a relatively rare disease, the number of patients over a period of 5 years are limited; hence, regression analysis for testing of the confounders is limited in the present study.

There is a scarcity of data on IVIG in IIM patients, especially with infections. India being a developing country, has more prevalence of infections. Thus, its utility in IIM might be of higher value. We could not find any literature on IVIG use and its results in Indian IIM patients. Thus, this maiden attempt of studying the effect of IVIG and its utility in IIM with infections might be of higher value. The use of IVIG in inflammatory myositis had been described already with medium priority and a moderate level of evidence.[7] Significant outcomes with the treatment of IVIG in IIMs are the improvement of manual muscle testing score-8, reduction in muscle enzymes, and reduction in extra-muscular manifestations of the diseases.[7] The level of evidence for IVIG in IIM patients is not so strong. The European Dermatology Forum and the European Federation of Neurological Societies support the use of IVIG for PM (level of evidence C) and DM (level of evidence B) to reduce the dose of GC or in resistant disease.[8],[9]

Based on our record review, it was found that IVIG was administered within 3–5 days of admission in all patients. The average duration of hospital stay was 20 days in the IVIG group. This had ascertained that adequate time was given for IVIG action. Poor disease outcome after IVIG use in the present study might suggest that IVIG does not mitigate infections, which are a major cause of mortality in IIM patients. Apart from immune deficiencies and HIV in the pediatric population, IVIG is not approved for use to combat infections.[10] This study points out that IVIG is an immunomodulator and not an agent to fight against infections.

World literature has already proved utility if IVIG in IIM patients with response rate up to 70%–77%. Studies had also shown that IVIG was effective even in severe cases with esophageal ± respiratory muscle weakness.[11],[12],[13] IVIG therapy was rarely employed as first-line therapy in PM/DM in these studies, and it was used for 3–6 months. While in the present study, most of the patients in the IVIG group presented with rapid deterioration at initial presentation, and IVIG was used initially along with other first-line agents. Even though patients were treated aggressively with all possible treatment options, most of them had not shown any improvement.

Another exciting facet of the study was CMV infection. Five cases had active CMV infection with copies >1200 by the PCR method. Three of them died, and one had nonresponse to IVIG. It had been shown that CMV infection could exacerbate immune-mediated neuroinflammation. As CMV can provoke disturbances between CD4 cells and other types of lymphocytes, it might affect treatment response of immunomodulators, for example, IVIG in various autoimmune disorders.[14] Key messages of the study are given in [Table 3].
Table 3: Key messages of the present study

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Infections are major concerns IIM subjects. Chen et al. studied 192 IIM cases, which showed infections in 27.6% of cases. The incidence rate of major infections was 11.1 episodes per 100 patient-years in PM/DM patients. Aspiration pneumonia was the leading cause of major infections, followed by opportunistic infection. They also showed that one major infection episode decreased survival rates to 84.7% at 30 days and 68.3% at 1 year (standard-85.0% at 1 year). Multivariate analysis in their study showed that independent predictors of major infection were age older age of onset (>45 years), presence of arthritis/arthralgia, ILD, and the use of AZR or IVIG.[15] Due to the small sample size, multivariate analysis was not possible in the current study.

Similarly, Muhammed et al., in their Indian study, showed that infections were the major cause of death. In their study, out of 38 patients, six patients had esophageal muscle weakness, two had myocarditis, and 2 had respiratory muscle weakness.[16] Types of IIM, age, and extra-muscular involvement in their study are similar to the data of the present study. There is a conspicuous lack of data on IIM patients in India, and collaborative efforts are required to collect data on outcomes in such rare rheumatic diseases. In this regard, a pan-India collaborative network called Myositis India Collaborative Effort was created to build a cohort of IIM patients.[17] A similar effort in Europe goes by the name of the Euromysositis register.[18]

Major drawbacks of the present study are the retrospective nature of the study, nonhomogeneous population, single center study with the small patient number, and referral bias. Further studies are required with multicenter prospective randomized control trials or case–control studies.


  Conclusion Top


IVIG use was not so effective in our subset of rapidly deteriorating severe myositis patients, especially with infections. Infections were the major risk factors for poor disease outcome. IVIG may improve IIM, but it does not fight against infections. CMV may be one of the common micro-organisms that might affect the outcome in IIM patients. However, properly designed and adequately powered study is required to support the results of the present study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Elovaara I, Apostolski S, van Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J, et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol 2008;15:893-908.  Back to cited text no. 8
    
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Enk A. European Dermatology Forum Guideline Subcommittee. Guidelines on the use of high-dose intravenous immunoglobulin in dermatology. Eur J Dermatol 2009;19:90-8.  Back to cited text no. 9
    
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Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol 2017;139:S1-46.  Back to cited text no. 10
    
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Foreman C, Russo P, Davies N, Hissaria P, Proudman S, Hughes T, et al. Use of intravenous immunoglobulin therapy for myositis: An audit in South Australian patients. Intern Med J 2017;47:112-5.  Back to cited text no. 11
    
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Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: An open study with thirty-five adult patients. Arthritis Rheum 2002;46:467-74.  Back to cited text no. 12
    
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Wang DX, Shu XM, Tian XL, Chen F, Zu N, Ma L, et al. Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: A systematic literature review. Clin Rheumatol 2012;31:801-6.  Back to cited text no. 13
    
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Vanheusden M, Broux B, Welten SP, Peeters LM, Panagioti E, Van Wijmeersch B, et al. Cytomegalovirus infection exacerbates autoimmune mediated neuroinflammation. Sci Rep 2017;7:663.  Back to cited text no. 14
    
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Chen IJ, Tsai WP, Jan Wu YJ, Luo SF, Ho HH, Liou LB, et al. Infections in polymyositis and dermatomyositis: Analysis of 192 cases. Rheumatology 2010;49:2429-37.  Back to cited text no. 15
    
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Muhammed H, Gupta L, Zanwar AA, Misra DP, Lawrence A, Agarwal V, et al. Infections are leading cause of in-hospital mortality in indian patients with inflammatory myositis. J Clin Rheumatol 2019. doi:10.1097/rhu.0000000000001214. PMID: 31804256.  Back to cited text no. 16
    
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Gupta L, Appani SK, Janardana R, Muhammed H, Lawrence A, Amin S, et al. Meeting report: MyoIN – Pan-India collaborative network for myositis research. Indian J Rheumatol 2019;14:136-42.  Back to cited text no. 17
  [Full text]  
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Lundberg IE, Vencovsky J. International collaboration including patients is essential to develop new therapies for patients with myositis. Curr Opin Rheumatol 2017;29:234-40.  Back to cited text no. 18
    


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