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Intravenous Immunoglobulin as Potential Adjunct Therapy

for Interstitial Lung Disease
Robert W. Hallowell1, Diana Amariei2, and Sonye K. Danoff3
Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts; 2Department of Internal Medicine, Johns Hopkins Hospital, Baltimore, Maryland; and 3Division of Pulmonary and Critical
Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Abstract autoimmune disorders and connective tissue diseases, and the

presence of ILD is associated with significant morbidity and
Intravenous Ig (IVIg) is a pooled plasma product consisting primarily mortality. Although there are currently no large studies to support the
of monomeric IgG. For the past several decades, the use of IVIg use of IVIg in the treatment of ILD, it is being used off-label with
has expanded to include the treatment of various autoimmune increasing frequency for refractory cases that have failed to respond
and inflammatory disorders, including Kawasaki’s disease, to standard immunosuppression. Although associated with less
antineutrophil cytoplasmic antibody–associated vasculitis, systemic systemic toxicity and global immunosuppression than traditional
lupus erythematosis, and the inflammatory myopathies. IVIg is agents, IVIg is much more costly. Therefore, although the routine use
thought to exert its immunomodulatory effects through a variety of of IVIg to treat ILD is not currently recommended, future studies to
mechanisms: neutralization of pathogenic autoantibodies; alteration determine its role in pulmonary disease are warranted.
of immune cell effector function; suppression of cytokine and
chemokine activity; and interference with complement activation. Keywords: intravenous Ig; dermatomyositis; polymyositis;
Interstitial lung disease (ILD) is a frequent complication of antisynthetase syndrome; interstitial lung disease

(Received in original form March 11, 2016; accepted in final form July 29, 2016 )
Correspondence and requests for reprints should be addressed to Robert W. Hallowell, M.D., 330 Brookline Avenue, Boston, MA 02215.
Ann Am Thorac Soc Vol 13, No 10, pp 1682–1688, Oct 2016
Copyright © 2016 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201603-179PS
Internet address:

Interstitial pneumonia frequently pulmonary toxicity, and exacerbations of is a preparation comprised of the pooled
complicates the various connective tissue pneumonitis (5–7). plasma from up to 20,000 donors. It
diseases and remains a leading cause of As such, alternative, less toxic therapies primarily contains intact monomeric IgG
morbidity and mortality (1–4). Therapies to treat challenging cases of ILD are needed. with only trace amounts of IgA, IgM, and
aimed at controlling the underlying Although the pathophysiology driving IgE, and the distribution of IgG subclasses
connective tissue disease are often effective pulmonary involvement in these conditions and antibody specificities approximate
at treating the associated pneumonitis; is not entirely understood, abnormalities the range found in normal human serum
however, all too frequently, physicians in immune cell function, the presence of (9, 10).
encounter patients with progressive autoantibodies, and an inappropriate Igs were first used in the 1940s to
interstitial lung disease (ILD) that fails cytokine response have all been implicated treat infections, such as measles, mumps,
to respond to high doses of prednisone in the development of parenchymal lung and pertussis. In 1952, the first case of
combined with other forms of disease (8). As discussed subsequently primary immunodeficiency was treated with
conventional immunosuppression. In here, each of these mechanisms has been subcutaneous gammaglobulin, and in the
such cases, lung transplantation or a suggested as a potential target for therapy years to follow, immune serum globulin
palliative approach is often the only with intravenous Ig (IVIg). became the standard treatment for the
option. Furthermore, even when effective, IVIg has been used for over 70 years antibody deficiency syndromes (11). Over
the standard immunosuppressive agents and has well established antiinflammatory the course of several decades, the use of
are associated with numerous side effects, and immunomodulatory properties that IVIg has expanded to include various
including a significant risk of infection, make it a potentially attractive candidate inflammatory and autoimmune conditions,
renal and hepatic toxicity, direct for the treatment of refractory ILD. IVIg including Kawasaki’s disease (12),

1682 AnnalsATS Volume 13 Number 10 | October 2016


Guillain-Barre syndrome (13), systemic an increase in alternatively polarized associated with known autoimmune
lupus erythematosis (9, 14–16), the macrophages, and these macrophages are diseases: anti-cardiolipin antibodies, anti–
antineutrophil cytoplasmic antibody– believed to participate in a positive-feedback neutrophil cytoplasmic antigen antibodies,
related vasculitides (9, 17–21), and systemic loop involving lung fibroblasts and and anti-DNA antibodies (45). As such,
sclerosis (22, 23). More recently, IVIg has increased collagen production (28, 29). In a IVIg has the ability to inhibit
also shown promise in the treatment of murine model of antibody-mediated autoantibody–antigen interaction and the
polymyositis (PM) and dermatomyositis immune thrombocytopenia, the injection subsequent autoimmune response
(DM) (24–26). Anecdotal evidence and of IVIg Fc fragments seemed to be escalation (27, 46).
several case series have also highlighted its protective through up-regulation of an Levy and colleagues (16) demonstrated
usefulness as adjunct treatment for ILD, inhibitory Fc-g receptor IIB on that, in patients with systemic lupus
emphasizing the need for further awareness macrophages (30). erythematosis, titers of anti-nuclear, anti–
and research into the use of IVIg in the Similarly, the presence of T cells and double-stranded DNA, anti–Sjögren’s
appropriate patient population. abnormalities in T cell function are also syndrome–related antigen A (SSA), and
associated with parenchymal lung disease anti-SSB antibodies decreased after treatment
(31–37). As an example, T cell polarization with IVIg. Furthermore, those patients
Mechanism of Action to a Th2 phenotype has been associated demonstrating a clinical response were
with the presence of active ILD and worse more likely to have elevated levels of these
There is evidence that IVIg exerts pulmonary function in patients with autoantibodies before the initiation of IVIg
antiinflammatory and immunomodulatory scleroderma (34). Furthermore, in one treatment. Although causality between
effects through multiple mechanisms, study, lavage fluid from patients with autoantibodies and ILD in patients with
depending on the disease process being myositis-associated ILD demonstrated an connective tissue disease has not been securely
treated: modulation of macrophage Fc increased number of lymphocytes in addition established, it is conceivable that, by inhibiting
receptor expression and function; alteration to an increase in T cell clonality when autoantibodies and the subsequent immune
of T cell and B cell function; inhibition compared with healthy control subjects (31). response, IVIg therapy could lead to a
of pathogenic autoantibodies; inhibition of In patients with chronic inflammatory decrease in pulmonary inflammation.
inflammatory cytokines, chemokines, demyelinating polyneuropathy, there is
or neurodegenerative molecules; and evidence that IVIg might regulate T cell IVIg Down-Regulates the Expression
inhibition of complement activation clonality and function by reducing the of Chemokines
(Table 1) (10, 27). Given that aberrant oligoclonal expansion of T cell receptors in A number of inflammatory cytokines
immune response and heightened both the CD41 and CD81 populations (38). have been implicated in the development
inflammation are hallmarks of ILD, IVIg As such, the ability of IVIg to influence the of ILD. For instance, serum levels of IL-6,
could potentially alter the course of function of immune cells implicated in IL-8, TNF-a, and IFN-g–induced protein
pulmonary disease through some of pulmonary inflammation might make it an 10 were all elevated in patients with
these mechanisms. effective immunomodulatory agent for the myopathy-associated ILD compared with
treatment of ILD. myopathy control subjects that did not
IVIg Regulates Immune Cells have pulmonary involvement, and these
Abnormalities in both innate and adaptive IVIg Interacts with Autoantibodies levels decreased after immunosuppression
immunity have been implicated in the The presence of specific autoantibodies (47). Furthermore, in vitro studies, animal
development of ILD, and there is predicts the development of ILD in a variety models, and human research indicate that
growing evidence that IVIg may possess of connective tissue diseases. Antibodies transforming growth factor (TGF)-b is
antiinflammatory properties through an targeting citrullinated proteins are involved in promoting epithelial damage,
ability to alter the function of immune associated with the presence of ILD in activation and proliferation of
effector cells. Lavage fluid from patients patients with rheumatoid arthritis (39, 40), myofibroblasts, and the subsequent
with fibrotic lung disease demonstrates whereas antibodies against ribonucleoprotein, development of pulmonary fibrosis (48, 49).
topoisomerase I (Scl-70), and transfer There is evidence that IVIg may exert its
RNA synthetases are associated with the immunomodulatory effects by decreasing
Table 1. Intravenous Ig mechanisms of presence of ILD in other connective tissue both circulating levels and tissue expression
action diseases, including systemic sclerosis, of various inflammatory cytokines,
systemic lupus erythematosis, and the chemokines, chemokine receptors, and
Mechanisms inflammatory myopathies (39–44). Igs in adhesion molecules, including: IFN-a, IL-1a,
IVIg preparations can bind the idiotype IL-6, IL-10, granulocyte/macrophage
Inhibition of pathogenic autoantibodies of autoantibodies. For example, F(ab9)2 colony–stimulating factor, and TGF-b
(27, 45, 46, 82, 83) fragments have demonstrated a high (45, 46, 50–53). In a murine model of
Modulation of macrophage Fc receptor
expression and function (30).
frequency of binding to the variable region scleroderma using subcutaneous injections
Inhibition of inflammatory cytokines, of naturally occurring IgG and IgM of bleomycin, the administration of IVIg
chemokines, or neurodegenerative autoantibodies secreted from B cell lines inhibited both the development of fibrotic
molecules (45, 46, 50–53) of healthy patients. In addition, the skin changes and the expression of TGF-b1
Inhibition of complement activation (84–87) antibodies in IVIg have demonstrated (51). Furthermore, in a study involving
Alteration of T cell and B cell function (38, 88)
in vitro neutralization of autoantibodies patients with DM, monthly IVIg treatments

Perspectives 1683

were associated with decreased expression initiation of both cyclosphosphamide and IVIg was 41.6%, similar to that of those
of muscle TGF-b1 mRNA, and this effect was IVIg. Unfortunately, it is impossible to patients receiving either cyclophosphamide
most pronounced in those demonstrating a discern the separate contribution that each or azathioprine, but higher than those
clinical response to therapy (50). Given that of these agents made to his clinical receiving mycophenolate or methotrexate.
inflammatory cytokines, and in particular, improvement, as cyclophosphamide itself However, the study was retrospective, the
TGF-b, have been implicated in the is a potent immunosuppressant and may number of patients in each of the other
development of pulmonary fibrosis (48, 49), have been solely responsible for the noted treatment groups was small (ranging from
the ability of IVIg to alter the expression clinical improvement. 2 to 23), and the severity of ILD in each
and circulating levels of such cytokines may Diot and colleagues (66) describe a of the groups was not reported (70).
have implications for its use in the treatment man with PM-associated ILD who failed to Additional studies and case series focusing
of ILD. respond to high-dose steroids, with further on myositis-related ILD have reported only
clinical worsening after a dose of a handful of other patients that have
cyclophosphamide. However, after three received IVIg (41).
The Use of IVIg as Adjunct monthly courses of IVIg, there was a
Treatment for Myositis- marked improvement in both muscle and
Associated ILD pulmonary function, as measured by total IVIg as Adjunct Therapy for
lung capacity and diffusion capacity for Other Forms of ILD
The notion of using IVIg to treat ILD carbon monoxide. The authors also
originated from observations involving its reported regression of fibrotic changes seen Published evidence supporting the use of
utility in the treatment of DM and PM, two on computed tomography (CT) scan, IVIg in myositis-associated ILD remains
conditions associated with a high incidence although the comparative images were not limited, and there are even fewer published
of pulmonary involvement. Over the past published. In addition, Bakewell and Raghu cases involving the treatment of other forms
few decades, numerous case reports, larger (67) published another case of severe of ILD. Matsubara and colleagues (71)
case series, and retrospective studies focusing PM-associated ILD without clinical reported on a woman with common
on muscle strength, creatinine kinase improvement after high-dose steroids, but a variable immunodeficiency-associated
levels, and skin lesions have described a significant improvement in symptoms and lymphoid interstitial pneumonia who was
favorable response to IVIg therapy in patients diffusion capacity for carbon monoxide treated successfully with a combination of
with severe myositis refractory to traditional after IVIg 2 g/kg monthly for 3 months. IVIg and steroids. The authors noted a
immunosuppression (24, 54–63). The initial CT scan demonstrated ground significant radiographic improvement,
Subsequently, randomized trials have glass opacities with subtle honeycombing although the benefit of IVIg remains
demonstrated the ability of IVIg to improve consistent with nonspecific interstitial unclear, as steroids have traditionally been
the rash, muscle strength, and neurological pneumonia. These findings resolved used as effective monotherapy for the
symptoms in patients with steroid-resistant completely, and, 2 years after therapy, the treatment of lymphoid interstitial
myositis (25, 26). patient still had no supplemental oxygen pneumonia. Another group reported the
ILD frequently complicates both requirement. case of a woman with CT findings
PM and DM, and its presence is associated Suzuki and colleagues (68) conducted consistent with NSIP in the setting of a
with increased morbidity and mortality a review of five patients with refractory myositis/systemic sclerosis overlap
(4, 64). Although IVIg seems to be effective and rapidly progressive ILD in association syndrome and a positive anti–PM-Scl
at treating the muscular manifestations of with either PM or amyopathic DM. Each antibody. After a flare of her muscular
DM, it is unclear whether the pathological patient presented with treatment failure disease, she was also noted to have
mechanisms leading to myopathy are also despite high-dose prednisone and progression of her ILD on CT imaging
responsible for the concurrent pulmonary cyclosporine, and, in each case, CT imaging with a FVC of 53% predicted. She was
disease, or if IVIg would also be effective demonstrated ground glass opacities or treated with a combination of monthly IVIg
at treating ILD in these patients. Over consolidations without the presence of and azathioprine, and, after six infusions,
the past 10 years, emerging anecdotal honeycombing. After a course of IVIg her FVC normalized and the subpleural
evidence has suggested that IVIg might (0.4 g/kg/d for 5 d), two patients survived, ground glass opacities and septal thickening
be contributing to the pulmonary and two had an initial positive response, completely resolved (72).
improvement seen in patients receiving followed by a subsequent decline and death. More recently, IVIg has been used
this form of immunosuppression for Although, at first glance, this outcome may as adjunct therapy in the treatment of
inflammatory myositis with associated ILD. seem disappointing, the rapidly progressive idiopathic pulmonary fibrosis (IPF)
Murota and colleagues (65) described form of ILD in patients with idiopathic flares. Donahoe and colleagues (73)
the case of a man with DM and ILD myopathy often carries a dismal prognosis, reported 11 consecutive cases of acute
in a radiographic pattern consistent with with reported 6-month mortality rates IPF exacerbations treated with plasma
nonspecific interstitial pneumonia. ranging from 60 to 72% (64, 69). exchange and rituximab, and these patients
Although his pulmonary disease progressed In a review of 197 patients with either had significantly better mortality rates
despite therapy with steroids and DM or PM, of which 69 had associated and subsequent pulmonary function than
cyclosporine, there was a significant ILD, a combination of IVIg and historical control subjects. The last four
decrease in dyspnea, oxygen requirements, corticosteroids was used in 36 cases. patients in the study also received IVIg
and radiographic abnormalities after the The mortality rate among those receiving therapy, and they demonstrated a more

1684 AnnalsATS Volume 13 Number 10 | October 2016


prolonged response than those receiving infection (75). It is postulated that IVIg may Table 2. Intravenous Ig side effects
plasma exchange and rituximab alone. be less immunosuppressive than these
However, these same patients also received traditional agents, and therefore carry a Side Effects
additional plasma exchange sessions. lower infection risk.
As such, although IVIg may have worked Furthermore, IVIg is generally well Common side effects
either alone or synergistically with the tolerated (Table 2), with minor side effects, Headache
baseline therapy to mitigate autoantibody such as headache, fever, nausea, or Fever
rebound, it is also possible that the myalgias, occurring in 0.5–7.3% of patients. Chills
more enduring response of the last four More serious side effects, such as DVT, Myalgias
patients was simply the result of having stroke, or aseptic meningitis, are seemingly Arthralgias
received addition plasma exchange rare (76, 77). Wittstock and colleagues (76) Rash
sessions. prospectively analyzed 117 patients with Pruritis
In another small, prospective study, various neurological diseases who received Hypertension
10 patients with progressive IPF received IVIg a combined total of 1,361 courses of IVIg Rare side effects
for either 5 consecutive days (5-day group), therapy. In their study, deep venous Aseptic meningitis
or once monthly for 5 consecutive months thrombosis occurred in two patients (1.7%), Deep venous thrombosis
(5-month group), with a cumulative dose with headaches, fevers, or chills occurring Stroke
Acute kidney injury
totaling 2 g/kg in both groups. In the 5-day in eight patients (6.8%). Four patients Anaphylaxis*
group, respiratory symptoms were improved (3.4%) reported either urticarial or palmar
in two patients and stable in the other itching, and these symptoms lasted an See References 46, 76, and 77.
four; although the vital capacity initially average of 2 weeks. They calculated an *Risk is increased in patients with underlying IgA
improved in five of six patients, this effect overall adverse event rate of 4% of
waned after 3 months. In the 5-month group, treatment courses, and no patients had a
symptoms were improved in two out of four permanent termination of therapy. In our
patients; vital capacity increased in three experience, the development of allergic Current Use and
patients; percent diffusion capacity for carbon reactions (itching, rash) after repeated Future Directions
monoxide increased in three patients; and infusions can be ameliorated by changing
HRCT abnormalities were improved in two the brand of IVIg, slowing the infusion rate, As previously discussed, evidence
patients. In contrast to the 5-day group, these or prehydrating with normal saline; a supporting IVIg for the treatment of ILD
changes were sustained at 6 months, and discontinuation of therapy is rarely is limited to case series and anecdotal
there was a rapid decline in pulmonary necessary. reports. As such, it remains largely
function test parameters after the cessation of experimental, and has been used
IVIg (74). The dose of IVIg used in this primarily as salvage therapy when
study was significantly lower than that Challenges to the Use of IVIg in traditional immunosuppression has
used to treat other inflammatory disorders, the Treatment of ILD either failed or been poorly tolerated.
where 2 g/kg is typically infused on a Multiple trials have already demonstrated
monthly basis. As such, although the results Despite its relatively favorable side-effect the efficacy of IVIg in the treatment of
of such a small study should not justify the profile, there are currently several inflammatory and autoimmune disorders,
use of IVIg in the treatment of IPF, they drawbacks to the use of IVIg in the treatment although, to date, there is no conclusive
should spark interest in larger, randomized, of ILD (Table 3). Although the treatments
controlled trials. are monthly, they are administered over
3–5 days and require intravenous access.
Table 3. The pros and cons of
For some patients, this may prove
intravenous Ig therapy in the treatment of
Possible Advantages to Using logistically difficult. Furthermore, if
interstitial lung disease
IVIg in the Treatment of ILD repeatedly obtaining intravenous access is
challenging, the placement of an infusion
IVIg has yet to be established as an port may be necessary. In addition, IVIg Pros and Cons
appropriate adjunct therapy for ILD. therapy remains costly. For example, a
However, if future studies demonstrate dose of IVIg for a 70-kg patient (2 g/kg) Pros
Alternative mechanisms of action compared
convincing evidence of its efficacy, then its has an average cost ranging from $14,000 with traditional immunotherapy
monthly administration and favorable side to $21,840 per month; conversely, the Less immunosuppression and risk of
effect profile would make IVIg an attractive monthly cost for a standard dose of infection compared with traditional
option for patients with refractory disease. azathioprine, mycophenolate, or oral immunotherapy
Traditional immunomodulatory agents, cyclophosphamide ranges from $118 to Favorable side-effect profile
Proven safe and effective for the
such as corticosteroids, methotrexate, $1,542 (78–81). Finally, experience with IVIg treatment of various other disorders
azathioprine, mycophenolate, and for the treatment of ILD remains relatively Cons
cyclophosphamide, are associated with limited, and, to date, no convincing data Expensive
significant side effects and toxicity, supporting its use in this context have been Requires serial visits to an infusion center
Currently no adequate data to support its use
including an increased risk of opportunistic published.

Perspectives 1685

evidence to support its routine use in the radiographic improvement, and quality of limited reports suggesting the utility of IVIg
treatment of ILD, regardless of the life scores being predefined outcomes. in the treatment of various forms of ILD.
underlying cause. However, the need for However, although IVIg is relatively well
alternative therapies in a subset of patients tolerated, it is much more expensive than
with ILD, combined with the favorable Conclusions traditional therapies, and there are currently
safety profile of IVIg, makes the use of this not adequate data to support its routine use
agent an attractive topic for future clinical IVIg has been used for decades to treat a in this context. As such, clinical trials are
trials. As such, the true efficacy of IVIg wide array of infectious, inflammatory, and necessary to determine if IVIg has a role in
should be determined and compared with autoimmune conditions, and its mechanism the treatment of ILD. n
more traditional forms of of action likely varies in conjunction with
immunosuppression, with steroid dose the disease being treated. In recent years, Author disclosures are available with the text
reduction, pulmonary function tests, there has been anecdotal evidence and of this article at

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1688 AnnalsATS Volume 13 Number 10 | October 2016