Immunosuppressive Therapies Used for ILDs: Comparison
Please note this is a comparison between Version 1 by Said Chaaban and Version 3 by Dean Liu.

There are about 200 different types of interstitial lung disease (ILD), and a crucial initial step in the assessment of a patient with suspected ILD is achieving an appropriate diagnosis. Some ILDs respond to immunosuppressive agents, while immunosuppression can be detrimental in others, hence treatment is based on the most confident diagnosis with consideration of a patient’s risk factors.

  • interstitial lung disease
  • immunosuppressants
  • pulmonary fibrosis

1. Steroids

Steroids have multiple anti-inflammatory and immunosuppressive effects, and can affect any immune cell [1][13]. The mechanisms by which steroids exhibit immune suppressive effects include the inhibition of macrophage differentiation and the synthesis of proinflammatory prostaglandins and leukotrienes, interleukin 1, interleukin 6, and tumor necrosis factor [1][13]. They also inhibit the tumoricidal and microbicidal functions of activated macrophages [1][13]. Additionally, steroids prevent neutrophils from adhering to endothelial cells and hinder the release of lysosomal enzymes, respiratory burst, and chemotaxis to the area of inflammation [1][13]. All lymphocyte subpopulations are susceptible to marked lymphopenia secondary to glucocorticoids, which also prevent T-cell activation by blocking interleukins 2, 3, and 4 [1][13]. This also affects the maturation of T lymphocytes and immunosuppresses the formation and operation of dendritic cells [1][13]. Corticosteroids can increase the risk of infection in a dose-dependent manner as studies suggest that there is a dose-dependent effect on the immune system [2][14]. T lymphocyte counts are decreased at dosages of 2 mg/kg (CD4+ > CD8+), and at higher doses (>2 mg/kg) there is inhibition of lymphocyte activation and the B cell production of antibodies [2][14].
The typical dosage of prednisone for immunosuppression in the ILD patient is on average 0.5 to 1 mg/kg ideal body weight per day for four weeks, followed by 30 to 40 mg/day for 8 weeks. If patients respond and/or stabilize, then the dosage is slowly tapered, with the aim to reach a minimum (such as 5 mg) every other day, with a goal to discontinue use after a year. Treatment may be for a longer period, with a range of 17.4 ± 12.1 months [3][4][15,16]. The precise duration or even whether there is a need for indefinite treatment has not been described. Additionally, there is a lack of consensus with regards to the optimal timing to add a cytotoxic agent. The addition of a steroid sparing agent has been described at diagnosis, with progression or if the patient is deemed dependent on corticosteroid therapy [3][15].
The risk of infection increases with dosage and treatment duration, but tends to stay low in patients exposed to low doses, even with high cumulative dosages [2][14].
Most of the available information about the risk of infections associated with corticosteroids comes from randomized controlled trials and observational studies (both population-based and single/multicenter) [1][13]. Unfortunately, most of these studies are limited by the small sample size, making it difficult to interpret studies and harder to extrapolate results to a larger population. Additionally, the underlying disease itself may contribute to a decline in immunity, and patients may be on other immunosuppressive drugs; thus, identifying a direct causal relationship between studies and the risk of infections with steroids is difficult [5][17].

2. Steroid Sparing Agents and Combination Therapy

Treatment of many of the interstitial lung diseases is becoming challenging and in many cases combination therapy is needed to treat these patients [6][38]. A recent large case series of patients with CTD-ILD demonstrates a tendency toward disease stabilization and possible improved lung function as well as the ability to significantly reduce corticosteroid dosing with combination therapy [6][38]. Cytotoxic agents are typically combined with corticosteroids with the aim of controlling the disease and reducing the corticosteroid dose to help avoid side effects [7][2]. Which agent and combinations of agents are used, the duration of treatment, and the timing of selected agents is based on expert opinion confined to case series and uncontrolled clinical trials rather than guidelines and recommendations [8][39].
The management of the patient with CTD-ILD usually targets the immune system, which is associated with the production of autoantibodies associated with CTD. Azathioprine was examined in three retrospective trials in patients with CTD-ILD and was shown to have similar efficacy compared to mycophenolate with the stability of lung function testing [8][9][39,40].
Multiple randomized controlled trials in systemic sclerosis associated with ILD note that cyclophosphamide compared to placebo is tolerable, and mycophenolate is non-inferior [9][10][40,41]. In the SCENSIS trial, patients who were on mycophenolate alone or in combination with nintenadib witnessed a smaller decline in lung function testing compared to those who were on mycophenolate alone [11][42]. Tociluzimab and Rituximab have shown promising results in the treatment of systemic sclerosis with ILD [9][40]. The use of combination therapy is a harbinger of advanced interstitial disease, which further increases the risk of infection. 

It is important to emphasize that most of the literature used  in this review is extrapolated from other diseases that utilize the same therapies that have been described in ILD. There is very scarce data on bacterial infection risk in ILD patients who are on immunosuppression therapy. There also may be a confounding risk of the underlying disease affecting the risk for bacterial infection that cannot be elucidated without more trials.

Researchers reviewed the immunosuppressants that have been used in ILD, excluding sarcoidosis management, and point out their risk of bacterial infections in the following sections.

We hereby review the immunosuppressants that have been used in ILD, excluding sarcoidosis management, and point out their risk of bacterial infections in the following sections.

2.1 Azathioprine

Azathioprine (AZA) leads to myelosuppression and to the inhibition of B and T cell proliferation. Patients with leukopenia secondary to AZA are susceptible to bacterial infections [2][12][14,43]. In a retrospective trial, Boerner et al. show that 20% (11/56) of patients suffered from an infection, however only 5% (3/56) had to discontinue treatment secondary to infection [9][40]. In a larger case control study, which included 23,000 patients with rheumatoid arthritis, an increased risk of infection with the use of AZA compared to MTX is described. Patients who were taking AZA show a moderate to increased risk of severe infections, with 20% (52/259) of patients exposed suffered from pneumonia [13][25]. Another study described that AZA is associated with 12% (3/25) risk of infection with otitis media, necrotizing pneumonia and cellulitis described [12][43]. These data indicate that the risk of bacterial infection is significant in patients who are treated with AZA.

2.2 Mycophenolate Mofetil

Mycophenolate, an inosine monophosphase dehydrogenase inhibitor that acts by decreasing T and B cell proliferation via a decrease in purine synthesis, leads to leukopenia [2][14][14,44]. In a study by Dheda et al. in which they treated patients with systemic sclerosis and ILD, Mycophenolate was associated with a nearly 5% risk of infection. However, it should be noted that a high percentage (94.4%) of patients where this risk was described were also concomitantly treated with prednisone (mean dose 8.22 mg/day) [14][44]. Kingdon et al. retrospectively studied the safety of mycophenolate in biopsy-proven lupus on 13 patients. Most patients were on concomitant steroids. In their cohort, 23% (3/23) of patients had infections. Infections described were salmonella gastroenteritis, staphylococcal abscess that required drainage, and respiratory failure [15][45]. Mycophenolate use in patients with scleroderma ILD is also associated with the risk of respiratory infection [10][41]. Overall, the data on mycophenolate and infections are scant, as most of the studies include patients who were on a combination of steroids and mycophenolate, making it difficult to ascertain the effects of the individual agents. Further studies are needed to define mycophenolate and infection risk.

2.3 Cyclophosphamide

High-dose cyclophosphamide has recently been used in the treatment of ILD, especially those resulting from an autoimmune mechanism [16][46]. The use of cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia, and anemia), bone marrow failure, and severe immunosuppression, which may lead to serious and, sometimes, fatal infections. Neutropenia and lymphopenia associated with the use of cyclophosphamide can lead to an increase in the susceptibility to infection, mainly gram-positive and gram-negative infections [2][14]. Few studies provide details of infection occurrence in patients receiving cyclophosphamide. Sehgal et al. report that significant numbers of patients on cyclophosphamide developed neutropenia (96%), of whom 68% developed clinical infectious complications [16][46]. The majority of the bacterial infections described include streptococcus, staphylococcus, enterococcus, and C difficile. The risk of infection with the use of cyclophosphamide is related to neutropenia in addition to the underlying disease [17][47].

2.4 Rituximab

Rituximab is a chimeric human monoclonal antibody that is directed against the CD20 antigen on B lymphocytes [18][48]. As a result of binding to CD20, B lymphocytes, with the exception of plasma cells, are depleted through complement and/or antibody-dependent cellular cytotoxicity [2][14]. B-cell depletion lasts for 6 to 9 months or longer, and is associated with possible hypogammaglobulinemia [2][14]. Not only that, but after the depletion of the B cells, the new B cells that are produced are immature rather than memory B cells. The delayed development of memory B cells lasts for years following the last injection of Rituximab [19][49]. If the hypogammaglobulinemia is severe, then the patient is at risk for bacterial sinusitis and pneumonia [2][14]. Patients who had higher levels of IgG levels at baseline had less risk for infections. Thus, it has been proposed that providers consider IV Ig at levels of <5 g/L prior to Rituximab infusion, especially in patients who have a history of serious infection [19][49].
The risk of severe infections increases within two months from the first dose. Patients who were at increased risk and had serious infections were older, had concomitant diabetes mellitus, lower CD 19 counts, lower immunoglobulin levels, renal failure, and were continued on corticosteroids (>5 mg/day). Infections are mostly bacterial and the most common bacterial pathogens were pseudomonas Aeruginosa, Escherichia coli, and staphylococcus aureus [19][49]. Patients who are vaccinated against S. pneumoniae have a lower risk of infection [19][49]. Pneumococcal vaccinations 3–4 weeks before the first dose of Rituximab is preferred and having all live attenuated vaccines updated is also recommended [19][49].

2.5 Abatacept and Tociluzumab

Abatacept, approved for the treatment of moderate to severe RA, is a fusion protein made of cytotoxic T-lymphocyte-associated protein 4 and a crystallizable fragment portion of IgG1 that leads to the inhibition of T-lymphocyte co-stimulation. It is mainly used in patients that have not had a positive response to TNF inhibitors and disease-modifying antirheumatic drugs (DMARDs). There is growing evidence regarding its utility in RA-ILD. Compared to other therapies, it carries a good safety profile and is associated with a low risk for serious infections [20][50]. The risk of hospitalized infections and TB were not different when compared to patients receiving DMARDS [21][51]. More studies investigating infections associated with abatacept are needed to be able to elucidate its overall risk for bacterial infection [20][50].
Tocilizumab is an anti-IL 6 monoclonal antibody that has been used in the treatment of CTD ILD and has been approved by the Food and Drug Administration for the treatment of systemic sclerosis-associated ILD [22][52]. Infections documented with use of Tocilizumab include pneumonia, infective tenosynovitis, sepsis, and otitis media [23][53]. Future studies will inform about the risks related to infections with the use of Tocilizumab.

3. Prophylaxis

A mitigation strategy to help decrease the risk of some bacterial infections while patients are on immunosuppressive therapy is vaccination [24][25][54,55].
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