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Interstitial lung disease in dermatomyositis and polymyositis: Treatment

Interstitial lung disease in dermatomyositis and polymyositis: Treatment
Authors:
Paul F Dellaripa, MD
Sonye K Danoff, MD, PhD
Section Editors:
Ira N Targoff, MD
Kevin R Flaherty, MD, MS
Deputy Editors:
Paul Dieffenbach, MD
Philip Seo, MD, MHS
Literature review current through: Sep 2023.
This topic last updated: Jul 28, 2023.

INTRODUCTION — Interstitial lung disease (ILD) is a major cause of morbidity and mortality in dermatomyositis (DM) and polymyositis (PM). The histopathologic findings of ILD in DM and PM include nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, and acute interstitial pneumonia. (See "Idiopathic interstitial pneumonias: Classification and pathology".)

The treatment of interstitial lung disease associated with DM and PM will be reviewed here. The clinical manifestations, diagnosis, and differential diagnosis of interstitial lung disease in DM and PM and the management of myositis in DM and PM are discussed separately. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis" and "Initial treatment of dermatomyositis and polymyositis in adults" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults" and "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis".)

APPROACH TO THERAPY — When determining the need for treatment in patients with ILD due to PM or DM, we assess the severity of respiratory impairment and the rate of progression.

Overview — The natural history of ILD due to PM or DM varies broadly, thus some patients who are asymptomatic or follow a slowly-progressive course may not require specific therapy [1]. While formal guidelines are not available, we observe patients without treatment in the setting of the following characteristics: minimal to no dyspnea on exertion, <10 percent involvement on high resolution computed tomography, forced vital capacity >75 percent of predicted, and/or diffusing capacity for carbon monoxide (DLCO) >65 percent of predicted and no evidence of progression over 6 to 12 months [2]. Immunosuppressive therapy is generally indicated for patients with a greater degree of respiratory impairment, more pronounced abnormalities on imaging or pulmonary function tests, or for those with specific high-risk antibodies, including antimelanoma differentiation-associated gene 5 (MDA5) or antisynthetase antibodies.

For patients with DM or PM who are already receiving immunosuppressive therapy for their myositis, it is essential to exclude infection or drug-induced pulmonary toxicity as causes of lung disease. In addition, patients with DM and PM are at increased risk of malignancy, including cancers involving the lungs [3]. Thus, it is prudent to ascertain that the patient has undergone appropriate cancer screening. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Malignancy in dermatomyositis and polymyositis", section on 'Approach to screening'.)

By contrast, for some patients, the pulmonary involvement may be the first and, sometimes, the only clinically apparent manifestation associated with myositis-specific (MSA) or myositis-associated antibodies (MAA).

The choice of therapy for PM/DM-associated ILD may differ from the regimen used to treat the underlying inflammatory myopathy. The response of muscle and skin involvement does not correlate with or predict the response of ILD to a given therapeutic regimen [2]. (See "Initial treatment of dermatomyositis and polymyositis in adults" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

The degree of respiratory impairment and the type of ILD will guide the approach to therapy (table 1). The majority of patients with DM or PM who develop ILD have histopathologic and radiographic patterns of nonspecific interstitial pneumonia (NSIP) or organizing pneumonia (OP) [2,4,5]. Usual interstitial pneumonia (UIP) or lymphoid interstitial pneumonia (LIP) may be seen infrequently. Occasionally, acute interstitial pneumonia (AIP; diffuse alveolar damage [DAD]) develops superimposed on NSIP, OP, or UIP [1,6] (see "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Determining the type of ILD'). A similar spectrum of radiographic patterns is seen in patients with ILD as the primary manifestation of MSA or MAA antibodies.

The following sections describe considerations for the specific types of ILD:

Nonspecific interstitial pneumonia — The decision to initiate treatment of NSIP in patients with DM or PM is usually based on the severity of dyspnea and pulmonary function test (PFT) abnormalities and evidence of disease progression by symptoms, PFTs, or imaging. Initial therapy for NSIP due to PM or DM is usually systemic glucocorticoids; additional immunosuppressive therapy is often added as described below. (See 'Adding a second agent' below.)

Organizing pneumonia — For patients with a clinical and histopathologic pattern of organizing pneumonia (previously known as bronchiolitis obliterans organizing pneumonia [BOOP]), glucocorticoid dosing and tapering would follow that for cryptogenic organizing pneumonia (COP); however, an additional immunosuppressive agent is typically needed as glucocorticoids are tapered. The choice of agent must take into account both the treatment for OP and the underlying myopathy. The treatment of COP is discussed separately. (See "Cryptogenic organizing pneumonia", section on 'Treatment' and 'Adding a second agent' below.)

Other types of ILD — Less commonly, patients with DM or PM will develop other patterns of ILD, such as UIP, AIP, or LIP. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Histopathology'.)

●Usual interstitial pneumonia – Generally, patients with radiographic or histologic UIP in the setting of DM or PM remain stable or progress slowly, but they can occasionally develop more rapidly progressive respiratory failure. Although patients with UIP in the setting of idiopathic pulmonary fibrosis do not benefit from systemic glucocorticoids and immunosuppressive therapy, these interventions may be effective in slowing disease progression in myositis-associated ILD with a UIP pattern. Based on the INBUILD trial of nintedanib in progressive fibrosing ILD, this agent may be an additional option for patients who fail to respond to immunosuppression [7,8]. However, data are limited by the small number of myositis patients were included in this study. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'.)

●Acute interstitial pneumonia – AIP is occasionally the initial ILD in patients with DM or PM, presenting as a rapidly progressive ILD, or can be superimposed on another ILD. The treatment of AIP is discussed separately. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)", section on 'Treatment'.)

●Lymphoid interstitial pneumonia – The treatment of lymphoid interstitial pneumonia in the context of rheumatic disease is discussed separately. (See "Lymphoid interstitial pneumonia", section on 'Treatment'.)

INITIAL GLUCOCORTICOID THERAPY — Systemic glucocorticoids are the mainstay of treatment of ILD in patients with PM or DM, regardless of whether the predominant feature of the patient's illness is pneumonitis or myositis. The initial regimen is typically the same as that used for the myositis alone (eg, prednisone at a dose of 1 mg/kg ideal body weight per day, to a maximum daily dose of 60 mg).

For patients with impending respiratory failure due to rapidly progressive interstitial pneumonitis, high-dose intravenous glucocorticoids (eg, methylprednisolone 1 gram intravenous (IV) daily for three days) are typically used at the start of therapy in addition to a second immunosuppressive agent (See "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Systemic glucocorticoids' and "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Histopathology'.)

After one month, if the patient has improved based on symptoms, imaging, and pulmonary function tests, prednisone is usually tapered to 40 mg/day followed by a slow taper (eg, 10 mg every two weeks) until reaching 20 mg/day and then decreased to a taper of 2.5 mg every two weeks for a total duration of steroid therapy between four and six months, dependent on the response to therapy (see 'Assessing the response and duration of therapy' below). At the same time that steroids are being tapered, a steroid sparing agent is added.

It has been estimated that about 50 percent of patients with ILD and either DM or PM respond favorably to glucocorticoid therapy, although no controlled trials have been undertaken [9-11]. Clinical features suggesting a high rate of response to systemic glucocorticoids include:

●Younger age [10]

●PM rather than DM [12]

●Organizing pneumonia [13,14]

●Elevated serum creatine kinase (CK) levels [15]

●Ground glass or consolidative opacities rather than honeycombing on high-resolution computed tomography (HRCT) scan [11,16,17]

●A pattern of NSIP rather than usual interstitial pneumonia (UIP) on lung biopsy [11,18]

ADDING A SECOND AGENT — A second immunosuppressive agent (steroid sparing) is typically added to glucocorticoid therapy for ILD, in part to decrease side effects from prolonged exposure to high-dose glucocorticoids. (See "Major side effects of systemic glucocorticoids".)

Indications — The exact indications for a second immunosuppressive agent in ILD due to DM or PM have not been determined. Many experts, including us, add a second immunosuppressive agent without waiting for a response to glucocorticoid therapy or a failure of tapering, although this choice has not been evaluated in clinical trials [19,20].

The initiation of a second immunosuppressant is routinely performed in the following clinical settings:

●Impending respiratory failure – For patients with rapidly progressive disease leading to high oxygen requirements (>10 liters per minute) or need for ventilatory support, we recommend initiation of intravenous immune globulin in addition to high-dose intravenous glucocorticoids due to its rapid onset of action. We suggest adding another rapidly acting agent (eg, rituximab, cyclophosphamide, or tacrolimus) to this regimen to facilitate tapering off high-dose glucocorticoid therapy.

●Other symptomatic patients, on presentation – For patients with severe pulmonary disease on presentation, such as hypoxemia with mild exertion, a significant reduction in FVC (typically <70 percent predicted) or a diffusing capacity for carbon monoxide <50 percent predicted, we generally add a rapidly acting second immunosuppressant due to the risk of respiratory failure with further clinical decline.

For initial therapy of other symptomatic patients with less severe presentations, we suggest the addition of oral agents with fewer toxicities.

●Clinical worsening on glucocorticoid therapy – For patients who exhibit a decline in pulmonary function tests (PFTs) (>10 percent in FVC or 15 percent in DLCO) or worsening of symptoms despite systemic glucocorticoid therapy at typical doses, the addition of a second agent is preferable to increasing the dose of systemic glucocorticoids.

●ILD associated with melanoma differentiation-associated gene 5 (MDA5) antibody positivity or the antisynthetase syndrome – In patients with MDA5 disease or antisynthetase syndrome who present with pulmonary symptoms or abnormal PFTs, we use a second agent given the high frequency of progressive disease [21]. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Clinical features'.)

●Patients who are intolerant of effective systemic glucocorticoid doses – Patients who have responded to glucocorticoids but are unable to taper or are intolerant of adverse effects should begin a second immunosuppressant to facilitate tapering to glucocorticoid doses that do not cause short- or long-term adverse effects. (See "Major side effects of systemic glucocorticoids".)

Choice of agent — The choice of a specific agent (eg, azathioprine, mycophenolate mofetil, calcineurin inhibitors, or methotrexate) is guided by the severity of the patient's lung disease, the relative toxicity of the agents, the agent used to treat the underlying myopathy, and the experience of the treating clinician with the various agents. The evidence supporting the different choices comes from case series and case reports.

●For patients with impending respiratory failure due to rapidly progressive interstitial pneumonitis, we typically add cyclophosphamide or tacrolimus to intravenous immune globulin (IVIG) and then transition to mycophenolate after six months. Alternatively, some groups favor the use of rituximab in this setting.

●For patients with severe or progressing lung disease without impending respiratory failure who have not previously received a second agent, we suggest the use of a rapidly acting immunosuppressive agent (eg, cyclophosphamide, rituximab, IVIG, or tacrolimus) with transition to mycophenolate after stabilization (typically three to six months). We typically use cyclophosphamide or tacrolimus, but some groups favor the other agents.

●For patients with mild to moderate pulmonary disease, azathioprine or mycophenolate are both reasonable options; the comparative efficacy of these agents for treatment of DM/PM-associated ILD is not known, but appears to be comparable [18,22]. Mycophenolate would be favored for patients with a low level of thiopurine methyltransferase (TPMT). While the use of tacrolimus as an initial glucocorticoid-sparing agent has been reported [23], we typically reserve this agent for patients with progressive disease or lung disease associated with MDA5 antibody due to frequent toxicity. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Structure and metabolism' and "Pharmacology of cyclosporine and tacrolimus".)

●For patients with progression of ILD despite glucocorticoids and six to nine months of therapy with azathioprine or mycophenolate, we typically substitute one for the other and continue prednisone, although formal data to support this choice are lacking. Tacrolimus is an alternate choice or may be used for continued progression [24]. IVIG or rituximab may be needed if oral agents are unsuccessful at preventing progression.

Information about the individual agents used to treat ILD in DM or PM is provided in the sections that follow.

Azathioprine — Based upon data from case series, azathioprine is often effective in the treatment of ILD due to DM or PM [9,18,22]. It is not known if azathioprine is effective in patients with usual interstitial pneumonia (UIP) due to DM or PM. (See "Treatment and prognosis of nonspecific interstitial pneumonia" and "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Azathioprine' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

Before beginning azathioprine, patients may be screened for thiopurine methyltransferase (TPMT) deficiency; practice varies due to the expense of testing and low rate of TPMT deficiency. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacology and biologic effects'.)

Azathioprine is usually started at a dose of 50 mg/day, and a complete blood count (CBC) is obtained after one week to ensure that counts are stable. The daily dose is then increased incrementally by 50 mg approximately every week, following the CBC and serum aminotransferases and alkaline phosphatase (to monitor for idiosyncratic liver toxicity), until the desired response is seen or a maximal total dose of 2 to 3 mg/kg per day (generally not higher than 200 mg/day, even in large individuals) is reached. A lower dose is indicated in patients with renal insufficiency. Additional details about dosing and monitoring are provided separately.

Mycophenolate mofetil — Mycophenolate mofetil (MMF) is an inhibitor of lymphocyte proliferation that has been used in case reports and case series to treat ILD associated with DM and PM, scleroderma, and other rheumatic diseases [25-30]. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Mycophenolate mofetil' and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Mycophenolate mofetil'.)

MMF is usually initiated at a dose of 500 mg given twice a day. The target dose is typically 2 to 3 g/day, lower in patients with renal insufficiency. If MMF is not tolerated, typically related to diarrhea, mycophenolic acid may be substituted and may be better tolerated. Information about the dosing and potential side effects of mycophenolate mofetil is presented separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Calcineurin inhibitors — Tacrolimus and cyclosporine are occasionally used in patients with ILD, including a small number of cases refractory to other therapies [31-36]. Tacrolimus is generally preferred over cyclosporine for the treatment of DM/PM-associated ILD due to perceived greater efficacy, but further study is needed to determine its efficacy and safety relative to the other immunosuppressive agents.

●Among 54 patients with PM/DM ILD, 23 failed conventional therapy, and 18 of these patients subsequently received tacrolimus [35]. ILD improved in 17, and the mean dose of prednisone decreased by 81 percent at one year.

●In a retrospective series of 49 patients with previously untreated PM/DM-associated ILD, two treatment groups were compared: 25 patients received tacrolimus (1 to 3 mg/day adjusted to a trough level of 5 to 20 ng/mL) and prednisolone (0.8 to 1 mg/kg/day) with cyclophosphamide (9 patients) and/or glucocorticoid pulse (18 patients), while 24 patients in the comparison group received prednisolone (0.8 to 1 mg/kg/day) and a glucocorticoid pulse (10 patients), cyclophosphamide (2 patients), and/or cyclosporin (7 patients) [34]. The tacrolimus group experienced a longer event and disease progression-free survival, but PFT parameters were not different between the groups [36].

●In a separate series, 13 patients with the antisynthetase syndrome (12 with antibodies to Jo-1) and ILD were treated with tacrolimus for a mean duration of 51 months [31]. The following benefits were noted: a reduction in the mean prednisone dose by 67 percent and improvements in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the diffusing capacity for carbon monoxide (DLCO).

The side effects of cyclosporine and tacrolimus are similar. Trough tacrolimus levels are typically followed to mitigate the risk of side effects with target trough levels of 3 to 6 ng/mL. Nephrotoxicity is the most common and clinically significant adverse effect of both drugs, and hypertension, caused by renal vasoconstriction and sodium retention, generally develops within the first few weeks of therapy. Other potential adverse effects include neurotoxicity, metabolic abnormalities, infections, and an increased risk of malignancy. General guidelines for the use of tacrolimus and cyclosporine are presented separately. (See "Pharmacology of cyclosporine and tacrolimus" and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Calcineurin inhibitors'.)

Methotrexate — Although methotrexate is used commonly as a glucocorticoid-sparing agent in DM and PM, it has been historically used with caution in patients with ILD because of its potential to cause pneumonitis [37]. However, that risk appears to be small based on recent data examining pneumonitis in RA. (See "Methotrexate-induced lung injury" and "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

REFRACTORY DISEASE — For patients with progressive ILD despite the combination of glucocorticoids and one of the second agents listed above, the next step is generally to try an alternative second agent (eg, rituximab) or add a third agent. Prior to a change in therapy, we always reassess the patient for other possible explanations for deteriorating lung function, such as superimposed infection, drug-induced pneumonitis, pulmonary hypertension, and respiratory muscle weakness. The evaluation and treatment of pulmonary infection, drug-induced pneumonitis, pulmonary hypertension, and respiratory muscle weakness in patients with DM or PM are discussed in greater detail separately. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Respiratory muscle weakness'.)

Rituximab — Limited data from case series and case reports suggest benefit from rituximab, a B cell depleting monoclonal anti-CD-20 antibody, in patients with progressive ILD in patients with PM or DM, including antisynthetase syndrome [38-47]. One trial (RECITAL) showed rituximab to be similarly effective to cyclophosphamide in a mixed group of patients with connective tissue disease-associated ILD, including myositis [48]. The dosing of rituximab has not been standardized, although a common regimen is to administer two 1 g doses two weeks apart [49]. The use of rituximab to treat myositis in DM and PM is discussed separately. (See "Overview of biologic agents in the rheumatic diseases", section on 'Rituximab' and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

Intravenous immune globulin — A number of case reports and case series have suggested that intravenous immune globulin (IVIG) is effective for ILD associated with DM or PM [50-52]. Further data from trials of IVIG will be valuable to assess its role in treating myositis ILD (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

Cyclophosphamide — The use of daily oral or monthly intravenous cyclophosphamide has been described in case reports and small series of patients with ILD and PM or DM [53-57]. Due to its associated toxicities, it is usually reserved for patients with severe or refractory ILD. One series evaluated monthly intravenous cyclophosphamide (300 to 800 mg/m2 every four weeks) plus daily prednisone for progressive ILD in 17 patients with DM or PM [53]. All patients received at least six courses. Eleven of the 17 patients showed improvement in dyspnea. Six of the seven patients who required supplemental oxygen were able to discontinue its use. Twelve patients had improvements in forced vital capacity (FVC) of at least 10 percent. For the group overall, the mean FVC improved by 15 percent over baseline, from 68 to 83 percent predicted.

Information about dosing, monitoring, and preventing side effects during cyclophosphamide therapy is presented separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)

Cyclophosphamide is typically administered for six months and then transitioned to an alternate immunosuppressive agent (eg, azathioprine or mycophenolate) because of the risk of bladder cancer with longer courses of therapy. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Bladder toxicity'.)

CD19-targeted chimeric antigen receptor T cells — For patients with anti-Jo-1 positive disease refractory to other anti-inflammatory therapies, case reports have described induction of remission using chimeric antigen receptor (CAR) T cells targeted against B cells and plasmablasts via CD19 [58,59]. While promising, this therapy remains restricted to specialized centers (in the context of clinical trials) and is not yet widely available.

ILD ASSOCIATED WITH MDA5 ANTIBODY — Patients who are melanoma differentiation-associated gene (MDA)-5 antibody positive may present with rapidly progressive ILD that is refractory to conventional treatment with high-dose glucocorticoids, cyclosporine, tacrolimus, and cyclophosphamide [60-64]. The six-month survival rate in some studies is 40 percent despite the therapies described above [61]. We routinely initiate tacrolimus in newly diagnosed patients with MDA 5 and follow trough levels to reduce the risk of side effects, however, a combination of immunosuppressive therapies are often needed [65]. For patients whose disease continues to progress, additional therapies may include one or more of the following: (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Rituximab — A few case reports of patients with MDA5 antibodies describe improvement in ILD with rituximab after failure of other immunosuppressive therapies [66,67]. (See 'Rituximab' above.)

Tofacitinib — Response to the Janus kinase (JAK) inhibitor tofacitinib has been reported in patients with MDA5 positive ILD after failure of conventional immunosuppressive therapy [68-71]. In an open-label study, consecutive patients with MDA5 antibodies and ILD were treated with the JAK inhibitor tofacitinib (5 mg twice daily) and compared with historical controls [68]. At six months, survival in the tofacitinib group (18 patients) was 100 percent; survival among historical controls, who had been variably treated with glucocorticoid, cyclosporine, mycophenolate, cyclophosphamide, or azathioprine, was 25 of 32 patients (78 percent, p = 0.04). Improvement in the diffusing capacity for carbon monoxide and high-resolution computed tomography (HRCT) findings was also noted with tofacitinib. A retrospective case series of 61 patients (26 treated with tofacitinib) also suggested a survival benefit compared with tacrolimus-based therapy (56 versus 44 percent) [71].

Basiliximab — Basiliximab is a monoclonal antibody that blocks the alpha chain (CD25) of the interleukin-2 (IL-2) receptor complex, thus interfering with T lymphocyte replication and B lymphocyte activation. In a case series of patients with MDA5 antibody positive ADM and rapidly progressive ILD despite prednisone, cyclosporine, and, intravenous immune globulin (IVIG; in two patients), addition of basiliximab (two intravenous infusions of 20 mg every seven days) was followed by improvement in the HRCT findings and pulmonary function in three of four patients [72]. The fourth patient died of respiratory failure three days after the first infusion of basiliximab. Whether the respiratory improvement in three patients was due to addition of basiliximab or delayed response to treatment with prednisone, cyclosporine, and IVIG is not known.

Other therapies — A few reports have described responses to additional immunosuppressive therapies. A patient with MDA5 antibodies and rapidly progressive ILD despite high-dose prednisone, cyclophosphamide, and cyclosporine had continued deterioration until treatment was initiated with plasma exchange [73]. Another report suggested benefit to use of daratumumab, an antiplasma cell agent, weekly for four weeks in a patient who had deteriorated despite multiple agents, including cyclophosphamide, rituximab, tofacitinib, and anakinra [74]. Case reports have also suggested benefit in refractory cases with IVIG and polymyxin B fiber columns [50,75]. (See 'Intravenous immune globulin' above.)

LUNG TRANSPLANTATION — For appropriate candidates (eg, under age 70 and without comorbid illness) with severe or progressive lung disease, referral to a lung transplant center may be appropriate. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

In a small case series, five patients underwent lung transplants for inflammatory myositis-related ILD; three had bilateral transplants; and two had a single lung transplant [76]. The survival was 100 percent at one year and 75 percent at two and five years. Recurrence of ILD was reported nine months after a bilateral lung transplant in a 15-year-old girl with PM [77]. Successful lung transplantation has also been reported in a patient with amyopathic dermatomyositis [78].

ASSESSING THE RESPONSE AND DURATION OF THERAPY — Patients with ILD due to DM or PM need ongoing monitoring to adjust therapy based on the treatment response. The response to initial therapy should be assessed at four- to eight-week intervals or more often if the patient develops worsening symptoms. A favorable response includes a reduction in dyspnea and cough, radiographic clearing, and physiologic improvement, as assessed by forced vital capacity, total lung capacity, diffusion capacity for carbon monoxide, and both resting and exercise oxygen saturation. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Pulmonary function tests'.)

If the patient has had a favorable response after one month of therapy, the initial dose of glucocorticoids is tapered as noted above (see 'Initial glucocorticoid therapy' above), while another immunosuppressive agent is uptitrated. In patients whose ILD continues to improve or stabilizes with treatment, the prednisone dose is gradually tapered, aiming to reach 5 to 10 mg daily over the course of four to six months. Cessation of glucocorticoid therapy may be considered if the ILD remains stable and the patient does not require glucocorticoids for treatment of their myositis or skin disease.

Other immunosuppressive agents are typically continued for one to two years, though there is no consensus on the duration of treatment or how to taper therapy. If the ILD remains in remission or stable, the immunosuppressive agent may be tapered and, if the lung disease remains stable, discontinued. However, many patients require long-term immunosuppressive therapy. For these patients, the goal is to maintain control of disease, using a regimen with the least toxicity possible. Flares of DM and PM may occur at any time, although they often do in the context of tapering immunosuppressive therapy. Whenever dyspnea, cough, and fever develop or worsen, a re-evaluation for possible complications of therapy or alternative explanations for increased dyspnea should be performed. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

COMPLICATIONS — Among patients with ILD due to PM or DM, complications may occur due to the underlying ILD or to the treatment regimen.

Spontaneous pneumomediastinum — Spontaneous pneumomediastinum may develop in patients with ILD with DM or PM, particularly in those with amyopathic DM. This usually presents with acute onset of retrosternal chest pain with neck and face swelling due to subcutaneous emphysema. Some patients also complain of dyspnea. This is typically manifest on plain chest radiograph. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Spontaneous pneumomediastinum' and "Spontaneous pneumomediastinum in children and adolescents", section on 'Evaluation'.)

The treatment of spontaneous pneumomediastinum usually involves supportive care with rest, observation, and supplemental oxygen [79]. If the pneumomediastinum occurs in the context of newly diagnosed or progressive ILD, treatment of the underlying ILD is usually initiated or intensified, as described above [80,81]. (See "Spontaneous pneumomediastinum in children and adolescents", section on 'Management' and 'Adding a second agent' above and 'Refractory disease' above.)

Prevention of treatment related complications — The predominant complications of the therapies described above are opportunistic infections and glucocorticoid-related osteoporosis, cataracts, and adrenal suppression; appropriate prophylaxis can help to prevent some of these complications.

We suggest prophylaxis against Pneumocystis jirovecii for patients who are on a combination of high-dose glucocorticoid (eg, prednisone 20 mg/day or more). This suggestion is largely based on data from a retrospective study of 47 patients with DM [82]. More than 25 percent of the patients who did not receive prophylaxis developed infections, primarily Pneumocystis pneumonia. The choice of agents for prophylaxis is discussed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Prevention of other complications of chronic systemic glucocorticoid therapy is discussed separately. (See "Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

PROGNOSIS — The course of ILD in patients with DM or PM is not uniform [83]. The patterns that have been described include the following [84]:

●Fulminant disease with fever and rapid progression of radiographic changes and respiratory failure indicative of acute interstitial pneumonia (AIP). (See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)

●Acute symptomatic ILD with response to immunosuppression either with resolution or with periodic episodes or worsening.

●Indolent disease with slow progression both radiographically and clinically over a period of years.

●Asymptomatic lung disease that is detectable only by chest imaging or pulmonary function tests and does not progress.

In a case series, among 107 patients with ILD associated with PM/DM, 33 percent experienced resolution of ILD, 51 percent improvement, and 16 percent worsening; the overall mortality was 8 percent [83]. Among patients with inflammatory myositis and symptomatic ILD, mortality is primarily due to progressive pulmonary disease [9]. Notably, survival in myositis associated ILD is far better than would be predicted by the gender-age-physiology (GAP) index which is useful for prognosis in IPF and other forms of autoimmune ILD [85]. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Gender-Age-Physiology (GAP) model'.)

Prognosis is also affected by the specific type of ILD [83]. As an example, nonspecific interstitial pneumonia (NSIP) appears to have a prognosis similar to that of idiopathic NSIP with a five-year survival of 60 percent [18]. Patients with organizing pneumonia (OP, formerly called bronchiolitis obliterans organizing pneumonia) tend to have the best prognosis and response to treatment, while those with diffuse alveolar damage (DAD)/AIP have the worst [13].

The subset of patients with melanoma differentiation-associated gene-5 (MDA5) antibody or antisynthetase antibody positivity can present with particularly severe and progressive ILD [21,86-90]. A large retrospective cohort study of 226 patients with anti-MDA5 antibody-associated dermatomyositis found that concomitant antiRo52 autoantibodies were common (present in 64 percent) and were associated with a nearly four-fold increased risk for rapidly progressive ILD (49 versus 13 percent) [91]. In another anti-MDA5 positive cohort, age >50 years and LDH >400 IU/L at presentation were identified as risk factors for rapidly progressive ILD and mortality [92].

Other factors that predict a poor prognosis include older age, symptomatic ILD, and lower values for vital capacity and diffusing capacity [83,90,93]. With respect to radiographic findings, survival is best in patients whose ILD has a ground glass appearance, which is most indicative of cellular NSIP, and worst in those with reticular patterns or honeycombing, which are most often due to usual interstitial pneumonia (UIP) [14,17,83,94].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatomyositis and polymyositis" and "Society guideline links: Interstitial lung disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Polymyositis, dermatomyositis, and other forms of idiopathic inflammatory myopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overall approach – The approach to therapy of ILD associated with DM or PM is guided by the severity of respiratory impairment and the trajectory of progression. The majority of patients with DM or PM who develop ILD have a radiographic and histopathologic pattern of nonspecific interstitial pneumonia (NSIP) or organizing pneumonia (OP). (See 'Approach to therapy' above.)

●Asymptomatic patients – For patients with DM or PM who have radiographic ILD but are asymptomatic and have minimal reductions in lung volumes and diffusing capacity, we suggest a period of observation and serial assessment of clinical status and pulmonary function tests (PFTs). (See 'Overview' above.)

●Initial therapy for patients with symptomatic ILD

•Glucocorticoids – For patients with DM or PM who develop symptomatic ILD, we recommend initiating systemic glucocorticoids or increasing the dose if the patient is already taking glucocorticoids for the myositis (Grade 1B). The usual starting dose is oral prednisone at a dose of 1 mg/kg ideal body weight per day to a maximum daily dose of 80 mg. High-dose intravenous glucocorticoids (eg, methylprednisolone 1 gram daily for three days) may be used at the start of therapy for patients with impending respiratory failure due to rapidly progressive interstitial pneumonitis. (See 'Initial glucocorticoid therapy' above.)

•Additional therapies

-Those with impending respiratory failure – For patients with rapidly progressive disease leading to high oxygen requirements (>10 liters per minute) or need for ventilatory support, we recommend the addition of intravenous immune globulin (IVIG) to high-dose intravenous glucocorticoids (Grade 1C), due to its rapid onset of action.

We also suggest the addition of another rapidly acting immunosuppressive agent (eg, rituximab, cyclophosphamide, or tacrolimus) to this regimen to facilitate tapering off high-dose glucocorticoid therapy (Grade 2C). (See 'Indications' above and 'Choice of agent' above.)

-All others – For other patients presenting with symptomatic lung disease, we also suggest addition of a second agent to glucocorticoids (Grade 2C). (See 'Indications' above.)

For patients with severe pulmonary disease on presentation, such as hypoxemia with mild exertion, a significant reduction in FVC (typically <70 percent predicted) or a diffusing capacity for carbon monoxide <50 percent predicted, we generally choose IVIG, tacrolimus, or cyclophosphamide, with later transition to oral therapies with fewer toxicities. (See 'Adding a second agent' above and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

For other symptomatic patients with less severe presentations, we suggest addition of azathioprine or mycophenolate rather than other immunosuppressants (Grade 2C). (See 'Adding a second agent' above.)

●Failed initial response to therapy – For patients who have less severe disease, but are not responding to combination glucocorticoids and azathioprine or mycophenolate, we suggest first substituting one of the secondary agents for the other before trying a different oral agent (Grade 2C). Tacrolimus is one possible choice if the initial substitution fails. (See 'Adding a second agent' above and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Calcineurin inhibitors' and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Mycophenolate mofetil'.)

●Refractory disease – For patients who have progressive ILD despite treatment with glucocorticoids plus another oral immunosuppressive agent, we suggest treatment with rituximab or IVIG (Grade 2C). If the disease remains refractory after rituximab or IVIG therapy, the opposite therapy can be substituted. Data in support of these choices are limited. (See 'Refractory disease' above and "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

●MDA5-associated ILD – Patients who are melanoma differentiation–associated gene (MDA)-5 antibody positive may present with rapidly progressive ILD that is refractory to conventional treatment with high-dose glucocorticoids, IVIG, cyclosporine, tacrolimus, and cyclophosphamide. Often, a combination of immunosuppressive therapies, which may include rituximab, tofacitinib, or other agents, is needed. (See 'ILD associated with MDA5 antibody' above.)

●Immunosuppressive prophylaxis – For patients treated with the combination of high-dose prednisone (eg, prednisone 20 mg/day or more), we suggest prophylaxis against Pneumocystis jirovecii infection (Grade 2B). A reasonable regimen is a single-strength tablet of trimethoprim-sulfamethoxazole (80 mg/400 mg) each day. Other regimens for prophylaxis are discussed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc Miller, MD, who contributed to earlier versions of this topic review.

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Topic 4357 Version 43.0

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51 : Polymyositis associated with severe interstitial lung disease: remission after three doses of IV immunoglobulin.

52 : Long-term treatment with human immunoglobulin for antisynthetase syndrome-associated interstitial lung disease.

53 : Intravenous cyclophosphamide therapy for progressive interstitial pneumonia in patients with polymyositis/dermatomyositis.

54 : Cyclophosphamide treatment of interstitial pulmonary fibrosis in polymyositis/dermatomyositis.

55 : Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis.

56 : Successful treatment of dermatomyositis-related rapidly progressive interstitial pneumonitis with sequential oral cyclophosphamide and azathioprine.

57 : Intravenous cyclophosphamide improves functional outcomes in interstitial lung disease related to idiopathic inflammatory myopathies.

58 : CD19-targeted CAR T cells in refractory antisynthetase syndrome.

59 : CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome.

60 : Classification and management of adult inflammatory myopathies.

61 : Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study.

62 : Utility of anti-melanoma differentiation-associated gene 5 antibody measurement in identifying patients with dermatomyositis and a high risk for developing rapidly progressive interstitial lung disease: a review of the literature and a meta-analysis.

63 : Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis.

64 : RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease.

65 : Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis.

66 : A case of anti-MDA5-positive rapidly progressive interstitial lung disease in a patient with clinically amyopathic dermatomyositis ameliorated by rituximab, in addition to standard immunosuppressive treatment.

67 : Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis.

68 : Tofacitinib in Amyopathic Dermatomyositis-Associated Interstitial Lung Disease.

69 : [Response of dermatomyositis with lung involvement to Janus kinase inhibitor treatment].

70 : Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis.

71 : A Retrospective Analysis of Outcome in Melanoma Differentiation-Associated Gene 5-Related Interstitial Lung Disease Treated with Tofacitinib or Tacrolimus.

72 : Basiliximab may improve the survival rate of rapidly progressive interstitial pneumonia in patients with clinically amyopathic dermatomyositis with anti-MDA5 antibody.

73 : Successful treatment of plasma exchange for rapidly progressive interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis: A case report.

74 : Successful Rescue Therapy With Daratumumab in Rapidly Progressive Interstitial Lung Disease Caused by MDA5-Positive Dermatomyositis.

75 : Intravenous immunoglobulin for interstitial lung diseases of anti-melanoma differentiation-associated gene 5-positive dermatomyositis.

76 : Is lung transplantation a valuable therapeutic option for patients with pulmonary polymyositis? Experiences from the Leuven transplant cohort.

77 : Recurrent polymyositis-associated lung disease after lung transplantation.

78 : High-Emergency Lung Transplantation for Interstitial Lung Disease Associated With Anti-MDA5 Dermatomyositis: A Case Report.

79 : Spontaneous pneumomediastinum: a comparative study and review of the literature.

80 : Pneumomediastinum in interstitial lung disease associated with dermatomyositis and polymyositis.

81 : Persistent pneumomediastinum and dermatomyositis: a case report and review of the literature.

82 : Peripheral blood lymphocyte subset counts in patients with dermatomyositis: clinical correlations and changes following therapy.

83 : Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients.

84 : Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset.

85 : The ILD-GAP risk prediction model performs poorly in myositis-associated interstitial lung disease.

86 : Prognostic factors for myositis-associated interstitial lung disease.

87 : Factors Associated with Interstitial Lung Disease in Patients with Polymyositis and Dermatomyositis: A Systematic Review and Meta-Analysis.

88 : Prognostic factors of interstitial lung disease progression at sequential HRCT in anti-synthetase syndrome.

89 : Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum.

90 : A Systematic Review and Metaanalysis of Predictors of Mortality in Idiopathic Inflammatory Myopathy-Associated Interstitial Lung Disease.

91 : Coexistence of Anti-Ro52 Antibodies in Anti-MDA5 Antibody-Positive Dermatomyositis Is Highly Associated With Rapidly Progressive Interstitial Lung Disease and Mortality Risk.

92 : Predictors of rapidly progressive interstitial lung disease and mortality in patients with autoantibodies against melanoma differentiation-associated protein 5 dermatomyositis.

93 : Assessment of Mortality in Autoimmune Myositis With and Without Associated Interstitial Lung Disease.

94 : Antisynthetase syndrome-related interstitial lung disease (ASyS-ILD): longitudinal imaging findings.

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