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A 60-Year-Old Man With Dyspnea, Proximal Muscle Weakness, and Pulmonary Arterial Hypertension

      Case Presentation

      A 60-year-old man with no significant medical history presented to the pulmonology clinic with 2 years of progressive weakness and shortness of breath. Showering and other activities of daily living caused him significant fatigue and dyspnea. He had a 20-pack-year smoking history, but no significant history of alcohol or illicit drug use. He did not take any prescribed or over-the-counter medications for chronic medical conditions and had never been on statin therapy. Vital signs were significant for an oxygen saturation of 91% on 4-L nasal cannula. He required up to 6 L of oxygen during a walk test. Physical examination showed mild inspiratory crackles in the lung bases, loud splitting of the second pulmonic valve (P2) with a right parasternal heave, and 2+ pitting edema in the lower extremities. There was muscle weakness, pain, and wasting of the proximal upper and lower extremities, particularly in his legs. He denied any joint pain, and there was no evidence of rash or dysphagia.
      Laboratory results showed a creatinine kinase (CK) of 7,314 units/L and an aldolase of 73.8 units/L. Basic metabolic panel results, including creatinine, were within normal limits. Extended autoantibody testing was unrevealing. CT of the chest displayed mild nonspecific peripheral reticulation with peripheral sparing, traction bronchiectasis without honeycombing, an enlarged pulmonary artery, and a dilated right atrium and ventricle (Fig 1). Pulmonary function tests revealed an isolated reduction in diffusing capacity, measuring <7.05 mL/min/mm Hg (<22% of predicted). Echocardiography showed a severely dilated right ventricle and atrium with preserved left ventricular function, as well as flattening of the interventricular septum during systole and diastole. Pulmonary artery systolic pressure was estimated at 70 to 75 mm Hg, whereas tricuspid annular plane systolic excursion was 13 mm. Follow-up right heart catheterization (RHC) displayed a mean pulmonary artery pressure (mPAP) of 50 mm Hg, a pulmonary artery occlusion pressure of 13 mm Hg, and a pulmonary vascular resistance of 7 Wood Units. Cardiac output was 5.3 L/minute, and cardiac index was 2.5 L/min/m2, as measured by thermodilution.
      Figure thumbnail gr1
      Figure 1Transverse (A) and coronal (B) cut planes of chest CT showing mild nonspecific peripheral reticulation with peripheral sparing. There is associated traction bronchiectasis without honeycombing. These findings are characteristic of nonspecific interstitial pneumonia. Mediastinal lymphadenopathy and a moderate sized pericardial effusion are present as well.
      Tadalafil 40 mg daily and macitentan 10 mg daily was started for his pulmonary arterial hypertension (PAH). Selexipag was soon added and up-titrated to 1,600 μg twice daily. He subsequently experienced remarkable improvement in his breathing, but the weakness in his legs persisted. Electromyography was performed and showed diffuse myositis with myopathic units and mild denervation, particularly in the proximal muscles. A biopsy of the left thigh revealed myofibers with scattered necrosis in varying stages of regeneration. Macrophage-predominant, pauci-lymphocytic infiltrates were also visible (Fig 2). Antibody testing for myositis autoantibodies anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP) were negative. Prednisone and mycophenolate mofetil were started. CK and aldolase trended to normal. Over several months, he achieved remission and is now able to exercise without difficulty breathing or residual muscle weakness.
      Figure thumbnail gr2
      Figure 2A, Hematoxylin and eosin (H & E) stain of left thigh muscle biopsy showing myopathic features with marked variation in myofiber diameter, including small and large rounded myofibers and occasional nuclear clumps. Regenerating fibers are also seen (black arrows). B and C, H & E stain showing myofiber necrosis (black arrows) and phagocytosis by mononuclear cells. D, Subsequent immunohistochemical staining showing CD68+ macrophages phagocytizing a necrotic myofiber (black arrow). CD3 immunohistochemical staining demonstrated few T-lymphocytes (not shown). Perivascular atrophy, “rimmed vacuoles,” “ragged-red fiber,” and inclusion bodies are all notably absent.
      What is the diagnosis?What is the most common extramuscular manifestation of this disease?In addition to steroids and immune suppressing agents, how should this patient be treated?
      Diagnosis: Seronegative immune-mediated necrotizing myopathy.Interstitial lung disease.Clinicians should consider starting patients with inflammatory myopathy and concomitant PAH on additional PAH-specific therapy.

      Clinical Discussion

      Immune-mediated necrotizing myopathy (IMNM) falls under the broad category of inflammatory myopathies, a group that also encompasses more well-known diseases such as dermatomyositis and inclusion body myositis. In the literature, inflammatory myopathies are also commonly referred to as “immune-mediated myopathies” or “idiopathic inflammatory myopathies.” All three terms are essentially equivalent, applying to the same group of diseases, which are characterized by various pathogenic mechanisms leading to a common end result—immune-mediated muscle injury. IMNM is often misdiagnosed as polymyositis; thus data on its prevalence are lacking.
      • Van der Meulen M.F.G.
      • Bronner I.M.
      • Hoogendijk J.E.
      • et al.
      Polymyositis: an overdiagnosed entity.
      However, it may constitute 10% to 20% of inflammatory myopathy cases.
      • Pinal-Fernandez I.
      • Casal-Dominguez M.
      • Mammen A.L.
      Immune-mediated necrotizing myopathy.
      In the late 19th century, the term polymyositis was first applied to what we now refer to as the inflammatory myopathies. It was described as a symmetric inflammation of multiple muscles leading to widespread paralysis, caused by “some toxic agent in the blood.” The suggested treatment was, among other things, small doses of mercury. Over the next 100 years, polymyositis was repeatedly recognized as a heterogenous grouping of diseases and subsequently split into several groups, of which IMNM is the newest.
      • Pinal-Fernandez I.
      • Casal-Dominguez M.
      • Mammen A.L.
      Immune-mediated necrotizing myopathy.
      IMNM typically presents with symmetric and bilateral proximal muscle weakness as the only symptom. Notably, the hip flexors display the most severe deficits, but in extreme cases generalized atrophy, dysphagia, or dyspnea secondary to respiratory muscle weakness can occur.
      • Allenbach Y.
      • Benveniste O.
      Peculiar clinicopathological features of immune-mediated necrotizing myopathies.
      Two of three IMNM subgroups have established autoantibodies. These include anti-HMGCR autoantibody and anti-SRP autoantibody.
      • Dalakas M.C.
      Inflammatory muscle diseases.
      Most cases of the former are seen in patients with exposure to statins. However, lack of statin exposure does not preclude a diagnosis of anti-HMGCR autoantibody IMNM. Both of these subgroups can be diagnosed by the presence of proximal muscle weakness, elevated CK, and the presence of anti-HMGCR or anti-SRP autoantibodies.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      Anti-SRP autoantibody IMNM is more likely to have extramuscular involvement, especially of the joints, heart, and lungs. However, these findings tend to be milder compared with the severe myopathy in this subgroup, which can be difficult to treat and has poorer outcomes.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      The third subgroup, seronegative IMNM, requires a muscle biopsy for definitive diagnosis. Because seronegative IMNM is not associated with a known autoantibody, extensive testing for myositis and connective tissue disorder-related antibodies must be performed to rule out other causes (Table 1). Unfortunately, a succinct clinical description of seronegative IMNM proves lacking within the literature.
      Table 1Common Autoantigens, Biopsy Findings, and Manifestation of the Inflammatory Myopathy Subgroups
      MyopathyCommon AutoantigensMuscle Biopsy Findings
      • Allenbach Y.
      • Benveniste O.
      Peculiar clinicopathological features of immune-mediated necrotizing myopathies.
      • Dalakas M.C.
      Inflammatory muscle diseases.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      Common Manifestations in Addition to Proximal Muscle Weakness
      DermatomyositisMDA-5,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      ,
      Anti-melanoma differentiation associated gene 5 (MDA5) antibodies are associated with decreased muscular symptoms (amyopathic) and a higher risk for rapidly progressive interstitial lung disease in dermatomyositis.
      Mi-2,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      NXP-2,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      ,
      Anti-nuclear matrix protein 2 (NXP2) and anti-transcriptional factor 1γ (TIF-1γ) antibodies are associated with increased risk of cancer in dermatomyositis.
      SAE1/2,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      TIF-1γ
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      ,
      Anti-nuclear matrix protein 2 (NXP2) and anti-transcriptional factor 1γ (TIF-1γ) antibodies are associated with increased risk of cancer in dermatomyositis.
      Perifascicular atrophy, capillary injury, CD4+ perimysial infiltrate; necrotic fibers in “wedge” distribution; nonnecrotic fiber invasion not commonPhotosensitive rash, ILD, increased association with cancer
      PolymyositisNone specific to this diseaseScattered necrotic fibers; nonnecrotic myofiber invasion primarily with CD8+ILD
      Immune-mediated necrotizing myopathyAnti-HMGCR3-Hydroxy-3-methyl glutaryl-CoA reductase (HMGCR)
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      Randomly distributed necrotic myofibers

      Signs of myophagocytosis, and regeneration; infiltrates macrophage predominant, paucilymphocytic; MHC 1 up-regulation; deposition of MAC on the sarcolemma of nonnecrotic fibers
      ILD, dysphagia, strong association with cancer (except for anti-SRP subgroup)
      Anti-SRPSignal recognition particle (SRP)
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      SeronegativeNone
      Antisynthetase syndromeEJ,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      Jo-1,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      OJ,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      Pl-7,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      PL-12,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      KS,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      Ha, Zo
      Perifascicular myofiber necrosisILD, “mechanic’s hands,” non-erosive arthritis
      Inclusion body myositiscN1A
      Also associated with connective tissue diseases such as Sjögren syndrome, lupus, scleroderma, and others.
      CD8+ infiltration of nonnecrotic fibers, rimmed vacuoles, ragged red fibers, inclusion bodies, congophilic material related to amyloid depositionDysphagia, muscle atrophy
      Other/nonspecific myositis (drug-induced, eosinophilic, granulomatous, etc.)PM-Scl,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      Ku,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      U1 RNP, U3 RNP,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      SS-A60,
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      SS-A52
      Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      VariedVaried
      Differentiating between inflammatory myopathies can be difficult. This table indicates the most common autoantigens/antibodies, muscle biopsy, and extramuscular findings associated with each. ILD = interstitial lung disease; MHC = major histocompatibility complex; MAC = membrane attack complex.
      a Indicates autoantigens/antibodies that were tested for and that were subsequently negative. Other autoantigens/antibodies that were tested and not included in the table include SS-A (Ro), SS-B (La), c-antineutrophil cytoplasmic antibodies (ANCA), p-ANCA, atypical p-ANCA, cyclic citrullinated peptide (CCP), rheumatoid factor (RF), and Scl 70.
      b Anti-melanoma differentiation associated gene 5 (MDA5) antibodies are associated with decreased muscular symptoms (amyopathic) and a higher risk for rapidly progressive interstitial lung disease in dermatomyositis.
      c Anti-nuclear matrix protein 2 (NXP2) and anti-transcriptional factor 1γ (TIF-1γ) antibodies are associated with increased risk of cancer in dermatomyositis.
      d Also associated with connective tissue diseases such as Sjögren syndrome, lupus, scleroderma, and others.
      Inflammatory myopathies are classically associated with malignancy. This association is approximately 24% in dermatomyositis and 10% in polymyositis.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      Interestingly, this association is strong in IMNM as well, with a rate of 21% in the seronegative subgroup, and a rate of 12% in the anti-HMGCR group.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      No particular type of cancer predominates.
      • Saketkoo L.A.
      • Ascherman D.P.
      • Cottin V.
      • Christopher-Stine L.
      • Danoff S.K.
      • Oddis C.V.
      Interstitial lung disease in idiopathic inflammatory myopathy.
      Anti-SRP IMNM has not been found to be associated with cancer.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      Cancer screening must be considered in all seronegative IMNM patients.
      Interstitial lung disease (ILD) is the most common extramuscular manifestation of inflammatory myopathy in general and is the main driver of morbidity and mortality.
      • Saketkoo L.A.
      • Ascherman D.P.
      • Cottin V.
      • Christopher-Stine L.
      • Danoff S.K.
      • Oddis C.V.
      Interstitial lung disease in idiopathic inflammatory myopathy.
      Although patients with IMNM frequently have ILD, it is usually milder than in other inflammatory myopathies. When inflammatory myopathy patients also have precapillary pulmonary hypertension (PH) on RHC, it is typically attributed to ILD. However, when signs of significant lung disease are absent, PAH should be considered.
      In inflammatory myopathy, involvement of the respiratory muscles can be a significant contributing factor to a patient’s dyspnea. In these patients, it may be difficult to determine whether the cause of their dyspnea is due to ILD, PH, or respiratory muscle depression. If the latter is suspected, measuring the patient’s maximal inspiratory pressure (PImax) can assess the strength of the patient’s respiratory muscles, particularly the diaphragm. A decreased absolute value or percentage of predicted value of PImax is a surrogate marker for respiratory muscle strength. PImax is typically only mildly reduced in ILD and PH. Therefore, in a patient with underlying inflammatory myopathy, a significantly reduced PImax can be an indication that the neuromuscular aspect of the disease is driving the patient’s dyspnea, rather than the concomitant lung or pulmonary vascular component.
      • Kalluri M.
      • Oddis C.V.
      Pulmonary manifestations of the idiopathic inflammatory myopathies.
      PImax can also be useful in tracking disease progression, and it can help monitor a patient’s response to therapy. Although PImax was not measured in the patient in our study, clinicians should consider using this marker to assess respiratory muscle strength in patients with inflammatory myopathy and associated dyspnea.
      Because ILD is the most common extramuscular manifestation of inflammatory myopathy, these patients commonly present with symptoms of lung disease alone. In fact, a large percentage of patients who present with idiopathic nonspecific interstitial pneumonia (NSIP), a common form of ILD, go on to develop an inflammatory myopathy or collagen vascular disease.
      • Saketkoo L.A.
      • Ascherman D.P.
      • Cottin V.
      • Christopher-Stine L.
      • Danoff S.K.
      • Oddis C.V.
      Interstitial lung disease in idiopathic inflammatory myopathy.
      Therefore, to prevent the delay of immunosuppressive therapy, underlying inflammatory myopathy and related connective tissue diseases should be considered in the differential diagnosis for patients presenting with ILD.
      Patients with IMNM and other inflammatory myopathies should be treated with immune suppressing agents. For patients with ILD in the setting of inflammatory myopathies or connective tissue disorders, mycophenolate mofetil can improve dyspnea and preserve lung function.
      • Mira-Avendano I.C.
      • Parambil J.G.
      • Yadav R.
      • et al.
      A retrospective review of clinical features and treatment outcomes in steroid-resistant interstitial lung disease from polymyositis/dermatomyositis.
      There also might be a role for rituximab induction therapy, followed by mycophenolate mofetil maintenance treatment in these patients.
      • Mira-Avendano I.C.
      • Parambil J.G.
      • Yadav R.
      • et al.
      A retrospective review of clinical features and treatment outcomes in steroid-resistant interstitial lung disease from polymyositis/dermatomyositis.
      In those with concomitant PAH, PAH-specific drugs should be considered. The role of traditional PAH medications has not been well established in these patients, although case reports suggest that treating the underlying myositis is not enough to allay symptoms of PAH.
      • Sanges S.
      • Yelnik C.M.
      • Sitbon O.
      • et al.
      Pulmonary arterial hypertension in idiopathic inflammatory myopathies: data from the French pulmonary hypertension registry and review of literature.
      Patients will likely require combination treatment with phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and prostacyclin pathway therapies. In line with this, the patient in our study experienced remarkable respiratory improvement after starting triple oral therapy with tadalafil, macitentan, and selexipag. The patient in our study was World Health Organization functional class III at the time of presentation, experiencing significant PH-related symptoms with activities of daily living, requiring maximum daily doses of these drugs. This is the only patient to our knowledge who had severe group 1 PAH in the setting of IMNM in whom triple oral therapy supported a return to baseline activity.

      Radiological Discussion

      The radiologic characteristics of ILD in inflammatory myopathy is broad. It commonly presents subacutely or chronically as NSIP (Fig 1). As with NSIP in general, CT features include mild interstitial inflammation, preservation of the alveolar architecture, and lack of honeycombing.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      Conversely, patients also can present with severe hypoxemia due to acute interstitial pneumonia (AIP). The clinical and radiological presentation, as well as the histological progression of AIP, is very similar to ARDS. Lack of recent insult should be used to distinguish AIP from ARDS.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      In the patient described here, it proved difficult to differentiate group 1 from group 3 PH. Both are considered precapillary PH by RHC, because they are characterized by increased mean pulmonary artery pressure, high pulmonary vascular resistance, and low pulmonary artery occlusion pressure. Treatment therefore hinges on determining whether the increased vascular resistance is due to vascular occlusion (via vascular remodeling or increased vascular tone as seen in group 1) or decreased cross-sectional area (as seen in group 3). CT or other imaging may be required to differentiate the two. The patient in our study's CT (Fig 1) showed mild nonspecific reticulation with peripheral sparing and traction bronchiectasis without honeycombing, likely because of nonspecific interstitial pneumonia. However, his disease likely represented group 1 PAH associated with myopathy, not group 3 PH, based on normal spirometry and lung volumes, mild ILD by imaging, and degree of precapillary PH.
      Although it was not performed in the patient in our study, MRI of skeletal muscles can be used to assess disease extent and severity. It also can be useful in determining a muscle biopsy target, helping to avoid the sampling bias inherent in muscle biopsy. Typical inflammatory myopathy MRI findings include muscle edema, fascial edema, muscle atrophy, and fatty replacement. Although these findings are nonspecific, they are sensitive because entire muscle groups can be examined. Few studies are available that attempt to differentiate MRI findings in IMNM from other inflammatory myopathies. However, it appears that IMNM, and especially the anti-SRP subgroup, is associated with a higher proportion of thigh muscle edema, atrophy, and fatty replacement.
      • Pinal-Fernandez I.
      • Casal-Dominguez M.
      • Carrino J.A.
      • et al.
      Thigh muscle MRI in immune-mediated necrotizing myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity.

      Pathological Discussion

      A paucity of literature exists to differentiate the pathology of IMNM subtypes. The general pathologic criteria include predominant muscle necrosis with little inflammatory infiltrate. Necrotic fibers distribute randomly and intermingle with regenerating fibers. Interestingly, the proportion of necrotic fibers may be low (<4%), but it tends to correlate with disease severity.
      • Allenbach Y.
      • Benveniste O.
      Peculiar clinicopathological features of immune-mediated necrotizing myopathies.
      Biopsy further shows macrophage-dominant cellular infiltrate with myophagocytosis, although a paucilymphocytic infiltrate also may be present.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      A detailed pathologic description specific to seronegative IMNM proves lacking.
      • Allenbach Y.
      • Benveniste O.
      Peculiar clinicopathological features of immune-mediated necrotizing myopathies.
      Nonetheless, all of these findings were present in the patient in our study and can be seen in Figure 2. Molecularly, IMNM is characterized by up-regulated major histocompatibility complex I, and membrane attack complex has been found on capillaries and the sarcolemma of nonnecrotic muscle fibers.
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      This suggests a complement-mediated role. Finally, up to a quarter of IMNM displays inflammatory infiltrates similar to other myositides.
      • Allenbach Y.
      • Benveniste O.
      Peculiar clinicopathological features of immune-mediated necrotizing myopathies.
      ,
      • Allenbach Y.
      • Mammen A.L.
      • Benveniste O.
      • Stenzel W.
      224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016.
      Common muscle biopsy findings of inflammatory myopathies are summarized in Table 1.

      Conclusion

      • IMNM is a rare inflammatory myopathy characterized by proximal muscle weakness, highly elevated serum CK, and the presence of either anti-HMGCR or anti-SRP antibodies. If these antibodies are absent, extensive myositis and connective tissue disease serologic testing and muscle biopsy are required for the diagnosis of seronegative IMNM.
      • The most common extramuscular manifestation of IMNM and inflammatory myopathies in general is ILD, which is also the main driver of morbidity and mortality in these patients.
      • Clinicians should consider PAH drugs for treatment of patients who have inflammatory myopathy with significant PH and little to no lung involvement based on chest CT and pulmonary function tests.
      • Patients with anti-HMGCR and seronegative IMNM should undergo screening for malignancy.

      Acknowledgments

      Financial/nonfinancial disclosures: None declared.
      Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

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