History of present illness
A 40-year-old woman presented to the outpatient interstitial lung disease (ILD) clinic for a second opinion due to progressive dyspnea and cough for the past year. She was first noted to have symptoms 1 year prior to presentation, and a high-resolution computed tomography (HRCT) scan of the chest demonstrated a reticular interstitial pattern in the lower zones. An initial autoimmune serology was negative, and a lung biopsy was suggested but the patient declined and was lost to follow-up.
Shortly before being seen in the ILD clinic, she re-presented to her local pulmonologist with morning stiffness without obvious joint swelling, worsening cough, and exertional dyspnea. Pulmonary function tests at that time demonstrated moderate restrictive impairment and moderate gas transfer defect ( Fig 14.1 ). A new chest HRCT ( Fig 14.2 ) showed lower lobe predominant peripheral reticulation with extensive ground-glass opacities, traction bronchiectasis, and areas of subpleural sparing. An autoimmune workup was repeated, and a low-titer (1:40) antinuclear antibody (ANA) level with cytoplasmic pattern was found. A surgical lung biopsy was performed, and histology was interpreted as unclassifiable pattern of fibrosis with lymphocytic inflammation and occasional giant cells. She was placed empirically on prednisone 0.5 mg/kg per day and referred to the ILD clinic for further evaluation.
Past medical history
The patient was a never smoker, and she worked as a veterinary technician, with intermittent exposure to pet birds and rodents. The only pertinent past medical history was obesity, acid reflux controlled on proton pump inhibitor and lifestyle modification, and postnasal drip. She had no family history of rheumatological or pulmonary disease.
Physical examination and early clinical findings
Physical examination was notable for a pleasant woman in no acute distress, who was morbidly obese (body mass index 38.92 kg/m 2 ), hypertensive (blood pressure 150/90 mmHg), afebrile, and with an oxygen saturation of 99% on room air. She had a normal cardiopulmonary examination but with digital fissuring and hyperkeratosis of the medial surfaces of her second digits bilaterally, so-called “mechanic’s hands” ( Fig 14.3 ). She had no joint swelling or tenosynovitis.
Clinical course
Given the patient’s examination findings of mechanic’s hands, joint pain with morning stiffness, and ILD, the leading differential diagnosis was antisynthetase syndrome. Doctors also considered hypersensitivity pneumonitis, given her occupational exposure to birds. Further testing involved laboratory evaluation of myositis-specific and myositis-associated antibodies to complete the autoimmune workup. Her myositis autoantibody panel showed a positive anti–PL-12 antibody.
Recommended therapy and further indications
Doctors confirmed the diagnosis of antisynthetase syndrome; the patient was initiated on steroid-sparing therapy (in this case, mycophenolate mofetil), and her prednisone was slowly weaned over several months. She was referred for co-management with rheumatology for other organ surveillance.
Follow-up and outcomes
Fortunately, this patient improved with the institution of a steroid-sparing agent and was able to taper off prednisone. She had monitoring safety labs to limit the risk from her immunosuppressive therapy. Pulmonary function tests were evaluated every 3 months for the first year and demonstrated improving lung function, which correlated with her improved functional capacity. She also participated in pulmonary rehabilitation, which contributed to improved strength and endurance. She was counseled on weight loss to achieve a healthier BMI. She underwent age-appropriate cancer screening. She was also encouraged to remain up to date on her vaccinations. After 1 year from her ILD consultation, she was continuing on mycophenolate.
Idiopathic inflammatory myopathies (IIMs) are a diverse group of autoimmune disorders usually characterized by muscle weakness and inflammation; however, extramuscular manifestations are often present. Historically, the three major subgroups were polymyositis, dermatomyositis (DM), and inclusion body myositis. However, the discovery of several myositis-specific and myositis-associated antibodies has expanded the existing subgroups to include clinically amyopathic dermatomyositis (CADM), overlap myositis syndrome, the antisynthetase syndrome, and immune-mediated necrotizing myopathy. Of these subgroups, the following are associated with ILD ( Table 14.1 ): the antisynthetase syndrome, CADM, DM, polymyositis, and myositis-overlap syndromes (with features of other rheumatological diseases).
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DM involves characteristic skin manifestations and proximal muscle involvement and may present in juvenile and adult forms. Notable skin findings include periorbital heliotrope rash, facial erythema, V-shaped rash on anterior trunk (V-sign) or back (shawl sign), and Gottron papules, which are erythematous papules on the joints of the dorsal surface of the hands that may also be seen on the knees and elbows. Myositis-specific antibodies include anti-melanoma differentiation–associated gene 5 ( MDA5 ), anti-transcriptional intermediary factor 1 (TIF1), anti-nuclear matrix protein 2 (NXP2), anti–small ubiquitin–like modifier activating enzyme (SAE), and anti–Mi-2, although 20% of cases are seronegative. CADM is an important subtype characterized by skin and/or extramuscular manifestations only; muscle involvement is often minimal or absent. MDA5 is associated with CADM as well as rapidly progressive ILD.
Polymyositis was previously defined as the subtype of IIM with chronic muscle weakness without skin findings. Immune-mediated necrotizing myopathy, myositis-overlap syndromes, and the antisynthetase syndrome were often described as polymyositis but are now described as separate entities. Polymyositis now exists as a designation of clinical myositis not involving these subgroups.
IIMs are rare diseases, but the exact epidemiology is difficult to characterize given inconsistencies of subgroup classifications across studies, as well as ascertainment bias (in subsets of patients who underwent muscle biopsies or were seen in specialized centers).
ILD is a significant cause of morbidity and mortality in IIMs and occurs in 23% to 53% of patients, with a higher prevalence in Asian individuals with IIMs than in American and European populations. There was a temporal trend with an increasing prevalence reported since 2010, although this may be a result of greater recognition among clinicians and wider availability of clinical myositis autoantibody testing.
Risk factors for developing ILD in IIM include older age, fever, arthralgias, elevated inflammatory markers, and the presence of antisynthetase antibodies and MDA5 antibodies.
The mechanism by which ILD develops in IIMs is poorly understood. The most common hypothesis is an unidentified environmental trigger leading to autoimmunity in the setting of genetic predisposition. Viral infections have been posited as an inciting event in the development of myositis. Preceding viral infections have been associated with dermatomyositis and polymyositis in a large Swedish nationwide registry. Recently, COVID-19 infection has been associated with the development of dermatomyositis-associated antibodies. Other environmental exposures have been explored. Smoking is an important exposure associated with anti–Jo-1 positivity and the antisynthetase syndrome in Caucasians but negatively associated with the anti–transcriptional intermediary factor 1 (TIF1) antibody associated with DM. Ultraviolet radiation density and lower latitudes are associated with dermatomyositis. However, the reported associations are weak and not clearly associated with the development of ILD.
Studies have implicated genes of the major histocompatibility complex in the pathogenesis of IIMs. Two landmark genomewide association studies in European populations found that alleles of the MHC 8.1 ancestral haplotype convey the strongest risk of DM/PM. HLA-DRB1*03-DQA1*05-DQB1*02 was strongly associated with ILD in a UK case-control study of 225 patients with myositis and 527 control subjects. Importantly, while the single nucleotide polymorphism in the promoter region of the mucin 5B (MUC5B) gene is associated with sporadic and familial cases of idiopathic pulmonary fibrosis, it has not been shown to be significantly associated with ILD in myositis.
Activated macrophages and CD8 + T cells are present in lung specimens of patients with myositis-associated ILD. Several histological patterns of ILD may be present, including nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), usual interstitial pneumonia (UIP), lymphocytic interstitial pneumonia (LIP), and an unclassifiable pattern. An NSIP–OP overlap may be observed as well. Data are sparse, as lung biopsies are not routinely performed. NSIP is the most common pattern observed in two case series of patients with DM/polymyositis. In a cohort of 17 patients who underwent surgical lung biopsies, NSIP was observed in 65%, UIP in 12%, OP in 12%, LIP in 6%, and unclassifiable in 6%. Findings were similar in a cohort of 41 biopsy specimens, in which NSIP was observed in 61%, OP in 22%, and UIP in 17%. For patients with respiratory failure or rapidly progressive ILD, the most common histological subtype is diffuse alveolar damage.
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