A 24-Year-Old Woman With Cough, Arthralgia, and Skin Ulcerations

Case PresentationA 24-year-old Senegalese woman without remarkable history except anemia and iron deficiency related to excessive menstrual bleeding and sickle cell trait was admitted to our internal medicine department with 4-month fever, weight loss (−13 kg), dyspnea for limited efforts, intermittent productive cough, and bilateral metacarpophalangeal (MCP) and interphalangeal arthralgia. She was born and lived in France. She traveled previously to Senegal in 2015. She had no history of tobacco, alcohol, or drug use nor proximity with animals. She was taking no medication. A 24-year-old Senegalese woman without remarkable history except anemia and iron deficiency related to excessive menstrual bleeding and sickle cell trait was admitted to our internal medicine department with 4-month fever, weight loss (−13 kg), dyspnea for limited efforts, intermittent productive cough, and bilateral metacarpophalangeal (MCP) and interphalangeal arthralgia. She was born and lived in France. She traveled previously to Senegal in 2015. She had no history of tobacco, alcohol, or drug use nor proximity with animals. She was taking no medication. On admission, vital signs were as follows: temperature 39.8 °C, oxygen saturation 91% on room air, respiratory rate 22 breaths/min, heart rate 143 beats/min, and BP 135/84 mm Hg. Physical examination showed normal chest auscultation, periorbital edema, flagellate hyperpigmentation on the outside of the right arm, cracked fingertips, and superficial rounded ulcerations of elbows and MCP joints (Fig 1A-E). Synovitis was present on proximal interphalangeal and MCP joints of her right thumb. She denied Raynaud’s syndrome and dysphagia. She did not complain of muscle weakness or arthritis. Laboratory tests showed hemoglobin of 8.5 g/dL, WBC count of 3.6 G/L (neutrophils, 64.0%; monocytes, 0.3%; lymphocytes, 23.0%), platelet count of 281 G/L, serum creatinine of 62 μM, aspartate aminotransferase of 133 IU/L, alanine aminotransferase of 28 IU/L, alkaline phosphatase of 40 IU/L, g-glutamyltransferase of 32 IU/L, bilirubin of 15 μM, lactate dehydrogenase of 616 IU/L, and creatine kinase (CK) of 127 IU/L, C-reactive protein of 12 mg/L, ferritin 657 ng/mL (15-185), anti-Sjögren-syndrome-related antigen A autoantibodies (anti-SSA/Ro) positivity of 52 kD, and polyclonal hypergammaglobulinemia. Sars-Cov-2 polymerase chain reaction test was negative and Sars-Cov-2 serology positive despite no previous vaccination. Chest CT scan performed 2 months after the onset of cough showed bilateral subpleural ground-glass opacities in the lower lobes (Fig 2A). The BAL fluid showed 2.4 × 106 cells with 61% lymphocytes without alveolar hemorrhage. Pneumocystis jirovecii polymerase chain reaction was positive (low cycle threshold, 38.6) despite the absence of HIV infection. Actinomyces odontolyticus grew in BAL culture. The patient received a 2-week oral amoxicillin course in combination with a 2-week 10-mg/day prednisone course for disabling arthralgia. Her condition improved moderately, and she was discharged from the hospital. One month later, recurrent fever, persistent cough, and progressive shortness of breath led to performing a second chest CT scan (Fig 2B), which showed bilateral basal condensations and ground-glass opacities in the upper lobes and the lower part of the middle lobe. Broad-spectrum IV antibiotics including trimethoprim/sulfamethoxazole for an eventual pneumocystis pneumoniae were added. Electromyography, MRI of the skeletal muscles, echocardiography, and pulmonary function testing were not performed. Anti-nuclear and anti-dsDNA antibodies were negative. Among extractable nuclear antigens, only anti-SSA/Ro 52kD was positive. Testing for specific myositis antibodies was performed. Despite large-spectrum antimicrobial and combined immunosuppressors including methylprednisolone bolus (1 g daily for 3 days followed by oral prednisone 1 mg/kg daily), plasma exchange (3 sessions), tacrolimus, and tofacitinib, acute hypoxemic respiratory failure progressed. She was admitted to the ICU and placed under mechanical ventilation and veno-venous extracorporeal membrane oxygenation (vv-ECMO) 6 days after diagnosis in a bridge-to-transplantation process. The patient underwent a double-lung transplantation 4 days later, after having been registered on the French National Lung Transplant Waiting List with high priority. The patient's lung explant showed severe diffuse alveolar damage (DAD) (Fig 3). What is the diagnosis?What is the most severe manifestation of this disease?In addition to corticosteroids and immunosuppressive agents, how should this patient be treated? Diagnosis: Anti-melanoma differentiation-associated protein 5 clinically amyopathic dermatomyositis (anti-MDA5 CADM)Severe manifestation: Rapidly progressive interstitial lung disease (RP-ILD)Treatment: Clinicians should consider vv-ECMO as a bridge to lung transplantation strategy in anti-MDA5 CADM patients who present with RP-ILD refractory to immunosuppressive therapy. Idiopathic inflammatory myopathies (IIM) represent a heterogeneous group of acquired myositis that may affect the muscle at various impairment degrees, ranging from clinically amyopathic or hypomyopathic with normal serum CK to severe muscle damage with elevated serum CK. IIM may involve additional organs, especially in case of dermatomyositis (DM), anti-synthetase syndrome (ASS), and overlapping myositis (if associated with another autoimmune disease). Most involve the skin, with typical rashes and ulcers, mechanic's hands and Raynaud phenomenon, the joints, or the lungs with ILD, which may lead to life-threatening diffuse interstitial pneumonia. ILD is observed in 40% of IIM patients, whereas 1% of ILD is associated with IIM.1Sun K.-Y. Fan Y. Wang Y.-X. Zhong Y.-J. Wang G.-F. Prevalence of interstitial lung disease in polymyositis and dermatomyositis: a meta-analysis from 2000 to 2020.Semin Arthritis Rheum. 2021; 51: 175-191Crossref PubMed Scopus (28) Google Scholar Risk factors for ILD development in IIM patients include age at the disease onset, female sex, presence of anti-Ro-52 antibodies, ASS with anti-JO1 (prevalence, 77%) or anti-PL12 antibodies (85%), and anti-MDA5 DM (88%). The patient developed a RP-ILD revealing anti-MDA5 CADM. Diagnosis was based on a rigorous clinical examination and immunological testing for specific myositis antibodies (Table 1).Table 1Clinical and Immunological Characteristics With Muscular and Extramuscular Tropisms According to the Type of Idiopathic Inflammatory Myopathy and Specific Myositis AntibodiesType of Idiopathic Inflammatory MyopathyLevel of CK at DiagnosisMuscle Clinical SignsExtramuscular ManifestationsMuscle PathologySpecific Myositis Antibodies Useful for Diagnosis (Main Clinical Phenotype)DermatomyositisNormal to highWeakness affecting predominantly the shoulder girdle musculature, sometimes amyopathicCutaneous and pulmonary involvementNot useful if presence of antibodies and compatible clinical phenotypePerifascicular atrophy, perimysial and perivascular inflammatory infiltrates•Tif1γ (skin, dysphagia, cancer)•Mi2 (skin, muscle)•NXP2 (calcinosis, muscle, cancer)•MDA-5 (cutaneous ulcers, mechanic’s hands, RP-ILD, amyopathic)•SAE (skin)Anti-synthetase syndromeHigh to very highInconstant muscle weakness, affecting predominantly the pelvic girdle musculatureArticular, cutaneous, pulmonary, and cardiac involvementRaynaud phenomenon (20%-48%)Mechanic's hands (11%-27%)Not useful if presence of antibodies and compatible clinical phenotypePerifascicular atrophy with necrosis/regeneration, perifascicular MHC-class I antigen expression•Jo1•PL7•PL12•EJ•OJ•KSOverlap myositisNormal to highVariable muscle weakness predominantly affecting the girdles’ musculatureArticular, cutaneous, pulmonary, vascular, cardiac, and renal involvementOften needed: highly variableMuscle necrosis, perivascular inflammation, muscle fibrosis•Pm/Scl•RNP•KuNecrotizing autoimmune myopathyVery high (on average 25N)Weakness predominantly affecting the pelvic girdle musculatureRapid progressionRareExceptionally, cutaneous, pulmonary, and cardiac involvementNot useful if presence of antibodies and compatible clinical phenotypeFibers in necrosis/regeneration, C5B-9 deposits•HMGCGR•SRPInclusion body myositisModerately high (3-4N) even normalWeakness of the quadriceps and finger distal flexors, dysphagiaGradual onsetNoneEssentialMHC-class I antigen expression, ragged red fibers, congophilic inclusionsNoneCK = serum creatinine kinase; HMGCR = 3-hydroxy-3-methylglutaryl-coA reductase; MHC = major histocompatibility complex; RNP = ribonucleoprotéin; RP-ILD = rapidly progressive interstitial lung disease; SRP = signal recognition particles; Tif1γ = transcriptional intermediary factor 1 γ. Open table in a new tab CK = serum creatinine kinase; HMGCR = 3-hydroxy-3-methylglutaryl-coA reductase; MHC = major histocompatibility complex; RNP = ribonucleoprotéin; RP-ILD = rapidly progressive interstitial lung disease; SRP = signal recognition particles; Tif1γ = transcriptional intermediary factor 1 γ. ASS and anti-MDA5 DM represent the main IIM at risk of RP-ILD, which may progress to ARDS.2Vuillard C. Pineton de Chambrun M. et al.Clinical features and outcome of patients with acute respiratory failure revealing anti-synthetase or anti-MDA-5 dermato-pulmonary syndrome: a French multicenter retrospective study.Ann Intensive Care. 2018; 8: 87Crossref PubMed Scopus (44) Google Scholar Distinguishing ASS from anti-MDA5 DM may sometimes be difficult because of similar initial presentations. Diagnosis of DM- or ASS-associated ILD also may be challenging because extra-respiratory manifestations such as muscular, cutaneous, and articular signs are commonly lacking. DM mostly affects 40- to 60-year-old Afro-Caribbean women. Muscular manifestations mainly affect the shoulder girdle, with variable deficits. Muscle deficit may be marked or absent, as in this patient with anti-MDA5 CADM, recently identified as a subset of DM with myositis related to anti-MDA5 autoantibodies. The classic pathognomonic skin involvement of DM combines a heliotropic rash and Gottron’s papules presented as erythematous-to-violaceous papules, plaques, and sometimes ulcers, found over bony prominences, particularly the metacarpophalangeal joints.3Charrow A. Vleugels R.A. Cutaneous ulcerations in anti-MDA5 dermatomyositis.N Engl J Med. 2019; 381: 465Crossref PubMed Scopus (12) Google Scholar Skin manifestations are exceptionally absent. The clinical presentation of anti-MDA5 CADM differs from that of other DM forms, with three distinct clinical phenotypes in relation to the predominance of pulmonary, skin-articular, or vascular manifestations.4Allenbach Y. Uzunhan Y. Toquet S. et al.Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: study of 121 cases.Neurology. 2020; 95: e70-e78Crossref PubMed Scopus (77) Google Scholar Clinical presentation, outcome, and treatment strategy of anti-MDA5 CADM with three distinct clinical phenotypes are described in Table 2. RP-ILD develops in 30% of anti-MDA5 DM patients. This patient subgroup are frequently amyopathic but usually present with skin ulcerations, Gottron’s papules, or mechanic’s hands. In most patients, CADM does not progress to myositis. Anti-MDA5 CADM patients with RP-ILD have an extremely high mortality rate, estimated at 60% to 80% (Table 2).Table 2Clinical Presentation of Anti-MDA5 CADM With Three Distinct Clinical Phenotypes (Cluster) and Treatment StrategyManifestions Prognosis and TreatmentsCluster 1Pulmonary PredominanceCluster 2Skin-Articular PredominanceCluster 3VascularPredominanceSkinClassical DM signsMechanic's handsClassical DM signsRaynaud syndromeCutaneous vasculopathySkin ulcerationsDigital necrosisJoint+++++Muscle+±++Lung+++RP-ILD (90%)+++RP-ILD (20%)PronosticExtremely high mortalityGood prognosisIntermediate prognosis related to RP-ILDSkin damageTreatment strategy according to the presence of ILD•No ILD:High dose of GC (1 mg/kg/d) + IS (MTX or AZA)± IVIg if severe muscular manifestations or deglutition deficit± JAK inhibitor if refractory cutaneous DM•ILD:High dose of GC + IS (tofacitinib or tacrolimus or CYC)•RP-ILD:High dose of GC + combined IS (tofacitinib + tacrolimus ± CYC)± Plasmatic exchange± Lung transplantationCotrimoxazole prophylaxisClassical DM signs = pathognomonic heliotropic rash and Gottron’s papules. AZA = azathioprine; CYC = cyclophosphamide; GC = glucocorticoids; IS = immunosuppressor; MTX = methotrexate. Open table in a new tab Classical DM signs = pathognomonic heliotropic rash and Gottron’s papules. AZA = azathioprine; CYC = cyclophosphamide; GC = glucocorticoids; IS = immunosuppressor; MTX = methotrexate. Treatment strategy of anti-MDA5 DM is based on glucocorticoids and immunosuppressive or targeted therapies according to the presence of ILD (Table 2). Pneumocystis jirovecii colonization and hyperferritinemia, especially levels greater than 1,500 ng/mL, are described as severity marker in MDA5-related ILD, which should prompt early discussion of intensive treatment. We recommend that intensive treatment needs to be considered early in the course of the disease, regardless of the serum ferritin level. However, outcome is poor despite aggressive immunosuppression and vv-ECMO implementation. Recently growing data support successful management if vv-ECMO is implemented as a bridge to lung transplantation. Therefore, we encourage physicians in charge of anti-MDA5 DM patients with RP-ILD presenting refractory respiratory failure to consider this strategy as the unique emerging rescue therapy.5Bay P. Chambrun M.P. de Roux A. et al.Extracorporeal life support allows lung transplant in anti-MDA5+ rapidly progressive-interstitial lung disease.Eur Respir J. 2022; 592102968Crossref PubMed Scopus (3) Google Scholar ILD is the most severe extramuscular manifestation of IIM. ILD prevalence is variable, depending on reports and countries, but it appears to be increasingly diagnosed over time, with a prevalence ranging from 20% to 50% among IIM patients.1Sun K.-Y. Fan Y. Wang Y.-X. Zhong Y.-J. Wang G.-F. Prevalence of interstitial lung disease in polymyositis and dermatomyositis: a meta-analysis from 2000 to 2020.Semin Arthritis Rheum. 2021; 51: 175-191Crossref PubMed Scopus (28) Google Scholar Three presentations of IIM-associated ILD are possible, but the one defined by a progressive onset is the most frequent. Overall outcome is dependent on the initial clinical and radiological presentation and long-term sequelae. ILD is pauci-symptomatic, usually with good prognosis. However, in some ASS and anti-MDA5 CADM patients, slow progression may lead to pulmonary fibrosis, with acute (<1 month) or rapid progression (1-3 months) to extremely poor outcome. Initial presentations are broad ranging, from chronic to subacute forms, which include nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP) to subacute-to-acute lung injury, which includes RP-ILD and diffuse alveolar damage. Chest CT scan findings may identify different ILD patterns, including cysts, consolidations, and reticulations, that could be discriminatory and associated with various clinical phenotypes and myositis-specific autoantibodies.6Laporte A. Mariampillai K. Allenbach Y. et al.Idiopathic inflammatory myopathies: CT characteristics of interstitial lung disease and their association(s) with myositis-specific autoantibodies.Eur Radiol. 2022; 32: 3480-3489Crossref PubMed Scopus (2) Google Scholar However, phenotypes overlap because various degrees of inflammation and lesions coexist. Anti-MDA5 DM is associated with ILD more frequently than any other IIM, in approximately 40% at the time of diagnosis and up to 76% during follow-up.3Charrow A. Vleugels R.A. Cutaneous ulcerations in anti-MDA5 dermatomyositis.N Engl J Med. 2019; 381: 465Crossref PubMed Scopus (12) Google Scholar,6Laporte A. Mariampillai K. Allenbach Y. et al.Idiopathic inflammatory myopathies: CT characteristics of interstitial lung disease and their association(s) with myositis-specific autoantibodies.Eur Radiol. 2022; 32: 3480-3489Crossref PubMed Scopus (2) Google Scholar No radiological pattern is specific to anti-MDA5-associated ILD; however, the most frequent form is NSIP (49%), OP (12%), and their combination (NSIP-OP, 10%), whereas usual interstitial pneumonia patterns are less frequent (13%).6Laporte A. Mariampillai K. Allenbach Y. et al.Idiopathic inflammatory myopathies: CT characteristics of interstitial lung disease and their association(s) with myositis-specific autoantibodies.Eur Radiol. 2022; 32: 3480-3489Crossref PubMed Scopus (2) Google Scholar,7Cavagna L. Meloni F. Meyer A. et al.Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.Clin Exp Rheumatol. 2022; 40: 274-283Crossref PubMed Google Scholar One third of the patients may show OP with fibrosis.7Cavagna L. Meloni F. Meyer A. et al.Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.Clin Exp Rheumatol. 2022; 40: 274-283Crossref PubMed Google Scholar CT scan findings include ground-glass attenuation and reticulation, distributed as lower and peribronchovascular lesions. RP-ILD is the main prognostic factor of death, either directly by contributing to the disease progress or indirectly by enhancing the consequences of immunosuppression-related complications.3Charrow A. Vleugels R.A. Cutaneous ulcerations in anti-MDA5 dermatomyositis.N Engl J Med. 2019; 381: 465Crossref PubMed Scopus (12) Google Scholar,6Laporte A. Mariampillai K. Allenbach Y. et al.Idiopathic inflammatory myopathies: CT characteristics of interstitial lung disease and their association(s) with myositis-specific autoantibodies.Eur Radiol. 2022; 32: 3480-3489Crossref PubMed Scopus (2) Google Scholar Increasing evidence supports that the presence of anti-Ro52 kD autoantibodies worsens ILD associated with inflammatory and anti-MDA5 DM and contributes to RP-ILD and death.6Laporte A. Mariampillai K. Allenbach Y. et al.Idiopathic inflammatory myopathies: CT characteristics of interstitial lung disease and their association(s) with myositis-specific autoantibodies.Eur Radiol. 2022; 32: 3480-3489Crossref PubMed Scopus (2) Google Scholar Similarly, colonization or active infection with Pneumocystis jirovecii worsens the outcome, with a mortality rate estimated at 83.3% in a recent study.8Huang L. Fu Q. Ye Y. Lin Y. Yan Q. Chen S. High incidence and mortality of Pneumocystis jirovecii infection in anti-MDA5-antibody-positive dermatomyositis: experience from a single center.Arthritis Res Ther. 2021; 23: 232Crossref PubMed Scopus (10) Google Scholar MRI of skeletal muscles can be used to assess the extent and severity of muscular involvement and to guide muscular biopsy. However, MRI was not performed in this patient. MRI findings are nonspecific and not recommended for IIM diagnosis and classification.9Lundberg I.E. Tjärnlund A. Bottai M. et al.2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.Arthritis Rheumatol Hoboken NJ. 2017; 69: 2271-2282Crossref PubMed Scopus (299) Google Scholar Histopathologic patterns described in IIM-associated ILD patients include OP, NSIP with inflammatory or fibrotic lesions, UIP, and DAD.10Cottin V. Thivolet-Béjui F. Reynaud-Gaubert M. et al.Interstitial lung disease in amyopathic dermatomyositis, dermatomyositis and polymyositis.Eur Respir J. 2003; 22: 245-250Crossref PubMed Scopus (216) Google Scholar A DM-induced inflammatory process often leads to irreversible tissue damage. Radiological patterns showing perilobular opacities with rapid thickening and progression to consolidations correspond to DAD. The predominant histopathologic pattern found in RP-ILD patients with anti-MDA5 CADM is DAD. In our patient, histology was obtained on the explanted lungs (Fig 3). Areas of ongoing exudative damage coexisted with areas of organizing fibroproliferative DAD with inconspicuous fibrosis. An underlying pattern of cellular NSIP was strongly suspected, because of the co-existence of a chronic lymphocytic infiltrate with the lesions of alveolar damage, as evidenced in Figure 3C. No significant collagen deposition was observed outside the organizing DAD. The NSIP hypothesis was also supported by the clinical and radiological data. Anti-MDA5 CADM is a rare inflammatory myopathy characterized by typical DM cutaneous manifestations but no myositis and normal serum CK.