DANIELI, Maria Giovanna

GELARDI, CHIARA

MENGHINI, DENISE

MEZZANOTTE, CRISTINA

MONTEFORTE, FERNANDO

PEDINI, VERONICA

Maria Giovanna Danieli

Denise Menghini

Chiara Gelardi

Veronica Pedini

Fernando Monteforte

IRIS UniversitÃ  Politecnica delle Marche

CASE COMMUNICATIONS494 21 2019facilitated subcutaneous immunoglobulin, immunomodulation, interstitial lung disease, polymyositis, subcutaneous immunoglobulinIMAJ 2019; 21: 494–496imab can be useful in inducing remission. Weekly infusions of 20% subcutaneous immunoglobulin (20% SCIg) may help in controlling disease activity [1]. A new thera-peutic modality can be represented by 10% facilitated subcutaneous immunoglobulin (10% fSCIg), with the possibility to infuse large drug volumes without resorting to intravenous administration.PATIENT DESCRIPTION A 61-year-old Caucasian man came to our attention in February 2018 due to worsen-ing hyposthenia and dyspnoea. His past medical history included mellitus diabetes type 2, systemic arterial hypertension, severe mitral insufficiency. The patient smoked until the age of 30 years. Muscle weakness started in 2017 with involvement in the girdles regions, increased serum levels of creatine kinase (CK), and myopathic changes at electromy-ography. Findings during muscular biopsies were consistent with the diagnosis of poly-myositis. The patient was initially treated by glucocorticoids with partial improvement, and subsequently, with immunosuppres-sants, including azathioprine, methotrexate, mycophenolate mofetil, and cyclosporine A, with poor response.When he was referred to our medical facility, physical examination confirmed the four-limb proximal hyposthenia, with a manual muscle test score (MMT8) of 70/80 points. Cardiovascular examination was significant for a 2/6 systolic murmur in the absence of signs of cardiac failure. Polymyositis is a rare immune-medi-ated disease. Therapeutic options comprise glucocorticoids, immunosup-pressants and immunoglobulin, admin-istered intravenously (IVIg) or subcuta-neously (SCIg). Recently a new modality of immunoglobulin administration, the facilitated SCIg (fSCIg, 10% immuno-globulin plus recombinant human hyal-uronidase), has been used.Idiopathic inflammatory myopathies (IIM) consist of a group of chronic autoim-mune diseases mainly affecting musculo-skeletal systems and the skin in the form of dermatomyositis. Patients usually present with progressive proximal muscle weak-ness, muscle enzyme elevation, or a typical inflammatory pattern on muscular biopsy. Nevertheless, IIM can affect extra-muscular areas such as the lungs, heart, joints, and gastrointestinal tract. A first-line treatment is represented by high-dose oral or intravenous gluco-corticoids. Second-line therapy consists in immunosuppressive drugs like aza-thioprine, methotrexate, mycophenolate mofetil, or cyclosporine A. If response to glucocorticoids is unsatisfactory, IVIg at immunomodulatory doses and/or ritux-Lung auscultation revealed bilateral basal crackles with 94% oxygen saturation. During hospitalization, the patient’s con-dition rapidly deteriorated, with a decline in muscular strength, aggravation of dys-pnoea, and reduction of oxygen saturation. Blood tests showed a significant increase in serum CK levels (1246 U/L, normal values < 170 U/L). At the autoantibodies screening, we found antinuclear antibodies (ANA 1:320, granular pattern). Myositis specific antibodies and myositis-associated antibodies results were negative. A magnetic resonance imaging (MRI) of the proximal inferior limbs documented edema of the thigh muscles, with particular involvement of the left femoral biceps.The diagnosis of polymyositis was con-firmed according to Bohan and Peter’s cri-teria and to the new diagnostic criteria of the European League Against Rheumatism/American College of Rheumatology.Pulmonary function tests revealed a restrictive pattern with a marked DLCO reduction. A chest computed tomography showed a severe interstitial lung disease with non-specific interstitial pneumonia (NSIP) radiological pattern [Figure 1A]. An echocardiography and a cardiac MRI confirmed the already known severe mitral insufficiency, evidenced a cardiac hypertensive hypertrophy and excluded both pericarditis and myocarditis. We definitively ascribed dyspnoea to ILD in course of rapidly progressive IIM in phase of severe activity. To control the rapid disease progres-sion, we firstly administered intravenous KEY WORDS:High-Dose Facilitated Subcutaneous Immunoglobulin in a Patient with Refractory Polymyositis and Severe Interstitial Lung DiseaseMaria Giovanna Danieli MD PhD1, Denise Menghini MD1, Cristina Mezzanotte MD1, Chiara Gelardi MD1, Veronica Pedini MD1 and Fernando Monteforte MD21Department of Clinical and Molecular Sciences, Marche Polytechnic University, Riuniti Hospital, Ancona, Italy 2Department of Radiodiagnostics, Ospedale di Casarano, Lecce, ItalyCASE COMMUNICATIONS 49521 2019methylprednisolone at the rate of 1 g/day on 3 consecutive days, followed by oral prednisone 1 mg/kg/day with subsequent tapering. Rituximab (1 g/day for two infusions, 2 weeks apart) was added to the schedule. Subsequently, to definitively induce and maintain remission, the patient began treatment with IVIg 1 g/kg/day on two consecutive days each month (140 g/month).After 3 months, we obtained disease remission. To offer the patient the possibil-ity of a home self-administered therapy, we decided to maintain a schedule with fSCIg. Considering the severity of clinical condi-tions at the diagnosis, we chose a schedule with high-dose fSCIg at the previously IVIg dose (fSCIg 35 g/week = 140 g/month). We adopted this dose for 3 months and then we reduced it to 35 grams every 2 weeks.At 9 months follow-up, the patient reported complete normalization of CK serum levels, significant improvement of muscular strength (MMT8 78/80), and reduction of dyspnoea (oxygen saturation 96%) with concomitant reduction of a daily dose of prednisone, without relapses. Even the radiologic pattern showed an improve-ment, as shown in Figure 1B.COMMENT IIM can sometimes result in life-threat-ening conditions, requiring a massive immunosuppressive therapy [2]. Lung and heart involvements are usually con-nected to the most unfavorable outcomes, potentially developing into acute heart and respiratory failure. However, immunosup-pressive drugs can be linked to severe side effects such as new-onset infections or latent infections reactivation. Moreover, neoplasms and other co-morbidities can contraindicate their use. Immunoglobulin can thus represent a safe and effective therapy not just in cases of severe and refractory IIM, but also in presence of con-traindications to conventional medications. Nevertheless, immunoglobulin may be necessary for acquired hypogammaglobu-linemia, which can often arise following the administration of rituximab.The immunomodulatory role of IVIg is widely accepted and its use is approved in selected immune-mediated diseases (i.e., idiopathic thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy). Several mechanisms have been proposed to explain this action. Many are linked to the blood peak following the high-dose IVIg administration. Even 20% SCIg can have an immunomodulatory role, as reported in myositis and in other autoimmune conditions, probably linked to different mechanisms than IVIg. Our group already demonstrated the effective-ness and safety of SCIg in patients affected by IIM [1].Recently, a new combination of 10% SCIg and recombinant human hyaluroni-dase PH20 (fSCIg) has become available as replacement therapy in primary immu-nodeficiencies. Hyaluronidase, breaking the hyaluronan chemical bonds, creates a pocket in the subcutaneous tissue, facilitat-ing immunoglobulin passage in the lym-phatic vessels and enabling the administra-tion of large volumes of medicament. This may permit to employ immunomodulatory doses in patients with immune-mediated diseases. This aspect can also be rein-forced by the pharmacokinetic properties of fSCIg, whose administration leads to a blood IgG peak similar to the one of IVIg, even if lower and later. The use of high-dose fSCIg has already been tested not only in immune-mediated cytopenias related to common variable immunodeficiency, but Figure 1. High-resolution computed tomography findings [A] Before rituximab and fSCIg treatment (February 2018) showing parenchymal increased density (ground-glass opacities), traction bronchiectasis (orange arrows), bilateral pulmonary interstitial thickening with reticular opacities (green arrows), and small honey-combing subpleural areas (blue arrows), especially in pulmonary lower lobes. [B] After treatment (January 2019) showing reduction in bilateral ground-glass areas and improvement of pulmonary interstitial thickening. Traction bronchiectasis (orange arrows)fSCIg = facilitated subcutaneous immunoglobulin, HU = hounsfield unitBA-609 UH -777 UHCASE COMMUNICATIONS496 21 2019also in juvenile dermatomyositis, with sat-isfactory results [3-4]. In our case, the rapid progression of lung disease and the partial response to other immunosuppressants made neces-sary the use of rituximab. To strengthen its action, but also to reduce the potential risk of infection, we decided to associ-ate the administration of IVIg, shifting to fSCIg after 3 months. The high-dose fSCIg therapy was well tolerated, with no side effects. After 6 months, the patient completely recovered muscle strength and reported a relevant improvement of dys-pnoea. Moreover, it was possible to reduce prednisone daily dose without relapses, as documented for IVIg [5]. The patient did not report serious infectious episodes dur-ing the 9-month follow-up period.Considering the severity of clinical and radiological lung involvement, a notable aspect is represented by the great reduction of NSIP-pattern of pulmonary interstitial disease after rituximab and fSCIg therapy. While the effectiveness of IVIg in inducing remission in IIM is recognised, its use in ILD is rarely described in literature. Some case reports and case-series showed the impact of IVIg in ILD-IIM, in particular in association with immunosuppressive drugs in case of refractory or rapidly progressive ILD, or as first-line therapy in case of con-traindications to immunosuppressants. To the best of our knowledge, nobody  has investigated the potential role of SCIg on ILD, even in case of IIM. This case report can thus represent the first proof of fSCIg effectiveness and safety in maintaining remission of severe ILD in course of IIM.CONCLUSIONSOur preliminary data documented that immunomodulatory high-dose fSCIg was a feasible and safe maintenance treatment in a patient with refractory IIM associated with ILD requiring a high immunosuppres-sive therapy. fSCIg was not only effective in maintaining remission, but also in avoiding infections and as steroid-sparing agent. The subcutaneous infusion of immunoglobulin is associated to several advantages, such as the possibility of home self-administration, with a higher quality of life; better adverse reactions profile with lower incidence of systemic events; absence of hemodynamic overload and more stable serum IgG levels. However, further studies are necessary to investigate the potential immunomodulatory role of fSCIg in immune-mediated disorders. Correspondence Dr. M.G. Danieli Dept. of Clinical and Molecular Sciences, Marche Polytechnic University, Riuniti Hospital, Ancona 60020, Italy Phone: (39-71) 220-6105, Fax: (39-71) 220-6103 email: m.g.danieli@univpm.it References1. Danieli MG, Gelardi C, Pedini V, Moretti R, Gabrielli A, Logullo F. Subcutaneous IgG in immune-mediate diseases: proposed mechanisms of action and literature review. Autoimmun Rev 2014; 13: 1182-8. 2. Barba T, Fort R, Cottin V, Provencher S, Durieu I, Jardel S, et al. Treatment of idiopathic inflammatory myositis associated interstitial lung disease: q systematic review and meta-analysis. Autoimmun Rev 2019; 18: 113-22. 3. Pedini V, Savore I, Danieli MG. Facilitated subcutaneous immunoglobulin (fSCIg) in autoim- mune cytopenias associated with common variable immunodeficiency. IMAJ 2017; 19: 420-3.4. Speth F, Haas JP, Hinze CH. Treatment with high-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins in patients with juvenile dermatomyositis who are intolerant to intravenous immune globulins: a report of 5 cases. Pediatr Rheumatol Online J 2016; 14: 52.5. Watad A, Amital H, Shoenfeld Y. Intravenous immunoglobulin: a biological corticosteroid-sparing agent in some autoimmune conditions. Lupus 2017; 26: 1015-22.Classic anaphylaxis is thought to depend on immunoglobulin E (IgE) engagement of Fc receptors on granulocytes, but allergen-specific IgE is not always present. To resolve this conundrum, Jönsson and colleagues studied samples from people who experienced anaphylaxis after anesthesia. Drug-specific IgG complexes could trigger neutrophils ex vivo, and anaphylactic subjects had increased neutrophil extracellular traps. Not all of the subjects had detectable antidrug IgE. Thus, alternative pathways may be at play, and knowledge of these pathways could aid the development of tests to reduce risks in anesthesia.Sci Transl Med 2019; 11: eaat1479 Eitan IsraeliCapsuleA shocking contributor in anaphylaxisIn mice, the bacterial species in the gut microbiome are maternally inherited. Yardeni and colleagues found reduced gut microbiome species diversity in mice with variations in mitochondrial DNA (mtDNA) that were associated with increased reactive oxygen species (ROS) production. When pups were cross-fostered, the gut microbiome species after weening reflected not the microbiota community of the nursing mother but rather the inherited mtDNA variation. Pharmacological or genetic reductions in mitochondrial ROS levels increased microbiome diversity.Sci Signal 2019; 12: eaaw3159Eitan IsraeliCapsuleInheriting microbiome variation

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High-dose Facilitated subcutaneous Immunoglobulin in a Patient with refractory Polymyositis and severe Interstitial Lung disease

High-dose Facilitated subcutaneous Immunoglobulin in a Patient with refractory Polymyositis and severe Interstitial Lung disease

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