Three of the eight patients were female. Mean age at diagnosis was 48.5 years (range 13–79 years). Mean duration of treatment in our department is 51 months (24–92 months).
Laboratory findings
CK was in the normal range of our laboratory in every patient of this cohort at first presentation. C-reactive protein was elevated in five out of eight patients (mean 12.2 mg/L (0.7–36.6 mg/L). LDH was elevated in three patients. Ferritin was elevated in six out of eight patients (mean 900 µg/L (351–1862 µg/L)).
In the screening procedure, the following additional autoantibodies were identified: rheumatoid factor (two patients), ACPA (anti-citrullinated peptide) (one patient), ANA with a titer > 1:160 (seven patients), SS-A-antibodies (three patients), of these two with Ro52 antibodies.
Pulmonary involvement and pulmonary function testing
All eight patients had changes in the initial computed tomography of the chest (CT chest) at diagnosis. Three patients had basally emphasized interstitial lung disease, two patients had ground-glass opacities and another patient had a basal interstitial pneumonia (Table
2). In two patients, extensive interstitial lung parenchyma changes were described. In one patient, cicatricial contortions of the lung parenchyma were described, which were not typical for a lung fibrosis.
Table 2
Radiographic findings
P1 | Interstitial parenchyma changes, bihilary lymphadenopathy | Regression | 231 | Indurative lung parenchyma changes | 395 |
P2 | Extensive interstitial lung parenchyma changings | Regression | 376 | Minimal ground-glass opacity | 845 |
P3 | Basal emphasized interstitial lung disease | Regression | 1579 | n.a | n.a |
P4 | Basal emphasized interstitial lung disease | Unchanged | 1160 | n.a | n.a |
P5 | Basal emphasized interstitial lung disease | Unchanged | 270 | n.a | n.a |
P6 | Basal interstitial changing | Unchanged | 589 | No interstitial changing, basal pitted fibrosis | 3009 |
P7 | Extensive interstitial lung parenchyma changings | Regression | 246 | n.a | n.a |
P8 | Cicatricial contortions of the lung parenchyma | Unchanged | 353 | n.a | n.a |
A first follow-up CT of the chest was performed in eight patients after 600 days on average (231–1579 days). There were stable findings in four patients.
In four patients, an improvement of the initial radiological findings in the baseline CT was described. A second follow-up CT of the chest was performed in three patients (P1, P2 and P6) with no further changes compared to the first follow-up.
All patients received pulmonary function testing at first presentation (Table
3). During the course of treatment, there was an improvement in six patients in DLCO overall from 50% (25–79%) to 63% (40–97%). In one patient, DLCO remained stable and in another patient there was a decrease in DLCO (P8).
Table 3
Pulmonary function testing
P1 | 42 | 108 | 68 | 110 | 173 |
P2 | 25 | 47 | 51 | 67 | 1184 |
P3 | 61 | 69 | 73 | 70 | 735 |
P4 | 53 | 85 | 52 | 109 | 530 |
P5 | 46 | 46 | 55 | 50 | 542 |
P6 | 57 | 47 | 97 | 81 | 1770 |
P7 | 34 | 38 | 40 | 47 | 179 |
P8 | 79 | 67 | 68 | 75 | 333 |
In all patients, an improvement was measured in FVCex (Forced expiratory Capacity) during treatment. At diagnosis, mean FVCex was 63.4% (38–108%) and at follow-up 76.1% (47–110%). Follow-up was performed after 680 days on average (173–1184 days).
Treatment strategies
Individual treatments are listed in Table
4.
Table 4
Treatment strategies
Chemotherapy with R + CHOP by diagnosis of a non-Hodgkin lymphoma (R; Rituximab, C; Cyclophosphamide, H; Doxorubicin, O; Vincristine, P; Prednisone) | Prednisone 1.5 mg per day |
Steroid pulse (1000 mg per day for 3 days) followed by oral Prednisone 70 mg/day with tapering schedule + parallel plasmapharesis (7x) + parallel initiation Cyclophosphamide (every four weeks, for 6 times) + parallel intravenous immunoglobuline administration ( every four weeks, for 6 times (95 g each over 3–4 days) + parallel initiation Tacrolimus 9 mg 1–0–1 per day | Tacrolimus 7.5 mg 1–0–1 (Target serum level: 10 µg/L) |
Steroid pulse followed by oral Prednisone with tapering schedule + parallel Mycophenolate mofetil switch Azathioprine and Hydroxychloroquine + Tacrolimus topically | Azathioprine 50 mg 1–0–1 Hydroxychloroquine 200 mg 1–0–0 Tacrolimus topically |
oral Prednisone 50 mg/day with tapering schedule + parallel initiation Cyclophosphamide (every four weeks, for 6 times) + prostaglandine intravenous + parallel initiation Tacrolimus 4 mg 1–0–1 per day | Tacrolimus 4 mg 1–0–1 (Target serum level: 10 µg/L) Prednisone 4 mg per day |
Steroid pulse (500 mg per day for 3 days) followed by oral Prednisone 80 mg/day with tapering schedule + parallel plasmapharesis (5x) + parallel initiation Cyclophosphamide (every four weeks, for 6 times) + parallel initiation Tacrolimus 2 mg 1–0–1 per day | Tacrolimus 2.5 mg 1–0–1 Prednisone 5 mg per day Rituximab 1000 mg every six month |
Steroid pulses (2015–2018) followed by Mycophenolate mofetil followed by Tocilizumab followed by Cyclosporine A | Cyclosporine A 150 mg 1–0–1 |
Oral Prednisone and Methotrexate switch Methotrexate + Azathioprine + Hydroxychloroquine followed by oral Prednisone + prostaglandine intravenous + intravenous immunoglobuline (Proof of MDA5) Dose increase oral Prednisone 40 mg/day with tapering schedule + parallel initiation Cyclophosphamide (every four weeks, for 6 times) followed by R ituximab (every six month) + parallel initiation Tacrolimus 2 mg 1–0–1 per day | Tacrolimus 2 mg 1–0–1 (Target serum level: 10 µg/L) Hydroxychloroquine 200 mg 1–0–1 Prednisone 5 mg per day Rituximab 1000 mg every six month |
Chemotherapy with Dnr/AraC/Midostaurin by diagnosis of acute myeloid leukemia (Dnr; Daunorubicin, AraC; Cytarabin) (Proof of MDA5) Recommendation to start Tacrolimus orally, patient denied | Watch and wait |
In patient 1 (P1), a non-Hodgkin lymphoma was diagnosed concurrently to the diagnosis of the MDA5-positive DM and treated with RCHOP-chemotherapy regimen. Currently, P1 is in remission on a treatment with 1.5 mg prednisone per day.
Due to severe pulmonary involvement, patient 2 (P2) required oxygen supplementation at initial diagnosis and treatment at our rheumatology ward. Therapeutically, an intravenous steroid pulse with 1000 mg prednisone per day for three days followed by tapering oral glucocorticoids was initiated in combination with seven cycles of plasmapheresis. This induction therapy was followed by intravenous immunoglobulins and cyclophosphamide bolus therapy for overall 6 month. P2 obtained 90-g intravenous immunoglobulins every four weeks. Cyclophosphamide was administered first with 500 mg/m2, after four weeks 750 mg/m2, followed by 1000 mg/m2 every four weeks for a total of six infusions. In case of reduced leukocytes, ten days after the cyclophosphamide infusion the increase of the dose was suspended. An additional immunosuppressive therapy with oral tacrolimus was initiated (target serum level 10 µg/L) parallel to the first cycle of cyclophosphamide due to the disease severity and rapid progression of the interstitial pneumonia. The patient reached stable disease remission after 24 weeks and remains on a steroid-free maintenance therapy with tacrolimus (7.5 mg twice daily).
In patient 3 (P3), therapy was initially started with high-dose glucocorticoids and mycophenolate mofetil, followed by combination treatment of glucocorticoids, azathioprine and hydroxychloroquine. Tacrolimus was applied topically. This therapy is still proceeded.
Patient 4 (P4) therapy was initiated with oral prednisone (1 mg/KG/kg) per day with tapering schedule. In parallel, cyclophosphamide was administered with 500 mg/m2, after four weeks 750 mg/m2, followed by 1000 mg/m2 every four weeks for a total of six infusions, and oral tacrolimus was initiated. For remission maintenance, only tacrolimus (4 mg twice daily) is currently necessary.
In patient 5 (P5), intravenous steroid pulse with 500 mg prednisone per day for three days was performed, followed by oral glucocorticoids with a tapering schedule. P5 received five cycles of plasmapheresis during the first stay in our hospital. Cyclophosphamide first was administered with 500 mg/m2, after four weeks 750 mg/m2, followed by 1000 mg/m2 every four weeks for a total of six infusions. And in parallel, oral tacrolimus orally was commenced. Currently, P5 obtains 2.5 mg of tacrolimus twice daily, and rituximab was started with a dose of 1000 mg every six months to maintain remission.
In patient 6 (P6), initially seronegative rheumatoid arthritis or undifferentiated connective tissue disease was suspected. Steroid pulses were performed, followed by a treatment with tocilizumab (anti-IL-6R antibody). After the detection of MDA5 antibodies and progressive disease in 2015, the treatment was switched to oral cyclosporine. Glucocorticoids were discontinued in 2019.
In patient 7 (P7), the diagnosis was unclear at the first onset of symptoms. P7 was treated with prednisone and methotrexate, followed by methotrexate plus azathioprine and hydroxychloroquine. When P7 deteriorated rapidly with extensive interstitial lung parenchyma changings, he received intravenous prostaglandins and immunoglobulins and was referred to our hospital. After the detection of MDA5 antibodies, the daily dose of prednisone was increased (40 mg/per day) and tapered subsequently, and in parallel, intravenous cyclophosphamide was administered with 500 mg/m2, after four weeks 750 mg/m2, followed by 1000 mg/m2 every four weeks for a total of six infusions. Furthermore, oral tacrolimus was initiated. After the six pulses of cyclophosphamide, rituximab was administered for remission maintenance. Thus, P7 is currently treated with hydroxychloroquine, tacrolimus, low dose prednisone and rituximab.
In patient 8 (P8), acute myeloid leukemia was diagnosed first. After induction therapy allogeneic stem cell transplantation was performed. Graft-versus-host disease occurred in the intestinal tract. Subsequently, P8 developed myalgia, arthralgia and thoracic pain. In the laboratory measurements, MDA5 antibodies were found. MRI of the upper arm was performed with diagnosis of myositis. Due to this findings including a restriction in the lung function testing, MDA5 CADM was diagnosed without typical CT morphological findings of the lung. Oral tacrolimus was recommended but fearing a leukemic relapse, P8 did not follow that advice. At the present time, MDA5 antibody is negative in P8. Watch and wait as therapy strategy seems possible, but regular lung function testing is still crucial to identify a potential disease progression.