A case report of ineffective immunosuppressive therapy for MDA5 related clinically amyopathic dermatomyositis during pregnancy and literature review

Introduction

Background

Dermatomyositis (DM), a rare condition, is an autoimmune connective tissue disease that primarily targets the muscle, skin, and lungs. The incidence of DM was 1.1 per 100,000 person-years, and prevalence was 13 per 100,000 (1). Minority race and lower family income are associated with worse morbidity and outcomes in subjects with DM (2). Some patients, involving the cutaneous manifestations of classic DM, but without muscle weakness or abnormal muscle enzymes [clinically amyopathic dermatomyositis (CADM)], produce an antibody against melanoma differentiation-associated gene 5 (MDA5), which is associated with particularly aggressive disease and a high risk of mortality (3-5).

MDA5-related CADM is common among Caucasian and Asian women, and it is associated with rapidly progressive interstitial lung disease (RP-ILD) in Asians. Common signs including upper respiratory tract infection symptoms, subungual erythema, splinter hemorrhage, erythema, Gottron’s sign, heliotrope rash, etc. may appear partially and gradually, and no muscle involvement or mild weakness but no elevated muscle enzymes (6,7). The cause of MDA5-related CADM disorders is multifactorial, complex, incompletely understood and may involve a combination of genetics, environment, viral infection, and immune abnormalities (8). Patients with MDA5-related CADM had unfavorable outcomes. The 6-month mortality risk is higher than DM (1). When dealing with CADM-related skin lesions, mild symptoms can be treated with sunblock and corticosteroid ointments. For moderate to severe cases, mycophenolate mofetil or methotrexate may be necessary. If there is concomitant systemic involvement, the mainstay of treatment is systemic corticosteroids, and in severe cases, an additional or combined immunosuppressant may be prescribed (9).

Rationale and knowledge gap

Anti-MDA5 antibody positive CADM developing during pregnancy or the postpartum period is especially rare. Abe et al. present a case of anti-MDA5 antibody positive CADM that developed during the postpartum period following childbirth without any pregnancy complication (10). We present a case of anti-MDA5 antibody positive CADM that developed during pregnancy, and immunosuppressive therapies including methylprednisolone, cyclophosphamide, gamma globulin, were ineffective to stop deteriorating of her condition at the end.

Objective

DM in pregnancy increases risk of miscarriage, preterm birth, maternal mortality, hypertensive disorders, and other adverse outcomes in both the fetus and mother have been reported frequently (11,12). We report pregnant woman complicated by CADM involving anti-MDA5 antibody, which has seldom reported before (13,14). Immunosuppressive therapies may be good at improving her symptom at first, while were ineffective to stop deteriorating of her condition at the end. This report concludes some different points in terms of treatment for CADM, especially MDA5 related CADM. We present this article in accordance with the CARE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-34/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from family members of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

A 43-year-old pregnant woman (gravida 4, para 1) was admitted to her local hospital at a gestational age of 21 weeks with dyspnea, dry cough, dizziness and fever, with body temperature reaching 38.8 ℃, purplish-red rash on her hands and around neck for 3 days. She denied any family rheumatoid arthritis history and had no specific past history. Upon admission to local hospital, the percutaneous arterial blood oxygen saturation was 97–98% on room air, the respiratory was 25 times per minute, the pulse was 90 times per minute, and levels of liver enzymes and rate of erythrocyte sedimentation were elevated, creatine kinase was normal. Albumin level was 21.6 g/L (reference range: 34 to 48 g/L); C-reactive protein, 53 mg/L (reference range: 0 to 8 mg/L); and ferritin, 36.4 ng/mL (reference range: 10 to 291 ng/mL). Ultrasonography revealed left pleural effusion, and chest X-ray examination (performed with consent) showed bilateral inflammation in the lung field, together with some pleural effusion. Coagulation, routine blood tests, procalcitonin, renal function and routine urinalysis were normal. Fetal ultrasonography showed normal fetal growth. The patient was diagnosed with pulmonary infection and given ceftriaxone sodium (intravenous drip, 2 g/day).

After 5 days (a gestational age of 21⁺⁵ weeks) of ceftriaxone sodium treatment, C-reactive protein and liver enzymes had risen above their levels at admission. B-ultrasound showed that the depth of water in right chest was 5.5 cm, the depth of water in left chest was 3.4 cm. Computed tomography showed pneumonia. The following tests were negative: coagulation function, rheumatoid factor, antistreptolysin, Mycoplasma pneumoniae, Chlamydia, Legionella pneumophila, aerobic pathogens in blood, anaerobes, (1,3)-p-D-glucan test, galactomannan test, tuberculosis antibody, tuberculosis-infected T cells, skin smear microscopy, respiratory syncytial virus, adenovirus, influenza A virus, influenza B virus, parainfluenza virus, Coxsackie virus and echovirus. Fetal ultrasound showed normal fetal growth. With ceftriaxone sodium (Intravenous drip, 2 g/day) for five days, her dyspnea, cough, and rash worsened, body temperature was 37.5 ℃.

On day 6 of hospitalization (a gestational age of 21⁺⁶ weeks), the patient, coughing severely and breathing difficult, and with purplish-red rashes on the finger joints, neck, and chest, was transferred to our hospital. The body temperature and breathing frequency was normal. Physical examination revealed symmetrical rough breathing sounds in the lungs but no rales. Percutaneous arterial blood oxygen saturation was 97–99% under oxygen inhalation. Fetal heart rate was elevated (160–170 bpm). Albumin level was 32.5 g/L and C-reactive protein level, 55 mg/L. The patient was re-diagnosed with pulmonary infection, and she continued to receive ceftriaxone sodium (intravenous drip, 2 g/day) and oxygen therapy. She was also given some traditional Chinese medicine to protect the liver. Arterial blood gas analysis showed the following: anion gap, 88 mmol/L; bicarbonate, 21.1 mmol/L; CO2 (carbon dioxide) partial pressure, 31.8 mmHg; hemoglobin, 106 g/L; total blood base excess, −2.3 mmol/L; and buffer base, 43.8 mmol/L. The patient’s symptoms did not improve on ceftriaxone sodium (Intravenous drip, 2 g/day) and oxygen therapy, then we replaced ceftriaxone sodium with piperacillin tazobactam (Intravenous drip, 4.5 g per 8 hour) and conducted myositis antibody tests. Persistent dry cough and aggravated dyspnea at night caused her to feel tired. Blood began to appear in her stool, and purplish-red rashes appeared mostly around her neck but also on her hips, where they peeled and caused itching, and on her hands, where they formed ulcers and scabs (Figures 1-3). She experienced fever, mainly at night, with body temperature fluctuating between 37.3 and 38.4 ℃. Under oxygen inhalation at 3 L/min, the percutaneous arterial blood oxygen saturation at 95–99%. C-reactive protein was higher than before than before the switch to piperacillin therapy and it remained high, while albumin fluctuated between 28 and 32 g/L.

Figure 1 Purplish-red rashes and scars (circles) on hands.

Figure 2 Purplish-red rashes (circle) around neck and V-neck.

Figure 3 Purplish-red rashes (circle), ulcers and scars around hips.

On day 13 of hospitalization (gestational week 22⁺⁶), paroxysmal lower abdominal pain accompanied by vaginal bleeding occurred suddenly. Ultrasound indicated that the fetus had died. She delivered the stillborn fetus while under oxygen inhalation at 2 L/min. The percutaneous arterial blood oxygen saturation remained at 88–93%. Although coagulation function tests showed persistent abnormality, she was transferred to the intensive care unit after delivery. Postpartum C-reactive protein fell from 56 to 23 g/L without any special treatment. Myositis antibody tests showed antibodies tests against melanoma differentiation-associated gene 5 (MDA5) and Ro52 were positive. She was diagnosed as MDA5 related CADM. Methylprednisolone (80 mg/day) therapy was given for 5 days.

On day 17 of her hospitalization, her respiratory rate reached 40–50 times/min, and percutaneous arterial blood oxygen saturation decreased despite continuous oxygen inhalation at 10 L/min through a mask. Her lung was filled with moist rales, and the condition was more serious on the right side of lung. She developed respiratory failure and became cloudiness. She was intubated and a gastric tube was inserted. Blood analysis gave the following results: myoglobin, 203 ng/mL; creatine kinase, 306 IU/L; C-reactive protein, 22.5 g/L; interleukin-6, 19.26 pg/mL; albumin, 23.5 g/L; ferritin, 833 ng/mL; and reduced T cell count. Pathological examination of bronchoalveolar lavage fluid excluded tumors. Base on methylprednisolone (80 mg/day) and piperacillin tazobactam (intravenous drip, 4.5 g per 8 hour), albumin supplement, and drugs to protect the liver and gastrointestinal tract, gamma globulin (10 g/day) was added for 5 days. She was maintained on endotracheal intubation.

On day 19 of hospitalization, the patient showed weaker dyspnea and normal oxygen saturation. The intubation tube was removed, and her breathing was assisted using a noninvasive ventilator. She tested negative for C-reactive protein and showed an interleukin-6 level of 11.4 pg/mL and albumin level of 26.9 g/L. On day 22, the observed respiratory improvement led us to transfer her to the general ward to continue treatment with methylprednisolone and antibiotics. On day 23, she began to experience dry cough. Her albumin level was 30.6 g/L and she tested positive for antibodies against herpes simplex virus, so the antiviral acyclovir treatment was added to her. The dry cough worsened but her dyspnea gradually improved, and the patient no longer required non-invasive ventilation to assist breathing, though she did require intermittent inhalation of oxygen through a mask.

On day 25, the patient showed dyspnea, fatigue, irritability, chest pain, strong dry cough, accelerated breathing, intermittent fever (up to 39.3 ℃), and stronger respiratory sounds in both lungs. Blood gas analysis showed pH of 7.47, pCO2 (partial pressure of carbon dioxide) of 38.4 mmHg, and pO2 (oxygen partial pressure) of 102 mmHg. Blood analysis showed the following results: C-reactive protein, 28.0 mg/L; albumin, 28.8 g/L; interleukin-6, 70.60 pg/mL; and Krebs Von den Lungen-6, 636.64 U/mL. Percutaneous arterial blood oxygen saturation remained stable at 87–92% under continuous, non-invasive ventilation with 70% oxygen. This ventilation increased lactate levels, increased pCO2 and reduced pO2 in the blood. High-resolution chest computed tomography showed NSIP. We diagnosed the patient with MDA5 related CADM complicated by RP-ILD. We increased the oxygen concentration (100%), adjusted the dose of methylprednisolone to 500 mg/day, and added cyclophosphamide (Intravenous drip, 1g/month), but the patient’s condition worsened. Given the patient’s long-term use of high-dose immunosuppressants, we tested her for fungal infection. Indeed, she tested positive for anaerobes, (1,3)-p-D-glucan and galactomannan. She was again placed on non-invasive ventilator-assisted respiration and given the anti-fungal drugs voriconazole and meropenem. Unfortunately, on day 28, she died of respiratory failure from RP-ILD. The timeline of events, and the details of treatment, in this case, is shown in Figure 4.

Figure 4 Timeline of this case report. Rx, recipe; CADM, clinically amyopathic dermatomyositis; MDA5, melanoma differentiation-associated gene 5; RP-ILD, rapidly progressive interstitial lung disease.

Discussion

Key findings

There is limited report about pregnancies complicated by DM/CADM, especially related with MDA5. In the present case, the woman had delivered a healthy baby successfully in her first pregnancy, and accepted two artificially induced abortions ever since. In her current pregnancy, the patient was diagnosed with pulmonary infection by her respiratory symptoms and auxiliary examination results at first, then given anti-pulmonary infection treatment. The rapid worsening of the patient’s condition during anti-pulmonary infection treatment suggests that this is not pneumonia, so doctors conducted many tests including DM testing. The patient was diagnosed with MDA5 related CADM and given immunosuppressive therapies including methylprednisolone, gamma globulin, cyclophosphamide. Immunosuppressive therapies were good at improving her symptom at first, while were ineffective to stop deteriorating of her condition at the end. High-resolution chest computed tomography showed NSIP. The woman died of respiratory failure for RP-ILD at last. In our case, the fetal ultrasonography showed normal fetal growth. Ultimately, the fetus died in utero before the mother was diagnosed with MDA5 related CADM.

Strengths and limitations

We report ineffective immunosuppressive therapy for pregnant woman complicated by CADM with MDA5 positive, which has seldom reported before. This case alerts clinicians whether immunosuppressive therapy be effective for pregnant woman with MDA5 related CADM, especially someone complicated by RP-ILD, need more extensive researches. The woman and fetal of this present case all dead in short period, and we do not know the affirmatory cause of her outburst till now. Whether pregnancy status induced her disease’s outburst or pregnancy status exacerbate disease was unclear.

Comparison with similar researches

To date, several reports report the outcome of pregnancy, before pregnancy or postpartum complicated with MDA5 related DM/CADM. The outcomes are closely associated with the DM disease activity and the antibody of the DM. We searched the PubMed and Scopus databases until December 2024 using the following keywords: ‘pregnancy’, ‘dermatomyositis’, and ‘MDA5’, according to the search strategy recommended for writing a narrative review (15). We reviewed 6 articles and summarised all relevant details in Table 1 (10,14,16-19).

Explanations of findings

The MDA5 antibody is a specific predictor for CADM, and is associated with a high prevalence of RP-ILD. The mortality rate of patients who develop RP-ILD is reported to be approximately 50% with most deaths occurring during the very early stages of the illness (19,20). Predictors of MDA5-related CADM had been discovered in no-pregnant patients gradually. Anti-MDA5 antibody was a strong predictor of poor outcome and significantly related to RP-ILD. Dual positive of anti-MDA5 antibody and anti-Ro52 antibody for CADM increased frequency of RP-ILD with cutaneous ulcerations, and had lower survival rate. Symptoms including skin ulceration, fever, pneumomediastinum, pneumothorax, and right middle lobe ground-glass opacities score, hypoxemia at the beginning of disease and complications including RP-ILD, cytomegalovirus or pneumocystis infection are more common with deterioration. Body indexes and cytokines containing elevated erythrocyte sedimentation rate, white blood cell, lactate dehydrogenase, ferritin (≥828 ng/mL), cancer antigen 15-3, cytokeratin 19 fragment, soluble forms of CD206 preferentially, chitinase-3-like-1 protein, serum osteopontin (≥3,000 pg/mL), alveolar-arterial oxygen difference (≥32 mmHg), decreased CD3⁺CD4⁺T cell counts and PaO2/FiO2 (<324 torr) are significantly related poorer outcome (21-32). A medical record review study showed higher forced expiratory volume in one second, forced vital capacity and diffusion capacity for carbon monoxide decreased risk of 1-year mortality for anti-MDA-5-positive patients, and treatment with intravenous immunoglobulin or mycophenolate increased risk of 1-year mortality for anti-MDA-5-positive patients (23). Obviously, most of predictors are related poor outcomes, which mean the disease’s treatment and prognosis are terrible.

Since CADM often complicates with life-threatening RP-ILD, initial therapies tend to focus on treating lung involvement, and pulmonary function should be closely monitored. Treatments for RP-ILD are usually empirical and often involve high-dose corticosteroid therapy (33). There is no consensus on optimal treatment of CADM. Treatments have been reported include corticosteroids (such as prednisone or methylprednisolone), immunosuppressant (such as methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil), calcineurin inhibitors (such as cyclosporine, tacrolimus, sirolimus), immunoglobulin, biological agents (rituximab), Janus-activated kinase inhibitor (tofacitinib), as well as hemoperfusion with polymyxin B may be effective. Refractory patients have been treated using rituximab. Refractory RP-ILD in CADM has been treated effectively using baliximab (9,30,34-42). Patients with ILD typically avoid the use of methotrexate which can induce ILD and even RP-ILD. We caution overinterpretation for that partial “may be effective” treatments are reported only in individual cases.

In our text, the condition of the patient had received immunosuppressive therapy was confusing. Immunosuppressive therapies improved her symptom at first, while were ineffective to stop deteriorating of her condition at the end. The woman died of respiratory failure for RP-ILD at last. This case alerts clinicians whether immunosuppressive therapy be effective for pregnant woman with MDA5 related CADM, especially someone complicated by RP-ILD, need more extensive researches.

These pharmaceutical substances for treating CADM and RP-ILD, especially high-dose immunosuppressant, can potentially exert influences on fetal development, so that management of pregnant woman complicated with CADM/DM is difficult. There is limited consensus on treatment of pregnant women with DM/CADM. When pregnant women use lower doses of corticosteroids (prednisone <15 mg/d), the risk to the fetus is relatively low. The use of calcineurin inhibitors for treat pregnant women with DM or MDA5 related CADM is attemptable (9). However, long-term use of higher corticosteroid doses by pregnant women can have toxic effects on the fetus or increase the risk of premature birth. methotrexate and cyclophosphamide are contraindicated during pregnancy due to their potential teratogenicity, mutagenicity, and embryotoxicity.

Implications and actions needed

Good prognosis of patients with clinical DM without myopathy depends on early detection, diagnosis and treatment. Even if treatment is effective, clinicians should be alert to the possibility of life-threatening RP-ILD and infections. The woman and fetal of this present case all dead in short period, and we do not know the affirmatory cause of her outburst till now. Whether pregnancy status induced her disease’s outburst or pregnancy status exacerbate disease was unclear. Even though, whether women with MDA5-related CADM can conceive or pregnancy with MDA5-related CADM should continue or terminate is decided by themselves completely, MDA5-related CADM is truly fatal. We propose pregnancy in women with MDA5-related CADM must deserves physician’s attention and need multidisciplinary team co-management. Women with CADM who are considering pregnancy should first bring their disease under control, and any such pregnancies should be monitored as high-risk by interdisciplinary teams from the departments of rheumatology, immunology, respiratory medicine, and dermatology.

Conclusions

In conclusion, our case demonstrates that MDA5 related CADM is an extremely dangerous disease. There is no consensus on optimal treatment of CADM. This case alerts clinicians whether immunosuppressive therapy be effective for pregnant woman with MDA5 related CADM, especially someone complicated by RP-ILD, need more extensive researches. The patient, especially pregnancy woman, with MDA5-related CADM must deserves physician team’s attention for the fatality for mother and foetus.

Acknowledgments

We would like to extend our greatest thanks to family members of the patient for trusting her care with us and allowing us to share her story.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-34/rc

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-34/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-34/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from family members of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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