Pregnant patient with dermatomyositis successfully treated with intravenous immunoglobulin therapy
The idiopathic inflammatory myopathies (IIMs) comprise a heterogeneous group of diseases of unknown etiology characterized by chronic inflammation of the skeletal muscles. IIMs are rare in subjects of reproductive age and very few cases of pregnancy in women affected by IIMs have been reported in the literature. Furthermore, these have generally been associated with a poor pregnancy outcome and relapses of disease activity, suggesting a negative effect of pregnancy on disease activity and vice versa (1–7). Here we describe the case of a woman with classic dermatomyositis (DM) that developed at the beginning of her pregnancy. She was treated with intravenous immunoglobulin therapy (IVIG) and corticosteroids and was delivered of a healthy 3,180-gm boy at 35 weeks' gestation.
A 32-year-old woman affected by dermatomyositis was referred to the Rheumatology Unit of Pisa University in June 2002, when she was 17 weeks pregnant. Disease onset dated to March 2002 with the appearance of diffuse myalgias, increasing proximal muscle weakness, and skin rash; blood tests at the time showed a marked increase in transaminases and creatine phosphokinase (CPK; 3,560 IU/liter, normal values <180 IU/liter). During the same timeframe, she underwent a pregnancy test, which proved positive. The patient was admitted to a local hospital where the diagnosis of DM was made on the basis of the findings of a heliotrope rash and Gottron's papules, an increase in muscle enzyme plasma levels, and a positive electromyogram (8). Moderate-dose steroid therapy (methylprednisolone 40 mg/day) was instituted, with a prompt improvement of the serologic markers (CPK 1,836 IU/liter). After this initial positive response in May 2002, however, the patient presented with a progressive increase in muscle weakness, a worsening of the cutaneous manifestations, and a further increase in CPK levels (up to 3,650 IU/liter). Her steroid dosage was increased to 60 mg/day methylprednisolone and she was transferred to the Rheumatology Unit of the University of Pisa.
Examination on admission revealed the presence of a heliotrope rash, Gottron's papules, and severe proximal muscle weakness in the shoulder and hip girdles. There was no peripheral edema, and her blood pressure values and chest and cardiac examinations were normal. The results of her laboratory tests were as follows: CPK 1,163 IU/liter; aspartate aminotransferase 141 U/liter (normal values <45 U/liter), alanine aminotransferase 91 U/liter (normal values <45 U/liter), normal renal function, no proteinuria, and a negative Coombs test. She was positive for antinuclear antibodies by indirect immunofluorescence (1/160 with a diffuse pattern), whereas assays for anti-Ro/SSA, anti-La/SSB, anti-Sm, anti-RNP, and anti-Jo1 antibodies by CIE were negative as were anticardiolipin antibodies and lupus anticoagulant. Capillaroscopy showed the presence of diffuse abnormalities with a polydermatomyositis pattern.
The obstetric evaluation was unremarkable. Sonography showed a viable fetus with body measurements within the normal range for gestational age.
Treatment with high-dose steroids (60 mg/day) was maintained and IVIG therapy at a dose of 1 gm/day for 2 consecutive days was instituted. The patient responded well, with a reduction of CPK levels to 669 IU/liter after 2 weeks, and a progressive increase in muscle strength and disappearance of the skin lesions. She was discharged and admitted to our pregnancy clinic for followup. This consisted of frequent monitoring of muscle enzyme, hemochrome, and uric acid levels and urine analysis every 15 days; IVIG infusion once per month; and monthly obstetric evaluations.
In July, clinical and laboratory examinations showed a dramatic improvement with a complete recovery of muscle strength and normalization of muscle enzyme levels. In view of the good clinical response, steroids were rapidly tapered to a maintenance dose of 8 mg/day by September 2002, with no worsening of the patient's status.
Monthly ultrasound examinations showed normal fetal growth and echoanatomy. Uterine artery Doppler velocimetry was normal at 20 weeks' gestation. Umbilical artery and middle cerebral artery velocimetry were also measured monthly from 28 weeks' gestation onward, and normal systolic/diastolic and pulsatility index, respectively, were obtained. Because of the increased risk of gestational diabetes mellitus linked to the use of steroids, a 100-gm oral glucose load was performed at 28 weeks and yielded normal results. Toxoplasma-specific IgG antibodies were detected at 25 weeks' gestation, whereas negative results had been obtained in previous monthly tests. Because IgM antibodies were not detectable, it was concluded that the IgG antibodies against toxoplasma had been passively administered with the IVIG therapy.
At 35 weeks' gestation, the patient presented at a local hospital with premature rupture of membranes and preterm labor with 4-cm cervical dilatation. The baby was delivered by cesarean section with epidural analgesia, as previously planned (see discussion below). The 3,180-gm boy had no neonatal complications and did not require neonatal intensive care; only a transient increase in CPK was observed.
After being delivered, the patient was discharged in good clinical condition, with instructions to continue maintenance therapy consisting of 4 mg methylprednisolone daily and IVIG every 8 weeks. No recurrence of her disease was observed during puerperium or after breastfeeding.
IVIG therapy was discontinued on March 2003. At her last checkup in June 2003 the patient was in good health and her disease was still inactive. No signs of disease have been observed in her son.
Pregnancy in association with an IIM is a rare event, and as a consequence the published data are based primarily on case reports or very small groups of patients (1–7). In a recent article, Silva et al (1) retrospectively examined their patient records and reviewed the existing literature on this subject. They concluded that, as with many other chronic conditions and autoimmune diseases (such as systemic lupus erythematosus), the pregnancy outcome appeared to be closely correlated with the health status of the mother: most pregnancies occurring during an active phase of the disease showed a negative outcome, whereas pregnancies appeared to have good fetal and maternal outcomes when the disease was inactive (1). However, in the case described above, pregnancy outcome was favorable for both mother and fetus in spite of the activity and severity of DM.
Many questions had to be addressed as we were planning the management and followup of this patient. First of all, what was the optimal therapy, one that would minimize the risks to the mother and the fetus? Corticosteroids are generally acknowledged to be very effective in the treatment of IIMs, but medium to high doses may be required to control disease activity, and therefore corticosteroid-sparing immunosuppressive drugs (methotrexate, cyclophosphamide, cyclosporine, azathioprine) are often used (9). Although some immunosuppressive drugs, such as azathioprine and cyclosporine, are used in pregnancy, their administration may carry adjunctive risks for the patients. Certainly, the administration of corticosteroids during pregnancy is considered to be relatively safe for both the mother and fetus, however caution must be exercised because the long-term use of medium to high doses carries the risk of complications, such as gestational diabetes mellitus, hypertension, osteoporosis, infection, and premature rupture of the membranes (10).
IVIG therapy has been shown to be very effective in the treatment of IIMs, in particular DM, and is widely used for various autoimmune conditions during pregnancy (11). It also is used in the treatment of other pregnancy complications, such as idiopathic thrombocytopenic purpura and recurrent miscarriages, and appears to be safe and well tolerated by pregnant patients (11, 12). In our patient, treatment with IVIG was aimed at maintaining disease remission while decreasing the corticosteroid dosage. Treatment with medium to low doses of steroids in combination with IVIG proved effective in controlling her disease, although she experienced premature rupture of the membranes. This occurred at 35 weeks' gestation, and the successfully delivered infant showed no signs of respiratory problems and did not require intensive care. His birth weight was above the 90th percentile for male infants, which might have been due to imperfect glucose control in the mother, although results of an oral glucose loading test were normal at 28 weeks' gestation, when she still was taking medium-dose steroids.
As the pregnancy progressed, we had to face a second problem—the route of delivery most suitable for this patient. Most of the cases reported in the literature involved either patients with active disease who underwent cesarean section because of maternal or fetal complications, or patients with longstanding inactive disease who had an uneventful vaginal delivery. However, our case did not fit either of these 2 situations: the disease was not active at the time of parturition, but remission had been achieved only recently.
Because there have been reports of increased CPK levels during physiologic labor, with the suggestion that this may be due to skeletal muscle damage associated with labor (13), and taking into consideration the recent onset of the disease, the risk of rhabdomyolisis and myoglobinuria seemed relevant (14). We decided to recommend an elective cesarean section to avoid excessive muscle exercise.
No signs of disease were observed in the son at birth or in the following months. The only abnormality found—a transient increase in CPK serum levels—is known to occur during the first 3 to 4 days in full-term infants as well, reaching a peak just a few hours after birth and normalizing within a few days (3).
Finally, this clinical case raises questions with regard to the pathogenesis of IIMs. Recently, cells of maternal origin have been observed in the inflamed muscles of subjects with juvenile IIM, suggesting maternal microchimerism. Furthermore, some authors have hypothesized that fetal cells circulating in the mother may to some extent be correlated with the development of autoimmune diseases in the mothers (4, 15, 16). Because the dermatomyositis was diagnosed during the first weeks of pregnancy in our patient, a correlation between fetomaternal cell trafficking and the pathogenesis of maternal disease does not seem likely.
Interestingly, the onset of disease during pregnancy may also suggest a pathogenetic role of sex hormones. During pregnancy, in fact, a rise in estrogen and progesterone concentrations is observed and the influence of these hormones on immune response has been described in animal models as well as in patients with other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis (17).
In conclusion, we have described the case of a pregnant patient with DM who was successfully treated with IVIG and was delivered of a healthy infant at 35 weeks' gestation. To our knowledge this represents the first reported case of DM with onset during the first trimester of pregnancy, in which treatment with IVIG resulted in remission of the maternal disease as well as a positive pregnancy outcome. In view of the rarity of pregnancy in active IIM, we suggest consideration of IVIG therapy as a possible therapeutic option, given its corticosteroid-sparing effect and the reduced risk of steroid-related side effects.
We gratefully acknowledge the help of Lisa Chien in correcting the English in this manuscript.