Regression of Sarcoidosis during Pregnancy: Case Report and Review of the Literature

Sarcoidosis is a chronic granulomatous disease characterized by non-caseating granuloma formation. It usually involves the lung, but may also affects many organs and systems such as the musculoskeletal system, eye, skin, and heart. The data on the course of sarcoidosis during pregnancy are controversial. Generally, sarcoidosis patients do not have a decrease in fertility, and there is no increase in the incidence of congenital abnormalities or premature birth. On the other hand, sarcoidosis may progress during pregnancy. In this report, we discussed the effects of pregnancy on the disease activity in a patient with sarcoidosis.


INTRODUCTION
Sarcoidosis is a chronic multisystemic disease characterized by non-caseating granuloma formation. Although its aetiology is not clear yet, it is probably considered to be a Th1 disease on a genetic background, that begins of the influence of environmental factors and infection agents. 1 It often presents with lung involvement, but may affects many organs and systems such as the eye, skin, and heart. Sarcoidosis is a diagnosis of exclusion and it is based on clinical, radiological, laboratory and histopathological findings. 2 It is a rare disease, with a prevalence of 4-65 / 100,000, which affecting more women than men. The disease is rare in pregnancy and its incidence is reported to be 0.02-0.06%. 3 Data on the course and prog-nosis of the disease during pregnancy are limited and contradictory. Most of them are based on case reports and case series, rather than prospective studies ( Table  1). Sarcoidosis shows three different radiological course during pregnancy: 1) normal chest radiographs before pregnancy, which remain the same during pregnancy; 2) stable residual disease, which remain stable during pregnancy; and 3) active disease improving during pregnancy. 4 Herein we reported the regression of disease during pregnancy and discussed the effects of pregnancy on disease course and prognosis in the light of the recent literature data.

CASE REPORT
A 32-year-old female patient which followed up in the rheumatology outpatient clinic with the diagnosis of sarcoidosis. One year ago, she was admitted with complaints of erythema nodosum, dry cough, effort dyspnoea, and ankle joint arthritis with 2-month duration. She had not reported any fever. On her medical history, she did not have any comorbid disease, was not a smoker, and had no family history of sarcoidosis.  Table 2). Thorax CT revealed findings consistent with stage 1 sarcoidosis (Figure 1). Pulmonary function tests (FVC: 88%, DLCO: 92%) were reported as normal.
An ophthalmologic examination revealed no retinopathy due to HQ use. The patient's general condition was good and the follow-up was continued.

DISCUSSION
Herein, we reported the pregnant sarcoidosis patient which delivery a healthy infant. The patient's complaints regressed during pregnancy and improvement in pulmonary function tests was observed. Three months after delivery, thorax CT revealed radiological regression. Sarcoidosis is a multisystem granulomatous disease which aetiology is not clear yet. Literature data on the course and prognosis of the disease in pregnancy is still contradictory. According to some researchers, pregnancy does not affect the morbidity and mortality of the mother and child.
In other words, the disease usually goes to remission during pregnancy and usually results in delivery of healthy babies. These researchers hypothesized that switching of Th1 to Th2 response occurs with the effect of oestrogen hormones, and weighted Th2 cytokines are secreted. 5 The shift of immune response from Th1 cells to Th2 cells resulting in progressive increase of progesterone and oestrogen levels during pregnancy. Oestrogen stimulates Th2-mediated immunological responses, and increases the anti-inflammatory cytokines IL-4 and IL-10. Oestrogen also suppresses the production of Th1 cytokines, such  as macrophage-attracting chemokines, IL-2, IL-12, and TNF-alpha. This is similar to other Th1 diseases such as rheumatoid arthritis or autoimmune thyroiditis. Sarcoidosis symptoms may improve during pregnancy, possibly due to increased levels of free cortisol in the circulation. Selroos et al. retrospectively evaluated 38 pregnancies in 252 female patients. 6 In 25 of them, the disease appeared after birth, and the most common symptom was erythema nodosum. The other 13 patients had been followed up with known sarcoidosis diagnosis, and no complications were observed. The authors, who advocate opposing views, argue that sarcoidosis poses a risk to pregnancy, especially in patients with cardiac involvement. Therefore, it is inconvenient for these cases to become pregnant, or should follow-up closely during pregnancy. Complications such as miscarriages, preterm delivery, preeclampsia/ eclampsia or foetal anomalies have been reported, but there is no increase of them compared to the normal population. 7 Hadid et al. reported 678 sarcoidosis cases among 7 million births (prevalence 9.9/100.000 births) during 8-year period follow-up. 8 They reported more preeclampsia, eclampsia, deep venous thrombosis, pulmonary embolism, and preterm birth in sarcoidosis patients. Wallmüller et al. reported a 35-year-old female patient with cardiac sarcoidosis. 9 She was hospitalised with sudden cardiac arrest in the 32 nd week of pregnancy, but despite cardiopulmonary resuscitation, both the mother and the baby died. They recommended the use of antiarrhythmic drugs, CS, and pacemaker in such cases. Seballos et al. reported a 27-year-old pregnant patient with sarcoid cardiomyopathy detected in endomyocardial biopsy due to heart failure 5 days after birth. 10 Despite treatment with CS, the patient died due to ventricular tachycardia and cardiac arrest. Cardiac sarcoidosis is an underdiagnosed disease that may be present in as many as 25% of patients with systemic sarcoidosis. Pregnant women with suspected cardiac involvement carry a considerable risk for a lethal cardiac event during pregnancy. However, not all patients with cardiac involvement had a poor prognosis during pregnancy. Euliano et al. reported 33-year-old pregnant sarcoidosis patient with pulmonary hypertension and cardiac involvement responded well to CS, digoxin, and anti-hypertensive drugs. 11 Ertekin et al. reported arrhythmia as the first symptom in pregnancy in two cases. 12 According to cardiac MRI and biopsy results, the diagnosis of sarcoidosis was made, and a healthy baby was born after treatment. Some studies showed that sarcoidosis is remitted in pregnancy, but may recur within the first 6 months after delivery. On other words, sarcoidosis behaves like a typical Th1 disease in pregnancy. Miyake et al. reported two cases of sarcoidosis with facial skin lesions appearing after delivery. 13 Sugishita et al. reported complete atrio-ventricular block due to postpartum syncope episodes in a 32-year-old woman with sarcoidosis. 14 They diagnosed cardiac sarcoidosis as a result of cardiac MRI and biopsy, and reported control of the disease with transient pacemaker and CS use. Data on the treatment of sarcoidosis in pregnancy are insufficient in the literature. As spontaneous remission and/ or stable disease is usually observed in pregnancy, most patients are followed up without medication. It is important to remember that some drugs (such as methotrexate, anti-TNF-alpha) are contraindicated during pregnancy.
Corticosteroids are the first choice in patients with severe organ involvement (neurosarcoidosis, heart, kidney). 15 It is possible to control the disease with moderate and/or high-dose CS. Sometimes as a steroid-sparing agent, as in our case, HQ may be preferable. Anti-arrhythmic drugs and transient or permanent pacemaker use have also been reported in patients with cardiac involvement. The efficacy of biologic drugs (especially TNF-alpha antagonists) in some severe form of sarcoidosis is well-known 16 ; however, there is no data of the use of anti-TNF-alpha drugs in pregnant sarcoidosis patients.

CONCLUSION
In conclusion, the data showing the impact of pregnancy on sarcoidosis course and prognosis are contradictory in the literature. Most of the studies supported the positive effect of pregnancy on the disease activity. However, there are also data showing that pregnancy can lead to disease progression. Prospective studies with a large number of patients are needed in this regard.