Clinical trial NCT01345071: Preconceptional Counselling in Active Rheumatoid Arthritis
Official title: PreConceptional Counselling in Active Rheumatoid Arthritis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Rheumatoid Arthritis
Pregnancy
Keywords: Rheumatoid Arthritis
Pregnancy
Anti-TNF
Preconceptional counselling
Disease activity
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Dutch Arthritis Association
First posted: 2011-04-29
Enrollment: 150
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: For first objective: Women with high disease activity of RA and a pregnancy wish.

For second objective: Women with a rheumatic disease that requires the use of anti-TNF before or during pregnancy

Brief summary: The first objective of the study is to evaluate a treat to target treatment strategy in women with moderate to high disease activity of RA and a pregnancy wish, from pre-pregnancy. The treatment strategy is based on deliberate treatment decisions to lower disease activity, including the continuation or start of biological treatment (in particular anti-Tumor Necrosis Factor \[anti-TNF\]), based on a standard care protocol in the Erasmus MC. The second objective is to evaluate the safety of the use of anti-TNF during pregnancy among women with a rheumatic disease that require the use of anti-TNF before or during pregnancy.

Detailed description: Rheumatoid Arthritis (RA) is an auto-inflammatory disease that particularly involves chronic inflammation of the joints.The disease is in essence a systemically active one that can affect almost any organ. Pregnancy can spontaneously reduce the activity of RA. This phenomenon has been investigated in the PARA-study (Pregnancy-induced Amelioration of Rheumatoid Arthritis study), a nationwide prospective cohort study initiated and coordinated by the department of Rheumatology, Erasmus University Medical Center, Rotterdam the Netherlands.

The PARA-study reconfirmed previous data that RA improved during pregnancy. However, it also showed that this improvement was less pronounced than previously thought since \> 50% of RA-patients still had active disease during third trimester of pregnancy. It also demonstrated that active RA was associated with lower birth weight and that children of mothers with active RA demonstrated rapid catch up growth in weight. Lower birth weight as well as rapid catch up growth in weight have been shown to be associated with a less favorable cardiovascular profile in early adulthood. Finally, it showed that time to pregnancy is prolonged in RA-patients with active disease. Also the use of prednisone \> 7,5 mg daily or the use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) were associated with a prolonged time to pregnancy. These latter associations were independent of disease activity.

The findings of the PARA-study implicate that one should strive for low disease activity in women with RA and a pregnancy wish, but that in the meantime NSAIDs and doses of prednisone exceeding 7.5 mg daily should be avoided. Since common drugs to treat RA, like methotrexate, are incompatible with pregnancy, lowering disease activity in pregnant RA-patients or with a pregnancy wish becomes a real challenge for the patient and the treating physician. This all underscores the importance of new treatment modalities for RA-patients with a pregnancy wish.

In the last decade new treatment options for RA, the so-called biologicals, became available. During pregnancy the most experience has been gained with biologicals belonging to the class of anti-TNF therapy. In the USA, anti-TNF has been approved for use during pregnancy as a FDA (Food and Drug Administration) class B (i.e. Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate, but well-controlled, studies of pregnant women have not been conducted). Registry studies show that anti-TNF use seems to be safe during pregnancy in humans also. Furthermore, anti-TNF therapy has been used intentionally preconceptionally to improve the chance of pregnancies in women with recurrent spontaneous abortions. Since no randomized controlled trials can be done during pregnancy, circumstantial evidence has led to decision making in daily practice. In case of high disease activity use of anti-TNF to control disease activity outweighs the risk of potential harm to the foetus.

Most anti-TNF medications are monoclonal antibodies of the IgG class. For that reason these antibodies are, from around week 14 of gestation, actively transported across the placenta. When used into third trimester of pregnancy, higher levels of these TNF-alpha antibodies are reached in the fetal circulation compared to the maternal circulation, making the newborn more prone for infections. Vaccination of newborns with live inactivated vaccines are therefore contraindicated till anti-TNF alpha antibody levels are not detectable anymore. It is often advised to stop anti-TNF in the first trimester of pregnancy. The rationale behind this approach is that RA improves during pregnancy anyway and that it is safe to taper off medication. In addition it is thought that with discontinuation of anti-TNFearly during pregnancy no placental transfer of anti-TNF antibodies will take place. However, currently no scientific evidence is available to support both assumptions.

An alternative approach is to prescribe Certolizumab during pregnancy or in women with a pregnancy wish. Certolizumab is a pegylated antibody against TNF-alpha. Since it lacks an Fc-tail it is not transported across the placenta and only trace amounts can be detected in the newborn. In the Erasmus MC a protocol was recently developed to standardize care for patients (already pregnant or with a pregnancy wish) that in theory might benefit from treatment with anti-TNF therapy. This protocol is being evaluated in the Pre-CARA study.

The Pre-CARA study is a continuation of the previous PARA study, but focuses on RA patients with high disease activity and a pregnancy wish. The first objective is to evaluate a treat to target treatment strategy in women with moderate to high disease activity of RA and a pregnancy wish, from pre-pregnancy till six months after delivery. The treatment strategy is based on deliberate treatment decisions to lower disease activity, including the continuation or start of biological treatment (anti-TNF), based on a standard care protocol in the Erasmus MC. The second objective is to evaluate the safety of the use of anti-TNF during in women with any chronic arthritide who require the use of this medication preconceptionally and/or during pregnancy.

Eligibility criteria: Inclusion criteria for first objective (150 subjects)

* Rheumatoid Arthritis according to 2010 ACR/EULAR criteria
* active pregnancy wish
* either DAS28(3)CRP \> 3.2 or the current use of anti-TNF

Inclusion criteria for second objective (no limit on number of subjects needed, recruitment will end when 150 RA patients have been included)

* rheumatic disease that requires the use of anti-TNF before or during pregnancy
* active pregnancy wish

Exclusion criteria:

- none

Primary outcomes:
measure: DAS28(3)CRP at all study points
timeFrame: Every 3 months from baseline till 6 months after delivery
Secondary outcomes:
measure: Time to pregnancy
timeFrame: At baseline and every 3 months till pregnant
measure: Number of miscarriages
timeFrame: After conception, every 3 months
measure: Complications during pregnancy
timeFrame: Every 3 months during pregnancy and first visit after delivery
measure: Gestational age of child
timeFrame: First visit after delivery
measure: Birth weight of child
timeFrame: First visit after delivery
measure: Congenital malformations
timeFrame: First visit after delivery
measure: Growth of child and tempo of growth during first year
timeFrame: One year after birth
measure: Maternal serum levels of anti-TNF
timeFrame: Every three months during pregnancy
measure: Levels of anti-TNF in cord blood
timeFrame: Collected at birth
measure: Levels of anti-TNF in child
timeFrame: Every six weeks after birth
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: ErasmusMC, University Medical Center Rotterdam, dept. of Rheumatology
Study officials:
affiliation: Staff Rheumatologist
name: Radboud Dolhain, PhD MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Man YA, Dolhain RJ, Hazes JM. Disease activity or remission of rheumatoid arthritis before, during and following pregnancy. Curr Opin Rheumatol. 2014 May;26(3):329-33. doi: 10.1097/BOR.0000000000000045.
citation: de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008 Sep 15;59(9):1241-8. doi: 10.1002/art.24003.
citation: de Man YA, Hazes JM, van der Heide H, Willemsen SP, de Groot CJ, Steegers EA, Dolhain RJ. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum. 2009 Nov;60(11):3196-206. doi: 10.1002/art.24914.