Like many patients with rheumatic disease, those with systemic sclerosis (SSc) face a range of challenges regarding reproductive health and pregnancy outcomes. Systemic sclerosis has a peak onset between the ages of 30 to 50 years, and an estimated one-half of women with SSc experience disease onset during childbearing years.1 Pregnancies occurring after an SSc diagnosis have become increasingly common among this population, “as a greater number of women are choosing to have children well into their thirties and forties.”2
Although research findings on this topic remain scarce, results of several recent studies have shed light on pregnancy-related outcomes in SSc and considerations for the management of pregnant patients with this disease.
In a cross-sectional study published in Rheumatology during September 2023, Dai et al identified multiple challenges affecting this population. Among 342 women with SSc, 31.8% reported reproductive health problems. Compared against women without SSc, those with SSc demonstrated higher rates of spontaneous abortion (12.2% vs 4.3%; P <.001), premature birth (21.8% vs 6.4%; P =.003), low birth weight infants (27.3% vs 5.5%; P <.001), and cesarean delivery (49.1% vs 19.1%; P <.001).3
Dai et al also found that patients with disease onset before menopause experienced earlier menopause, compared against those with later disease onset (45.2 ± 6.1 vs 48.2 ± 4.4 years; P <.001).3
In a retrospective, single-center study published in 2022 in Arthritis Research and Therapy, Barilaro et al compared outcomes between healthy patients and women with SSc, systemic lupus erythematosus (SLE), and antiphospholipid (aPL) syndrome (APS), A total of 154 participants were followed from 2008 to 2019 at a high-risk pregnancy unit.4
The results showed an increased overall risk for adverse pregnancy outcomes among patients with SSc compared against healthy individuals (60.6% vs 10.0%; odds ratio [OR], 14.42; 95% CI, 3.70-56.18; P =.001) and patients with SLE (60.6% vs 37.5%; OR, 3.56; 95% CI, 1.29-9.83; P =.014).4
In addition, patients with SSc demonstrated higher rates of preeclampsia (12% vs 0%; P =.038), first-trimester miscarriage (15% vs 0%; P =.016), and small-for-gestational-age newborns (21.2% vs 0%; P =.003) compared with healthy patients.4
Higher rates of preterm delivery were also observed in SSc pregnancies compared with healthy individuals (24.2% vs 5%; OR, 6.08; 95% CI, 1.19-31.02; P =.036) and patients with SLE (24.2% vs 7.5%; OR, 5.68; 95% CI, 1.1-29.38; P =.038).4
All patients with SSc maintained disease stability throughout pregnancy and up to one year following delivery.4
Similarly, a retrospective cohort study including women who had 1 or more pregnancies following an SSc diagnosis found no evidence of worse renal, respiratory, or global function outcomes up to 10 years after pregnancy, compared against nulliparous patients with SSc.5 “While this offers a hopeful message to systemic sclerosis patients planning a pregnancy, physicians and patients should remain vigilant for potential post-partum complications,” the study authors concluded.5
Consistent with findings from these retrospective studies, a 2020 meta-analysis of 16 studies found stable or improved disease manifestations among pregnant patients with SSc. However, results also revealed substantially higher odds of gestational hypertension, cesarean delivery, miscarriage, intrauterine growth retardation, preterm delivery, and low birth weight infants among SSc pregnancies compared with healthy individuals.6
Clinical Recommendations
In a review published in 2021 in EMJ Rheumatology, Maguire and O’Shea described various clinical considerations regarding pregnancy in SSc.7
For women with rheumatic diseases in general, optimization of disease control before conception decreases the risk for adverse pregnancy outcomes, and a “period of remission of at least 6 months prior to conception increases the chance of a successful conception while decreasing the risk of flares during pregnancy,” study authors wrote.7 Thus, rheumatologists should begin pregnancy planning and risk stratification with these patients prior to conception to allow for “transfer to pregnancy-compatible medications, disease [stabilization], determination of autoantibody status, and evaluation of end-organ damage.”7
Throughout the course of pregnancy in patients with rheumatic diseases, obstetricians and rheumatologists should monitor patients closely and frequent communication between specialists should occur. Additionally, “Medications should be reviewed at each stage of pregnancy to ensure compliance with the current American College of Rheumatology (ACR) guidelines and the adequate treatment of [rheumatic musculoskeletal disorders],” Maguire and O’Shea stated.7
According to a review written by Clark et al, although symptoms remain stable among most pregnant patients with SSc, those with early-stage disease are the most likely subgroup to report worsening symptoms including Raynaud phenomenon, digital ulceration, arthralgia, and skin thickening.8
Among patients with SSc, the greatest risk for pregnancy complications has been noted in those with diffuse cutaneous SSc (dcSSc) who become pregnant within 5 years of disease onset, patients with anti-topoisomerase or anti-RNA polymerase III antibodies, and those with pre-existing organ involvement such as scleroderma renal crisis, interstitial lung disease, pulmonary arterial hypertension (PAH), active myositis, and severe gastrointestinal involvement.8
In pregnant patients with SSc, the presence of PAH represents the leading cause of maternal mortality and is the primary clinical concern among these individuals.7 Patients with established PAH should be strongly advised against becoming pregnant, and termination may be advised if rapid deterioration occurs during early pregnancy.7,8
Patients with dcSSc should be advised to delay pregnancy until after the first 5 years of disease onset.8
Angiotensin-converting enzyme inhibitors should be continued in pregnant patients with SSc to avoid the risk for renal crisis, although a trial period on an alternative antihypertensive medication could be considered prior to conception.7
“All women with known aPL antibodies or a history of obstetric APS should be offered low-dose aspirin prophylaxis from 12 weeks’ gestation for pre-eclampsia prophylaxis,” according to Clark et al. For those with a history of APS, prophylactic [low-molecular-weight heparin] throughout pregnancy is required, and input from a hematologist may be indicated.8
“Low-molecular-weight heparin can reduce thrombotic risk, while sildenafil and epoprostenol are additional therapeutic options in pregnancy,” Maguire and O’Shea stated.7 “In cases of disease acceleration or rapid progression during pregnancy, additional life-saving therapies need to be considered, including preterm [labor] induction to allow use of additional medications not compatible with pregnancy.”7
In the postpartum period, decisions regarding medication use should aim to maximize maternal benefit while minimizing infant harm. For example, therapeutic options described in the 2020 ACR guidelines can be safely used during breastfeeding while optimizing disease control.7
Among other postpartum considerations, studies published in 2023 showed elevated rates of postpartum psychiatric disorders, including postpartum depression (17.2% vs 12.8% in age-matched controls; adjusted hazard ratio, 1.22; 95% CI, 1.09-1.36).9,10 Such findings highlight the need to monitor patients with SSc for postpartum depression symptoms and coordinate mental health treatment accordingly.
The American Thoracic Society has released an evidence-based clinical practice guideline for the treatment of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), as published in the American Journal of Respiratory and Critical Care Medicine.
The guideline strongly recommends treating patients with SSc-ILD with mycophenolate and conditionally recommends treatment with clyclophosphamide, nentedanib, rituximab, tocilizumab, and the combination of nintedanib plus mycophenolate.
Notably, the recommendations do not provide a hierarchy of which treatment to use. “[T]he committee felt that a prescriptive decision tree would not be appropriate for this patient population with the evidence that was available,” said the guideline authors. They therefore assessed the medications independently. They also encouraged clinicians to use their recommendations “in conjunction with shared decision-making with patients,” incorporating patient preferences and concerns with respect to side effects, route of administration, and/or cost.
“This guideline aims to serve as a starting point to highlight gaps in evidence to encourage future research into topics and comparisons that can then provide more prescriptive guidance,” stated the guideline authors, an international committee that included pulmonologists with ILD expertise, rheumatologists with SSc expertise, a general pulmonologist, a pulmonologist/rheumatologist with expertise in SSc and ILD, an information scientist, and 2 patients with SSc-ILD.
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The guideline strongly recommends treating patients with SSc-ILD with mycophenolate and conditionally recommends treatment with clyclophosphamide, nintedanib, rituximab, tocilizumab, and the combination of nintedanib plus mycophenolate.
The current recommendations are intended for a heterogenous population of patients with SSc-ILD, regardless of their disease status, said guideline authors. From the outset, the authors aimed to provide guidelines based on disease status for 3 patient subgroups: patients initially manifesting of SSc-ILD; patients with stable SSc-ILD; and patients with progressive SSc-ILD. Ultimately, this was not done because information on treatments effects according to disease status was not available.
The committee based its recommendations on a literature search in MEDLINE, EMBASE, the Cochrane Registry of Controlled Trials, Health Technology Assessment, and the Database of Abstracts of Reviews of Affects for relevant articles published through October 2022. The quality of evidence was based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.
Key Clinical Questions Addressed
The SSc-ILD guideline recommendations address 8 key clinical questions related to 6 individual therapies and 2 combination therapies.
Cyclophosphamide
Question 1 addresses whether patients with SSc-ILD should be treated with cyclophosphamide, a cytotoxic agent that has shown efficacy in some types of inflammation-associated ILD, including SSc-ILD. Cyclophosphamide is also associated with serious side effects, including bone marrow suppression and infections. Overall, the quality of evidence was rated as low, and the guideline committee issued a conditional recommendation for use of cyclophosphamide to treat patients with SSc-ILD. The committee noted that mycophenolate is used more frequently than cyclophosphamide owing to a more favorable side effect profile for mycophenolate, and most of the benefits of cyclophosphamide waned 1 year after cessation of treatment.
Mycophenolate
Question 2 concerns whether patients with SSc-ILD should be treated with mycophenolate, which is currently used as a standard-of-care treatment for patients with SSc. In 1 study, the mean forced vital capacity (FVC) percent predicted significantly improved from baseline to 12 and 24 months for mycophenolate compared with placebo. Significant differences in breathlessness, including at 24 months, also were observed in favor of mycophenolate vs placebo. Because of the reported significant decrease in disease progression and improvement in quality-of-life measures with minimal adverse events, the committee provided a strong recommendation for using mycophenolate to treat patients with SSc-ILD, although the evidence was of very low quality.
Rituximab
Question 3 asked whether patients with SSc-ILD should be treated with rituximab. A meta-analysis found that rituximab attenuated FVC percent predicted decline compared with placebo at 24 to 48 weeks. Rituximab also reduced the decline in diffusing capacity of the lung for carbon monoxide (DLCO) in 2 studies, and increased DLCO in 1 study. The committee issued a conditional recommendation for using rituximab to treat patients with SSc-ILD (very low-quality evidence).
Tocilizumab
Question 4 addressed whether patients with SSc-ILD should be treated with tocilizumab, for which a conditional recommendation was given (very low-quality evidence). The committee noted that tocilizumab was associated with significant reduction in disease progression; research found tocilizumab treatment vs placebo was associated with a favorable mean absolute change in FVC from baseline at 48 and 96 weeks.
Nintedanib
Question 5 asked whether patients with SSc-ILD should be treated with nintedanib, an oral intracellular tyrosine kinase inhibitor, for which the guideline committee issued a conditional recommendation (very low-quality evidence). The committee cited research showing a significant decrease in disease progression against gastrointestinal adverse events, which can be managed with medication discontinuation, though there are a limited number of randomized studies and the evidence was primarily from post hoc data analysis. The recommendation is for all patients with SSc-ILD, regardless of whether their disease is progressive or stable.
Nintedanib Plus Mycophenolate
Question 6 addressed whether patients with SSc-ILD should be treated with nintedanib plus mycophenolate. It is currently unknown whether a combination of treatments with different mechanisms of action may be preferable to individual agents; moreover, if dual therapy is preferred, it is unknown what the most effective combination would be. Research has shown a lower annual rate of decline in FVC and FVC percent predicted for combination therapy with nintedanib plus mycophenolate compared with placebo. Combination therapy also was associated with an increased risk for decreased appetite, as well as an increased risk for diarrhea, nausea, vomiting, and/or fatigue compared with placebo. The guideline committee provided a conditional recommendation for using the combination of nintedanib plus mycophenolate to treat patients with SSc-ILD (very low-quality evidence).
Pirfenidone
Question 7 asked whether patients with SSc-ILD should be treated with pirfenidone, an antifibrotic agent that has been recommended for use in idiopathic pulmonary fibrosis and has been evaluated in guidelines for progressive pulmonary fibrosis. Critical outcomes included disease progression and mortality. A systematic review identified 1 RCT on pirfenidone in SSc-ILD, but it was underpowered for the proposed outcomes. The committee recommended further research regarding the safety and efficacy of pirfenidone for patients with SSc-ILD, and the quality of evidence for critical and important outcomes was very low.
Pirfenidone Plus Mycophenolate
Question 8 addressed whether patients with SSc-ILD should be treated with pirfenidone plus mycophenolate. In 1 study, the combination of pirfenidone plus mycophenolate was associated with improvement in the Transition Dyspnea Index score at 16 weeks compared with mycophenolate alone, but no significant difference occurred in Health Assessment Questionnaire-Disability Index scores. The committee recommended further research regarding the safety and efficacy of pirfenidone plus mycophenolate combination therapy for treating patients with SSc-ILD, and the quality of evidence was very low.
Corticosteroids and Renal Crisis
The guideline committee also noted that renal crisis in patients with SSc is associated with systemic corticosteroid therapy in some cases, especially among patients who have early diffuse cutaneous SSc. Thus, the committee provided a best clinical practice statement, urging that caution should be taken in using systemic corticosteroids in patients with SSc with or without SSc-ILD, and the daily dose should not exceed the equivalent of 15 mg prednisone when possible.
Directions for Future Research
Further research is needed “to determine treatment efficacy, safety, and impact on patient QoL by disease status,” the guideline authors stressed. In particular, the question of whether there is a “differential treatment effect going from initial
diagnosis of SSc-ILD to development of progressive SSc-ILD” has yet to be addressed. “Furthermore, additional studies looking at combination therapy and the sequence of initiating each therapy would be of clinical benefit,” the guideline authors noted.
Disclosure: Committee members disclosed all potential conflicts of interest according to the ATS policies. Please see the original reference for a complete statement on disclosures.
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