Concurrent Ulcerative Colitis in a Pregnant Patient with Rheumatoid Arthritis

Abstract

We herein report a rare concurrent case of ulcerative colitis (UC) in a pregnant woman with rheumatoid arthritis (RA), which was well managed by biologics. When a 32-year-old woman with seropositive RA became pregnant, she began experiencing hematochezia; colonoscopy revealed diffuse inflammation with multiple ulcers. Based on clinical examinations and pathological assessments, she was diagnosed with severe UC. Although prednisolone had no curative effect and infliximab caused an infusion reaction, golimumab successfully induced remission with normal delivery. This case report describes the successful treatment of a pregnant woman with UC and RA through biologics administration.

Introduction

In recent years, the number of patients with ulcerative colitis (UC) has been increasing worldwide, and the number of clinicians dealing with cases of pregnancy complications has also been increasing because of the relatively high incidence of young patients with this disease.

Inflammatory bowel disease (IBD) medications are generally considered safe even for pregnant women, with the exception of some antimicrobial agents, including rifaximin and the antimetabolite methotrexate; however, these agents may be prescribed if the physician determines that their benefits outweigh their risks (1). In addition, the teratogenicity of thiopurine preparations, which had been empirically avoided in pregnant women, has been repudiated by recent prospective studies (2,3). Furthermore, the NUDT15 gene polymorphisms involved in thiopurine metabolism can be easily examined in blood samples, allowing for the safe administration of thiopurines to patients (4,5). However, there is some concern that if the gene in the mother is heterozygous, her fetus could be severely affected, depending on the polymorphism in her partner (6).

Biologics have not only brought about a paradigm shift in the treatment of IBD in this century due to their dramatic therapeutic effects but have also been widely used as a pivotal treatment for a variety of diseases, including psoriasis, rheumatoid arthritis (RA), and ankylosing spondylitis. Recently, the use of biologic antitumor necrosis factor (TNF)-α antibody agents for these diseases in pregnant women has been steadily increasing, but the majority of these agents were either infliximab or adalimumab (7,8), and case reports concerning the use of other agents in pregnant women are still limited.

It is well known that certain IBDs, such as UC and Crohn's disease, are often accompanied by extraintestinal manifestations (EIMs). Typical EIMs include scleritis, erythema nodosum, pyoderma gangrenosum, arthritis of the extremities, ankylosing spondylitis, sclerosing cholangitis, and biliary tract diseases. However, to our knowledge, there are only 12 published cases with overlap of chronic RA and UC (9-20).

In this study, we diagnosed a case of primary onset UC of the pancolitis type in a pregnant woman with RA, in which endoscopic remission of UC was safely achieved with the appropriate use of biologics without causing adverse effects to either the mother or her newborn baby.

Case Report

A 30-year-old woman with no medical history sought treatment for chronic right wrist pain, left thumb carpometacarpal joint pain, and bilateral forefoot pain. As shown in Table 1, blood tests showed high-titer positivity for both rheumatoid factor (72 U/mL) and anti-cyclic citrullinated protein (CCP) antibody (157.0 U/mL); an ultrasound showed active joint synovitis and bursitis coinciding with the painful area, leading to a confirmed diagnosis of RA (Fig. 1).

Table 1.

Results of Blood Examination at Admission.

Hematology					Biochemistry
White blood cell		13,700	/μL		Total protein		4.8	g/dL
Neutrocyte		69.0	%		Albumin		2.6	g/dL
Lymphocyte		16.0	%		Aspartate transferase		36	U/L
Monocyte		8.0	%		Alanine aminotransferase		17	U/L
Eosinocyte		4.0	%		Gamma-glutamyltransferase		8	U/L
Basocyte		0.0	%		Alkaline phosphatase		171	U/L
Red blood cell		3.74	×104/μL		Lactate dehydrogenase		211	U/L
Hemoglobin		11.6	g/dL		Cholinesterase		40	U/L
Hematocrit		34.2	%		Fasting glucose		81	mg/dL
Platelet		36.5	×104/μL		Urea nitrogen		3	mg/dL
					Creatinine		0.35	mg/dL
Erythrocyte sedimentation rate					Total bilirubin		0.3	mg/dL
1 h		41	mm		Sodium		132	mEq/L
2 h		69	mm		Potassium		3.1	mEq/L
					Chloride		95	mEq/L
Coagulation					Serology
Prothrombin time		12.6	s		C-reactive protein		5.26	mg/dL
Prothrombin INR		1.08			Rheumatoid factor		72	U/mL
					Anti-CCP antibody		157	U/mL

INR: international normalized ratio, CCP: cyclic citrullinated protein

Figure 1.

Ultrasonographic and radiographic images of the hands and feet. (A) Ultrasonographic images of the wrist. A dorsal longitudinal scan of the wrist revealed active synovitis. (B, C) Ultrasonographic images of the MTP joint. Dorsal longitudinal and transverse scans of the MTP4 joint revealed synovial hypertrophy. (D) Ultrasonographic images of the intermetatarsal space. A dorsal transverse scan of the joint between MT3 and MT4 revealed intermetatarsal bursitis. Radiographic images of the hands and feet (E, F, G). Radiographs of the hands and feet showed bone erosion of the right fourth metatarsal head (arrowhead). MTP: metatarsophalangeal, MT: metatarsal bone, PP: proximal phalanx

A combination of certolizumab pegol and methotrexate quickly induced clinical remission, which was maintained with certolizumab pegol monotherapy. After one and a half years of treatment, the patient became pregnant and was thus followed without medication. In the 14th week of pregnancy, the patient started experiencing diarrhea, and her symptoms, including hematochezia, worsened, so she was referred to our hospital.

At the time of admission, the frequency of defecation was approximately 10 times a day, and the stool characteristics were bloody diarrhea. An examination revealed no evidence of anemia, but a fever (39.7℃), tachycardia (141 beats/min), positive C-reactive protein (5.26 mg/dL), and elevated erythrocyte sedimentation rate (41 mm/h) were noted (Table 1). Diffusion-weighted magnetic resonance imaging of the entire colonic mucosa showed high-density signaling and a decreased diffusion coefficient score. Sigmoid colonoscopy with glycerin enema pretreatment performed at the same time showed diffuse inflammation of the left-sided colon from the rectum just above the anal canal to the sigmoid and descending colon, with multiple erosions and ulcers in addition to a friable mucosa prone to bleeding (Fig. 2A-D).

Figure 2.

Endoscopic images of ulcerative colitis and histopathological findings of the colon on admission. Endoscopic images of the rectum (A), sigmoid colon (B, C), and descending colon (D). Colonoscopy showed the absence of vascular patterns, friability, erythema, erosions, and ulcers. Histological image of the biopsied specimens from the sigmoid colon showed diffuse inflammatory cell infiltration, cryptitis, and crypt abscess (E, F).

A histopathological examination of the colon mucosa revealed a high degree of diffuse inflammatory cell infiltration, including neutrophils, and a decrease in goblet cells, as well as intramucosal hemorrhaging, a high degree of cryptitis, and crypt abscess (Fig. 2E, F). A general fecal culture showed no pathogenic bacteria, and other causes of colitis, such as drug-induced, angiopathy-related, or ischemia-related colitis, were ruled out, so a definite diagnosis of UC of moderate severity was made.

Since oral mesalamine (4,000 mg per day) and granulocyte apheresis therapy failed to induce clinical remission and corticosteroid therapy with prednisolone (30 mg per day) was completely ineffective (high-dose intravenous prednisolone therapy should be avoided during pregnancy), we attempted to induce remission with intravenous infliximab (5 mg/kg) (Fig. 3). After the first administration of infliximab, there was a definite improvement in the clinical symptoms, and following the second dose two weeks later, her disease became more manageable, and the patient was soon discharged. However, during the administration of the third dose of infliximab, the patient suddenly developed transient dyspnea and facial flushing, which could be considered an infusion reaction, and infliximab was discontinued. Since the clinical efficacy of the anti-TNF-α antibody preparation had been clearly confirmed, with the approval of the patient and her family, she was switched to golimumab (100 mg/body, subcutaneous injection every 4 weeks), a human anti-TNF-α antibody preparation. Subsequently, golimumab was continued until the 33rd week of gestation, followed by a period of temporary withdrawal based on the Toronto consensus statements (21) and the results of a recent clinical report (22), and a healthy baby (Apgar score of 8/8) was delivered by Caesarean section at week 39 of gestation. Cesarean section was selected because the patient went from weak labor to delivery arrest during the course of delivery after her water broke.

Figure 3.

Progress chart depicting the patient’s clinical course. GMA: granulocyte apheresis therapy, DOB: date of birth

Fortunately, the mother and her baby were healthy during the 60-week follow-up period after delivery, and remission of UC was successfully maintained with golimumab and oral mesalamine (4,000 mg per day). Total colonoscopy performed at the 22nd postpartum week showed multiple pseudopolyposis findings in addition to scarring changes after healing of extensive mucosal inflammation involving the entire colon, including the cecum, and the patient was judged to be in endoscopic remission of UC of the pancolitis type (Fig. 4). Dose escalation of oral mesalamine with its topical administration will be considered if UC worsens in the future. Flexor tendon sheath synovitis of the right index finger and left ring finger, which is considered to be a symptom of RA, was observed starting in the fifth week post-delivery, and RA treatment with methotrexate will be resumed if the symptoms worsen.

Figure 4.

Endoscopic images after 10 months of treatment with biologics. Cecum (A), transverse colon (B), descending colon (C), and sigmoid colon (D).

Discussion

We experienced a rare case of new-onset UC at 14 weeks' gestation in a young woman who had been successfully treated with certolizumab pegol and methotrexate for RA and was subsequently followed without medication.

According to previous reports, arthritic manifestations represent the most common EIMs of UC, affecting 31% of patients with UC (23). However, RA is seldom associated with UC, and only 0.14-0.8% of patients with UC also suffer from RA (24,25). Therefore, while nonspecific joint damage often develops in patients with UC, the combination of RA and UC is rare. In this regard, it is very important to differentiate whether arthritis is so-called enteropathic arthritis associated with IBD or RA. In enteropathic arthritis associated with IBD, serum indicators that are positive in RA cases, such as rheumatoid factor and anti-CCP antibodies, are basically negative (26), and enteritis symptoms precede arthritis. The present case did not meet the definition of enteropathic arthritis, as both the rheumatoid factor and CCP antibody titers were positive. In addition, the multiple-site nature and symmetrical onset of arthritis at the ends of the extremities clearly preceded the enteritis symptoms, a finding that positively supports arthritis of RA origin. Radiographs showed bone erosions typical of RA, while ultrasonography of the wrist clearly revealed the presence of active synovitis, and the total score of the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria (27,28) was eight points, which finally led to a definitive diagnosis of RA.

To correctly understand the pathogenesis of RA-associated enteritis, it is necessary to clearly differentiate ischemic enteritis caused by vasculitis, secondary amyloidosis, and anti-rheumatic drug-induced enteritis from UC. In the present case, a histological examination easily excluded the possibility of ischemic colitis or secondary amyloidosis; the symptoms of colitis appeared more than three months after the discontinuation of methotrexate and certolizumab pegol, and characteristic findings of drug-induced enteritis, including apoptotic bodies in the epithelial cells of the cryptic growth zone, eosinophilic infiltration in the mucosa, and increased T lymphocyte infiltration in the epithelium (29-31), were all absent. In addition, Krishnan et al. investigated the frequency of adverse events associated with the use of anti-TNF-α inhibitors and found 158 cases of IBD after treatment with anti-TNF-α inhibitors in patients with RA and juvenile RA (JRA) (32). No cases of new-onset IBD were reported with certolizumab pegol in RA or JRA patients. The majority of “suspected drug-involved cases” in patients with RA or JRA were reported to involve etanercept (1 patient, 100% and 40 patients, 90.9%, respectively). In contrast, although a weak association has been shown between new-onset IBD and anti-TNF-α inhibitor treatment in patients with RA, there are no confirmed cases of IBD induced by anti-TNF-α inhibitors. Based on these reports, we concluded that drug-induced enteritis could be ruled out.

The main biologics used in the treatment of RA have been antibodies that target inflammatory cytokines, such as TNF-α and interleukin-6, but the use of abatacept, a CTLA4-Fc fusion antibody that targets immune checkpoints that inhibit costimulation necessary for T-cell activation, has also increased over the last decade. Accordingly, several cases of enteritis very similar to UC have been reported in patients with chronic RA treated with abatacept or tocilizumab (33,34). The mucosal morphology of these types of immune checkpoint inhibitor (ICI)-associated enterocolitis is very similar to that of UC, making it difficult to distinguish them from each other by endoscopic findings. Histologically, however, it has been reported that the characteristic feature of enteritis is the presence of apoptotic bodies in the cryptic growth zone of the intestinal mucosal epithelium (35), which may be useful in determining the appropriate diagnosis.

Considering ours and the previously reported overlapping cases of UC and RA, we found that these criteria were applicable in all 13 cases (4 men and 9 women) (Table 2) (9-20). Seropositive RA preceded UC in all patients, and the median duration between the onset of the two diseases was six years. More than half of the cases (61.5%) were pancolitis, and the rest were left-sided colitis (38.5%). In addition to salazopyrin, mesalamine, and prednisolone, recent reports have shown cases of remission induced by apheresis or biologics (15,17,18).

Table 2.

Clinical Features of Cases with Rheumatoid Arthritis and Concomitant Ulcerative Colitis.

#		Sex		Age of RA		Age of UC		Serological test		UC type		UC treatment		Ref.
1		F		30		37		Positive		Left-sided		SASP, steroid		9
2		M		35		65		Positive		Pancolitis		Steroid		10
3		M		58		59		Positive		Left-sided		SASP, steroid		11
4		F		46		63		Positive		Pancolitis		SASP, steroid		12
5		F		44		50		Positive		Pancolitis		Colectomy		13
6		F		36		36		Positive		Pancolitis		Colectomy		14
7		F		27		56		Positive		Left-sided		Apheresis, steroid		15
8		F		X		X-12		Positive		Pancolitis		SASP, steroid		16
9		F		61		65		Positive		Pancolitis		Apheresis, steroid		17
10		M		75		81		Positive		Pancolitis		Infliximab		18
11		F		47		53		Positive		Left-sided		5ASA, steroid		19
12		M		41		45		Positive		Left-sided		SASP, steroid		20
13		F		30		32		Positive		Pancolitis		Golimumab		-

RA: rheumatoid arthritis, UC: ulcerative colitis, ASAP: salazosulfapyridine, 5ASA: mesalamine

It is clear that overlapping RA and UC occurs infrequently. Adachi et al. suggested that the molecular biological mechanism for this disease combination from the perspective of genetic factors involves human leukocyte antigen (11). Recently, genome-wide association studies have been used to identify and analyze disease susceptibility genes. However, the common genes associated with these two diseases have not yet been identified, so further research on this point will be needed in the future.

In conclusion, this is a rare case in which we were able to successfully treat a pregnant patient with UC and RA and support her safe delivery through the use of biologic agents. This report highlights a useful alternative treatment option for pregnant patients unable to tolerate infliximab.

The patient provided her written consent for reporting her case in an international published medical journal, including clinical details and images.

The authors state that they have no Conflict of Interest (COI).