Gastrointestinal and Hepatic Disease in Rheumatoid Arthritis

Synopsis

Gastrointestinal (GI) manifestations of rheumatoid arthritis (RA) are rare, but can be impactful for patients. Some GI processes are directly related to RA, while others may be sequelae of treatment or due to concomitant autoimmune diseases. In this article, we discuss the role of the GI tract in RA pathogenesis; the presentation, epidemiology, and diagnosis of RA-related GI manifestations; concomitant GI autoimmune diseases that may affect those with RA; and GI side effects of RA treatment. We note the importance of appropriately considering conditions unrelated to RA in the differential diagnosis when evaluating new GI symptoms in patients with RA.

Introduction

The importance of the gastrointestinal (GI) tract in development of autoimmunity has been increasingly appreciated in human diseases.^1,2 Many autoimmune diseases primarily affect the GI tract or the liver, including inflammatory bowel disease, Celiac disease, and various autoimmune liver diseases. Rheumatoid arthritis (RA) is a systemic autoimmune disease that can affect multiple organ systems. Understanding the range and prevalence of GI manifestations associated with RA itself, with related autoimmune disorders, and with RA treatments is essential for rheumatologists and other clinicians caring for patients with RA. All organs of the GI tract can be affected either directly from RA, through related autoimmune diseases, or as consequences of treatment (figure 1). In this article, we will discuss the presentation, epidemiology, and diagnosis of GI disease in patients with RA.

Figure 1.

An overview of digestive and hepatic complications from rheumatoid arthritis, its treatment, and related disorders

Epidemiology of RA

RA is a common rheumatologic disorder which affects up to 1.29 million adults in the US.³ Estimates of RA prevalence range between 0.5–1% of adults.³ Lifetime risk among Americans has been reported as 1.7% for men, and 3.6% for women.⁴ The prevalence of RA appears to be decreasing since the early 1960’s. In a 2008 study of RA in Olmstead County, MN, prevalence had decreased over time for most age groups. An increased prevalence was noted only in older age groups, suggesting an increase in chronicity, and decrease in incidence.³

Several factors have been associated with an increased risk for RA, including female sex, smoking, and certain infectious agents, such as GI pathogens, as discussed below. Genetic risk has also been identified, with higher risk for RA among those with the shared epitope – a sequence of five amino acids in the hypervariable segment common to several HLA-DRB chains.⁵ However, there remains considerable discordance even between identical twins in development of RA, speaking to a possible role of environmental risk factors.⁶ Numerous other mutations have been identified which predispose to RA, though none as strongly as the shared epitope, and none that are necessary or sufficient for development of disease.^7,8

The GI tract in RA pathogenesis

A growing literature suggests that the GI tract may play a major role in the pathogenesis of RA. This hypothesis was initially derived from an epidemiologic association between RA and periodontitis, a link which led early investigators to suspect a causal role of periodontitis in the development of RA.⁹

There are other clear cases of induction of arthritis in humans by GI pathogens. Reactive arthritis is triggered by certain pathogens such as Campylobacter, Chlamydia and Salmonella.¹⁰ Following ileojejunal bypass, intestinal bacterial overgrowth has been tied to a high rate of inflammatory arthritis, occurring in up to 50% of patients after this procedure.¹¹ Whipple’s disease is a prototypical case of inflammatory arthritis occurring in the setting of intestinal colonization by a single bacterial species in a susceptible host.¹²

Modern molecular investigative techniques have demonstrated a complex interplay between microbes, particularly of the gut, and the human immune system. Bacteroides fragilis and certain Clostridia species are able to directly upregulate T-regulatory cell activity, inducing an anti-inflammatory effect through production of IL-10.^13,14 Segmented filamentous bacteria have been demonstrated to induce TH-17 cell activity; these cells have been implicated in the pathogenesis of RA and secrete pro-inflammatory cytokines, including IL-17, TNF-alpha, IL-21, IL-22, and GM-CSF. ^15,16–19

It is hypothesized that dysbiosis, or relative change in the homeostatic balance of commensal bacteria, results in altered balance of anti- and pro-inflammatory interactions, and leads to dysregulation of a local immune response. As a result of this dysregulation, local T cells may migrate to distant lymphatic tissue, enabling them to exert effects distant to the site of activation in the intestine.

A growing literature supports this dysbiosis hypothesis, both in human and animal models. Germ-free or gnotobiotic mouse models (those raised in a germ-free environment with specific organisms introduced selectively) have been used in conjunction with mouse models of RA. Both Lactobacillus bifidus and segmented filamentous bacteria are able to produce arthritis in germ-free animals, associated with upregulation of TH-17 and downregulation of Treg cells.^20,21

Human evidence reflects similar findings. Fecal samples from patients with RA, compared to those with fibromyalgia, have significantly less Bifidobacteria and bacteria from the Bacteroides-Porphyromonas-Prevotella, Bacteroides fragilis, and Eubacterium rectale-Clostridium coccoides groups.²² Another investigation showed higher levels of Lactobacillus in those with early RA vs controls.²³ Two studies have shown increased levels of Prevotella copri in patients with early RA compared to controls, which corresponded with a decrease in Bacteroides fragilis populations.^24,25 Both of these studies suggested a pathogenic role of P. copri, with induction of disease and a TH-17 response following introduction of P. copri into a mouse model. A recent study comparing patients with RA to healthy controls showed lower abundance of Hemophilus species, which correlated with higher levels of autoantibodies in serum.²⁶ Intriguingly, those with RA treated with disease modifying anti-rheumatic drugs (DMARDs) had partial restoration of a “healthy” microbiome.²⁶

Finally, recent evidence points to the oral commensal bacteria Aggregatibacter actinomycetemcomitans, as a potential driver of anti-citrullinated peptide antibody (ACPA) formation. ²⁷ Through leukotoxin A, a pore-forming toxin, Aggregatibacter appears to induce dysregulation of citrullination in neutrophils, resulting in hypercitrullination of proteins. Exposure to leukotoxin Aa strains also correlated with ACPA levels in RA patients. Further supporting this hypothesis, the effect of shared epitope alleles on ACPA positivity in this study was seen only in those RA patients exposed to the leukotoxin A strain of Aggregatibacter.²⁷

These findings, taken together, suggest a complex role of the oral and intestinal microbiome in RA pathogenesis. The effect of the microbiome is likely modulated by the host environment and genome, the balance with other commensal bacteria, and other environmental factors. This remains an active and rapidly evolving field of research.

RA-related GI manifestations: epidemiology, presentation, and treatment

Patients with RA may develop digestive and hepatic complications of their disease. They can also develop related autoimmune diseases affecting the GI tract. A summary of these conditions by organ system is presented in table 1 and selected conditions are detailed below.

Table 1.

Overview of RA-related and concomitant autoimmune disease-related GI manifestations, by organ involvement

Organ	Involvement
Mouth	Secondary Sjogren’s syndrome (sicca)
	Oral ulcerations in associated inflammatory bowel disease
Esophagus	Dysphagia (from amyloidosis, skeletal deformities and other causes)
Stomach	GI bleeding or dysmotility from amyloidosis
Small intestine	Rheumatoid vasculitis
	Celiac Disease
	Amyloidosis
	Associated inflammatory bowel disease
Large intestine (including rectum)	Rheumatoid vasculitis
	Associated inflammatory bowel disease
	Amyloidosis
Pancreas	Autoimmune pancreatitis
Liver/Gallbladder	Hepatomegaly (in Felty’s syndrome, rheumatoid vasculitis)
	Hepatitis, cirrhosis, portal hypertension (in amyloidosis, autoimmune hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis)

Rheumatoid Vasculitis

Epidemiology

The incidence of rheumatoid vasculitis (RV) has declined considerably since the time of its initial description. The first estimated incidence from the 1970s in Bristol, UK, was approximately 6.0/million patients.²⁸ Between 1998–2000, incidence in the same UK cohort was reported as 3.0/million, and 3.9/million between 2001–2010.^29,30 Several hypotheses have been advanced to explain this drop in incidence, including improvements in RA therapy, decreased used of long-term high dose steroids, declines in smoking, and changes in oral microbiota.^29–31

GI involvement from RV remains a rare complication. In 1981, GI events due to RV, including acute abdomen or colitis, were reported in up to 10% of patients with RV.²⁸ In contrast, in the same cohort between 2001 and 2010, no GI events were seen among 18 patients; and only 2 events were seen among 47 patients between 1988 and 2000.³⁰

Clinical manifestations

The clinical presentation of RV is heterogeneous, ranging from mild cutaneous or nailbed disease to life-threatening organ involvement. The typical patient has longstanding seropositive, erosive and nodular RA.³² RV is rare among those with seronegative RA.³³ Uncommonly, cases with less than 5 years of RA disease duration have been described, as have occasional cases of RV as an initial manifestation of RA.³⁴

Constitutional signs including weight loss and hepatosplenomegaly are common, and fevers may occur in a smaller subset of patients. The most commonly affected organs are the skin and peripheral nervous system. Skin manifestations occur in 78–88% of patients, and may include purpuric lesions, cutaneous leukocytoclastic vasculitis, non-healing ulcerations similar to those seen in PAN, or gangrene.^28,30 Neurologic involvement, including peripheral neuropathy or mononeuritis multiplex, occurs in up to 50% of patients.^28,30 Other commonly affected organs include the heart (pericarditis), lung (alveolitis, ILD), kidney (necrotizing glomerulonephritis), and eye (scleritis, corneal melt).

Literature describing characteristics of GI involvement from RV is primarily limited to case reports and case series. GI involvement has been described both in association with other systemic manifestations, and as an isolated presentation. The presentation is similar to that of other vasculitides known to affect the GI tract, particularly polyarteritis nodosa (PAN), which must be considered in the differential diagnosis.

Among a case series of patients with GI involvement from varied systemic vasculitides, common characteristics arise. Abdominal pain is nearly universal.³⁵ Nausea, vomiting or diarrhea occur in about one third of patients.³⁵ Hematochezia/melena occurred in 16% of cases. Ulcerations of the stomach or small bowel were found in up to 27% of patients, and esophageal or colorectal ulcers in about 10%. More severe presentations, such as surgical abdomen, ischemia/infarct, or bowel perforation were reported in about 15%.³⁵

Involvement of several portions of the GI tract has been described in RV. Luminal involvement has been reported, with ulcerations of the small and large intestine.^36,37 Medium vessel involvement may lead to infarction, bowel perforation, and acute abdomen.^38–46 In the large intestine, pancolitis resembling ulcerative colitis, and appendicitis have been described.^47,48 One case presented with recurrent ileal strictures, which may mimic Crohn’s disease.⁴⁹ Within the pancreas, early reports described pancreatic necrosis secondary to medium vessel vasculitis. ³⁷ Intrahepatic hemorrhage, hepatic capsule rupture, and abdominal aneurysmal rupture with syncope have all been described.^50–52

Treatment

Due to the rarity of RV and lack of validated classification criteria, there is a paucity of evidence-based treatment recommendations. As such, treatment decisions are largely empirical and based on observational evidence.

Perhaps the most widely cited regimen, particularly for severe manifestations of RV, is that outlined by Scott and Bacon in 1981, a combination of IV cyclophosphamide and glucocorticoids.²⁸

Other approaches have been used, including the use of biologics. In a 2012 report of 17 patients treated with rituximab for RV, 71% achieved complete remission by 6 months, and 82% had complete sustained remission by 12 months.⁵³ Other biologics, including abatacept and tocilizumab, have been used in selected cases, though data supporting their efficacy is limited.^54,55

The use of TNF inhibitors has been controversial. These agents clearly play a role in therapy for RA, and have been used successfully in cases of refractory vasculitis.⁵⁶ However, observational data suggests that these agents may paradoxically trigger vasculitis.^54,55 Confounding by indication is a significant concern in this data, as those with more severe disease are both at higher risk for vasculitis and have higher likelihood of receiving TNF inhibitors. However, in light of these several reports, a degree of caution should be exercised in consideration of these agents for patients with a history of RV.

GI Dysmotility

Several authors have reported high rates of subjective dysphagia in patients with RA, with early studies demonstrating manometric changes including low peristaltic pressures, reduced lower esophageal sphincter pressures, and abnormal peristalsis.^57–59 However, these studies were small, and controls for medications and comorbidities such as amyloidosis and Sjogren’s syndrome, which are independently associated with esophageal dysfunction, were limited. A subsequent study of 2,131 patients with RA or osteoarthritis showed no difference in subjective dysphagia or gastro-esophageal reflux disease between these groups after controlling for use of NSAIDs and prednisone.⁶⁰

Oropharyngeal dysphagia is common in patients with temporomandibular joint involvement, as are impaired masticatory function and masticatory pain and fatigue.⁶¹ Dysphagia secondary to cranial nerve compression in atlantoaxial subluxation may occur, and several reports have described dysphagia in the setting of cervical deformities in RA.^62–66 Amyloidosis may cause dysmotility, and has been associated with goiter leading to extrinsic esophageal compression.^67–69

Though there is some suggestion that autonomic neuropathy may occur in patients with RA, GI involvement has not been described, as seen in other rheumatic diseases.^70,71 Gastroparesis and bowel dysmotility, while well-described in scleroderma, Sjogren’s syndrome, and SLE, have not been associated with RA.

Amyloidosis

AA amyloidosis is a rare complication of chronic inflammatory diseases, including rheumatoid arthritis. It is caused by deposition of the acute phase reactant serum amyloid A protein (SAA).

Epidemiology

Historically, the most common underlying cause of AA amyloidosis was chronic infections such as tuberculosis and osteomyelitis. However, the contribution of chronic infections has declined, and RA now stands as one of the most common causes of this disease.⁷²

Estimates of the prevalence of AA amyloidosis in RA vary widely depending upon population, year, and method used for detection. Due to a prolonged preclinical phase, estimates of clinical amyloidosis tend to be lower than those from autopsy studies or biopsies. Prevalence of clinical disease is estimated as low as 0.6–1.1% of patients with RA;^73,74 estimates of subclinical disease from random fat pad biopsy have been reported in up to 29% of RA patients.^75–77 The prevalence of AA amyloidosis in patients with RA in the biologic era is not well-described.

Clinical Manifestations

AA amyloidosis presents with GI manifestations in 10–70% of patients.⁷⁸ GI symptoms of amyloidosis include weight loss, diarrhea, abdominal pain, esophageal reflux, dysmotility, or bleeding resulting from vessel friability. GI bleeding may be severe, and fatal hemorrhage has been described.⁷⁹ Rare cases of protein-losing enteropathy and malabsorption have been reported.^80,81 Hepatic involvement leads to hepatosplenomegaly, obstructive symptoms such as jaundice and steatorrhea, as well as portal hypertension and its myriad complications.

Treatment

Treatment for AA amyloidosis involves treatment of the underlying inflammatory disorder. Both TNF inhibitors and the IL-6 receptor inhibitor, tocilizumab, have a body of literature supporting their efficacy in lowering SAA levels, and in some cases, inducing remission of disease.^82–90

Hepatic disease in Felty’s Syndrome

Felty’s syndrome is a rare complication of rheumatoid arthritis characterized by the triad of arthritis, splenomegaly, and neutropenia. This syndrome generally occurs in the presence of severe, poorly controlled RA with nodulosis and extra-articular features.

Liver abnormalities are common in Felty’s syndrome. About two thirds of patients develop hepatomegaly, and more than half have at least one abnormal liver function test.^91,92 Several findings have been described on biopsy, including nodular regenerative hyperplasia (NRH), sinusoidal lymphocytosis, and portal hypertension related to splenomegaly.^92,93 About 35% of patients with Felty’s syndrome with an abnormal liver enzyme have been found to have NRH on autopsy.⁹⁴ Distortion of the portal architecture due to NRH, along with splenomegaly, result in portal hypertension with its attendant complications, especially varices and ascites.⁹⁵

Secondary Sjogrens Syndrome

Sjogren’s syndrome and its GI manifestations are addressed in detail in the article Gastrointestinal and Hepatic Disease in Sjogren's by Drs. Salomon-Escoto and Popov in this issue. Sjogren’s syndrome occurs in both a primary form (pSS), unassociated with other autoimmune diseases, and a secondary form (sSS), which occurs in conjunction with other autoimmune disease. This section specifically addresses sSS associated with RA.

Epidemiology

RA is the most common autoimmune disease associated with secondary Sjogren’s, with reports showing that between 4% and 31% of patients with RA developing secondary Sjogren’s syndrome, depending upon classification criteria used and population included.^96–101

Clinical Manifestations

The clinical presentations of pSS and sSS are similar. Sicca symptoms remain the predominant manifestation. When compared to patients with pSS, sSS patients appear to have a slightly lower rate of xerostomia (98% vs 85% in sSS) and parotid enlargement (56% vs 9% in sSS).¹⁰¹ In addition, patients with sSS are less likely to have anti-SSA or SSB antibodies, and have lower titers of these antibodies, compared to those with pSS.¹⁰¹ Extraglandular manifestations including vasculitis, adenopathy, renal involvement, neuropathy, and arthritis appear similar between those with sSS and pSS.¹⁰¹

Gastrointestinal manifestations are commonly reported in Sjogren’s Syndrome. Table 2 summarizes associated abnormalities and frequency of these findings.

Table 2.

GI manifestations of Sjogren’s syndrome

	References	Notes
Mouth
Xerostomia	101,102,103	Included in classification criteria
Dysgeusia	102,103
Dental caries	102,103
Esophagus
Dysphagia	104–109	May relate to oropharyngeal function due to xerostomia, or esophageal dysmotility
Gastro-esophageal reflux disease	104–109
Esophageal dysmotility	104–109
Stomach
Chronic atrophic gastritis	110–113	Up to 81% of patients on EGD
Achlorhydria/Hypopepsinoginemia	114
Intestine
Protein-losing enteropathy	115–119	Rare
Celiac disease	114,120,121	Among those with CD, 3.3% may have SS; among those with SS, up to 14.7% may have CD on biopsy, though lower in cohort studies
Cryoglobulinemic vasculitis		Rare
Pancreas
Pancreatitis	122–125	Often subclinical. Presence of chronic pancreatitis (especially sclerosing) and salivary gland symptoms should raise suspicion for IgG4 related disease.
Pancreatic exocrine insufficiency	126,127	Often subclinical
Liver
Hepatomegaly	128
Abnormal liver enzymes	128–130	Usually mild, low grade. May follow multiple patterns of elevation.
Primary biliary cirrhosis	128–135	Of those with PBC, 18–38% have SS. Of those with SS, 2–7% have positive anti-mitochondrial antibody, and 92% of these patients will have histologic findings of PBC.
Autoimmune hepatitis	136,137	In one study, of those with SS with elevated LFT’s, 47% had AIH on biopsy

GI Malignancy in RA

The topic of risk for malignancy in RA, both related to the disease itself and to its treatment, has been widely studied. Based on a large meta-analysis, patients with RA do appear to be at modestly increased risk for all malignancies compared to the general population, with a standardized incidence ratio (SIR) of 1.09 (1.06–1.13).¹³⁸ However, when divided by specific cancer, this increased risk was explained mostly by higher incidences of lymphoma (SIR 2.26 (1.82–2.81)), melanoma (SIR 1.23 (1.01–1.49)) and lung cancer (SIR 1.64 (1.51–1.79)) compared to the general population. In contrast, the incidence of colorectal cancer appeared to be lower in patients with RA (SIR 0.78 (0.71–0.86)). The mechanism behind the decreased risk of colorectal cancer has been hypothesized to be related to higher use of NSAIDs in patients with RA, which may have a protective effect for colorectal cancer. ¹³⁸

Risk for other gastrointestinal cancers is less clear. In a large registry-based study of Japanese patients with RA, no significant difference in risk for gastric, esophageal, or pancreatic cancer was observed between patients with RA and the general population.¹³⁹ Surprisingly, in this cohort, a considerably lower incidence of liver cancer was observed among those with RA, with SIR 0.33 (0.15–0.51). However, it should be noted that overall risk of malignancy appeared lower in this group relative to those seen in other studies, with overall SIR 0.89 (0.82–0.97) for those with RA compared with overall population, raising a question of generalizeability.¹³⁹

Concomitant autoimmune diseases

Given the increased risk of certain autoimmune diseases in patients known to have RA,^140,141 it is important to consider autoimmune conditions as a cause of digestive, liver, or gallbladder dysfunction. This relationship is bidirectional, and those with certain GI autoimmune diseases are also at increased risk of developing RA. The concurrence of gastrointestinal autoimmune disease with RA is reviewed briefly below.

Autoimmune liver diseases

Autoimmune hepatitis is a rare disease causing chronic inflammation of the liver that can ultimately lead to hepatic dysfunction and cirrhosis. RA has been seen in 2–4% of patients with autoimmune hepatitis.¹⁴² In another study, anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor were seen in 8–10% of patients with autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC)), while 5% of those patients actually had a clinical diagnosis of RA.¹⁴³ There may be some shared genetic risk between RA and autoimmune hepatitis, as STAT4 polymorphisms have been associated with both conditions.¹⁴⁴

Like autoimmune hepatitis, PBC and PSC also share risk loci with RA and thus may have some relationship in terms of pathogenesis.¹⁴⁵ PSC patients often have concomitant inflammatory bowel disease (more commonly ulcerative colitis than Crohn’s disease), but can also have other autoimmune diseases. Rheumatoid arthritis was seen in only 1% of a cohort of 287 patients with primary sclerosing cholangitis, but represented 7.9% of non-IBD autoimmune disease in that cohort.¹⁴⁶

Inflammatory bowel disease

Inflammatory bowel disease (IBD), an autoimmune disease that can affect nearly every part of the digestive tract, includes Crohn’s disease and ulcerative colitis subtypes. In most studies evaluating risk for RA, the two subtypes of IBD are grouped together. In studies of patients with IBD and matched controls, the patients with IBD had 1.9 to 2 times higher odds of developing RA as compared to the controls.^147,148 IBD is also associated with arthropathy, so careful evaluation of clinical phenotype along with laboratory testing for rheumatoid factor and anti-CCP antibodies can be helpful in distinguishing the two entities.

Celiac disease

Celiac disease is an autoimmune disorder of the intestines precipitated by gluten exposure that can cause diarrhea and nutritional deficiencies. Celiac disease and RA share certain epidemiologic and genetic associations and can occur in the same patient.¹⁴⁹ As with IBD, arthralgias and inflammatory arthritis can also be seen in patients with Celiac disease.

Digestive and Hepatic consequences of treatment of RA

While RA and its related diseases may be associated with GI manifestations, it should again be noted that most of the conditions listed to this point are relatively rare findings in RA. Complications from the medications used in treatment of RA, in contrast, are not uncommon. The diagnosis and management of these attendant complications constitutes a major part of the daily practice of rheumatology. The GI effects from medications used in RA are addressed in detail in “Drug-induced Gastrointestinal and Hepatic Disease Associated with Biologics and non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDS)” by Drs. Wood and Caplan in this issue. In table 3, we briefly review the known adverse drug reactions associated with common medications used in the management of RA.

Table 3.

GI side effects of medications used in the treatment of RA

Medication	GI effects
NSAIDs	Ulcerations
	GI bleeding
	Colitis
	Hepatotoxicity
Corticosteroids	Thrush
	Ulcerations
	Visceral perforation
	Hepatic steatosis, NASH
	Hepatitis B reactivation
csDMARDs
Methotrexate	Stomatitis
	Nausea
	Abdominal pain
	Diarrhea
	Hepatotoxicity
Leflunomide	Nausea
	Abdominal pain
	Diarrhea
	Hepatotoxicity
Hydroxychloroquine	Abdominal pain
	Nausea
Sulfasalazine	Abdominal pain
	Nausea/vomiting
	Diarrhea
	Hepatotoxicity
Azathioprine	Anorexia
	Nausea/vomiting
	Hepatotoxicity
	Hypersensitivity reaction
JAK inhibitor
Tofacitinib	Abdominal pain
	Nausea/vomiting
	Gastritis
	Diarrhea
	Opportunistic infections
	GI perforations
	LFT abnormalities
	Hepatic steatosis
Biologics
TNF Inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab)	Nausea
	Abdominal pain
	Opportunistic infections
	Hepatotoxicity (especially infliximab)
	Hepatitis B reactivation
Abatacept	Dyspepsia
Rituximab	Abdominal pain
	Nausea/Vomiting
	Diarrhea
	Hepatitis B reactivation
	Bowel obstruction
	Bowel perforation
	Opportunistic infections
	LFT abnormalities
Tocilizumab	Oral ulceration
	Abdominal pain
	Gastritis
	Bowel perforation
	Opportunistic infections
	Hepatotoxicity

csDMARD: conventional synthetic DMARD. LFT: liver function tests. NSAIDs: non-steroidal anti-inflammatory drugs

Infections

Antirheumatic therapies, particularly steroids and biologic agents, are associated with an increased risk for opportunistic infections. Here, we briefly review several infections known to prominently affect the GI tract. A full review of infections associated with DMARD therapy is outside the scope of this article, as is treatment for these diseases.

Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis, most commonly affects the lung. Extrapulmonary disease is more common with immunosuppression. Among those that develop TB while being treated with biologics, 30–57% present with extrapulmonary manifestations, compared with a reported 20% among immunocompetent patients.^150–152 Patients with RA treated with biologic therapies are at significantly increased risk for TB, with about 3.7 to 4 times increased risk for active TB. ^153,154.

Tuberculous enteritis may affect any part of the GI tract, and may occur as a primary site of infection, or in the setting of disseminated, or miliary disease. It most commonly affects the peritoneum, ileum, colon, anorectum, and jejunum.¹⁵⁵ The symptoms of tuberculous enteritis are nonspecific, making diagnosis challenging even in endemic regions. Patients present with colicky abdominal pain related to obstruction (90–100%), weight loss (66%), fever (35–50%), and changes in bowel habits. Other symptoms may include malabsorption, anorexia, nausea, vomiting, or GI bleeding.¹⁵⁶

The lesions seen on imaging and colonoscopy may vary. Ulcerative lesions are most common, with multiple segments of ulcerations with or without nodules.¹⁵⁵ Hypertrophic lesions of the intestines including stricture and fibrosis may mimic Crohn’s disease. A combination of these findings may also occur, with thickening, ulceration, and inflammation of the intestinal wall and ileocecal valve, which may mimic carcinoma.¹⁵⁵

Nontuberculous Mycobacteria

Nontuberculous mycobacteria (NTM) are a broad group of mycobacterial organisms including M. avium, M. marinum, and rapidly growing Mycobacteria, among other species. As with tuberculosis, infection with NTM most commonly involves the lung, but may involve extrapulmonary sites. These infections are rare even among immunocompromised patients. In a study of 8,418 patients treated with TNF inhibitors, a NTM infection rate of 74 cases per 100,000 person years was observed. Of these cases, 69% were pulmonary, while 25% were extrapulmonary.¹⁵⁷ Among patients in clinical trials for multiple biologics, this rate was considerably lower, with only 1 case of NTM observed among 32,504 patients.¹⁵³ This lower rate may relate to the comparably shorter follow-up times in clinical trials.

Symptoms of NTM infection vary by the site involved and specific organism. GI involvement may result in diarrhea, abdominal pain, hepatosplenomegaly, and elevation of liver enzymes.

Endemic Mycoses

Histoplasma capsulatum is a dimorphic fungus endemic to the Midwestern and South Central United States.¹⁵⁸ Initial infection is often asymptomatic or associated with a mild flu-like illness. Immunocompromised patients may be prone to more severe, disseminated infections, either due to primary infection, or reactivation of previous infection. Immunosuppressive agents, including TNF inhibitors (especially infliximab), steroids, and conventional DMARDs, appear to be associated with an increased risk for histoplasmosis.^159–162

Constitutional signs including fevers, weight loss, lymphadenopathy, and hepatosplenomegaly are common.¹⁶¹ Patients most typically present with pulmonary involvement, often as a pneumonia which fails to respond to typical antibiotic therapy. GI involvement may occur in up to 70–90% of those with progressive disseminated disease, though it may remain asymptomatic and go undiagnosed.¹⁶³ Histoplasmosis may involve any part of the GI tract. Hepatosplenomegaly and abdominal lymphadenopathy are common. Esophageal involvement may occur due to direct infection with ulcer formation, or from external compression from fibrosing mediastinitis or mediastinal adenitis.¹⁶³ Involvement of the stomach and intestine may present with ulcers, GI bleeding, or as inflammatory masses that may mimic carcinoma.¹⁶³

Coccidioiodomycosis has also been reported in association with TNF inhibitor use (especially infliximab).^160,164 Coccidioidomycosis is endemic to the southwestern United States, though cases have been reported outside of this typical area.¹⁶⁵ GI manifestations are rare, though there have been cases reported of liver and pancreas involvement in disseminated coccidioidomycosis.¹⁶⁶

Patients on TNF inhibitors may also be at risk for blastomycosis. Blastomyces dermatitidis is endemic to the Ohio and Mississippi river valleys and the Great Lakes region, though cases have been reported outside this region.¹⁶⁷ The most commonly involved organs are the lung, skin, genitourinary tract, and osteoarticular structures.¹⁶⁷ GI manifestations are rare, but reported. Several cases of oral lesions have been described.^168–173 Other case reports have also described involvement of the esophagus^174,175 and pancreas.¹⁷⁶

Herpes simplex virus

The risk of viral infections appears to be modestly increased in patients using biologic therapies, with about 1.9 times higher odds for viral infection in those treated with biologics compared to other RA treatments (95% CI 1.02–3.58).¹⁵³ In a large meta-analysis of 70 clinical trials for biologic agents, 11 cases of herpes simplex virus (HSV) were described, and three were noted in a French registry study over 3 years.^153,177 HSV is most commonly associated with recurrent painful oral or anal lesions. It has been described to involve much of the GI tract, including pharyngeal ulcerations, esophagitis, proctitis, and scattered reports of gastritis, jejunitis, and colitis.¹⁷⁸ Both HSV1 and 2 are rare causes of potentially fulminant viral hepatitis.¹⁷⁸

Cytomegalovirus

Though a common concern in other immunocompromised populations, such as organ transplant recipients and patients with acquired immune deficiency syndrome, cytomegalovirus (CMV) infection is an extremely rare complication in patients treated for RA. In a large meta-analysis of 70 clinical trials for biologic agents, only one case of CMV infection was identified among 32,504 patients; and in a French registry of 57,711 patients, only four cases were noted over three years.¹⁵³ Several case reports of CMV reactivation with GI manifestations can be found in the literature, including in patients treated with MTX alone.^179–182

CMV has been described to cause myriad manifestations within the GI tract, including colitis, ulcerations, gastritis, esophagitis, ileitis, appendicitis, and hepatitis.^180–192 Patients may present with fever, abdominal pain, diarrhea, nausea/vomiting, or melena/hematochezia.

Management principles of RA in those with GI disease

Successful treatment of syndromes involving the GI tract in RA depends on identification of the underlying cause. It is therefore important to maintain high index of suspicion for more common causes of GI symptoms that are unrelated to RA. For example, acute diarrhea is most likely infectious and often self-limited, regardless of whether the patient has RA. Similarly, gastro-esophageal reflux disease (GERD) is a common problem in the general population, and management in patients with RA should proceed as in the general population, with empiric therapy and lifestyle modifications as a first line before progression to evaluation for more esoteric causes.

There are some unique issues to consider in treating patients with RA for their GI disease. In those with concomitant autoimmune diseases, choosing treatment that has efficacy both in RA and in the other autoimmune disease is a logical goal. For example, azathioprine can be used in IBD and autoimmune hepatitis and may help improve RA. Similarly, TNF-inhibitors, methotrexate and sulfasalazine may be used to treat IBD and are effective for RA.

Conversely, treatment for RA itself can be tailored when patients have GI comorbidities. In a patient with gastritis or peptic ulcer disease, injectable methotrexate may be preferable to the oral formulation. In patients with prior diverticulitis, providers should be cautious when using tocilizumab and tofacitinib due to risk of bowel perforation. Any major liver function abnormality is a relative contraindication for medications like methotrexate and leflunomide.

Summary

The GI tract and liver are uncommon sites for extra-articular manifestations of RA, but patients with RA may experience digestive and hepatic dysfunction for a variety of reasons. Evaluating potential medication side effects or infectious causes of GI dysfunction is important for RA patients on DMARDs, particularly corticosteroids, methotrexate, and TNF-inhibitors. Considering sequelae of longstanding or untreated RA, like amyloidosis and rheumatoid vasculitis, is appropriate in the right clinical setting. Patients with RA are also at increased risk for other GI and hepatic autoimmune diseases. Keeping in mind these unique features can help clinicians consider a full differential diagnosis when evaluating new digestive and hepatic disease in the setting of RA.

Key Points.

• -Gastrointestinal and hepatic disease are rare extra-articular manifestations of rheumatoid arthritis.
• -Treatment of rheumatoid arthritis can lead to digestive and hepatic dysfunction, either as a direct effect of medications, or from the infections to which RA patients are susceptible.
• -While rare in the modern era, complications of longstanding, poorly controlled RA (including rheumatoid vasculitis, Felty’s syndrome, and amyloidosis) may be associated with significant GI morbidity.