Rheumatic manifestations of inflammatory bowel disease

Abstract

This article reviews the literature concerning rheumatic manifestations of inflammatory bowel disease (IBD), including common immune-mediated pathways, frequency, clinical course and therapy. Musculoskeletal complications are frequent and well-recognized manifestations in IBD, and affect up to 33% of patients with IBD. The strong link between the bowel and the osteo-articular system is suggested by many clinical and experimental observations, notably in HLA-B27 transgenic rats. The autoimmune pathogenic mechanisms shared by IBD and spondyloarthropathies include genetic susceptibility to abnormal antigen presentation, aberrant recognition of self, the presence of autoantibodies against specific antigens shared by the colon and other extra-colonic tissues, and increased intestinal permeability. The response against microorganisms may have an important role through molecular mimicry and other mechanisms. Rheumatic manifestations of IBD have been divided into peripheral arthritis, and axial involvement, including sacroiliitis, with or without spondylitis, similar to idiopathic ankylosing spondylitis. Other periarticular features can occur, including enthesopathy, tendonitis, clubbing, periostitis, and granulomatous lesions of joints and bones. Osteoporosis and osteomalacia secondary to IBD and iatrogenic complications can also occur. The management of the rheumatic manifestations of IBD consists of physical therapy in combination with local injection of corticosteroids and nonsteroidal anti-inflammatory drugs; caution is in order however, because of their possible harmful effects on intestinal integrity, permeability, and even on gut inflammation. Sulfasalazine, methotrexate, azathioprine, cyclosporine and leflunomide should be used for selected indications. In some cases, tumor necrosis factor-α blocking agents should be considered as first-line therapy.

INTRODUCTION

The association between arthritis and inflammatory bowel disease (IBD) was originally described in 1929[1], but it was not until the 1950s when peripheral arthritis associated with IBD was distinguished from rheumatoid arthritis, and in the 1960s, the concept of spondyloarthropathy (SpA) was established[2-4]. Here, we present a review of all pertinent literature from Medline regarding rheumatic complications of IBD. We include original and review articles, as well as relevant case reports published from 1929 to 2009.

With time, clinical and experimental evidence of the close relationship between IBD and some rheumatic diseases, particularly seronegative SpAs, has grown. In fact, IBD is considered part of the concept of SpA[5].

Some studies have shown that up to 70% of patients with SpA have inflammatory intestinal lesions, and up to 26% of patients with SpA who undergo ileocolonoscopy have intestinal abnormalities compatible with Crohn’s disease (CD). In fact, 6%-10% of patients with SpA develop IBD on follow-up; besides, studies with serial ileocolonoscopy have shown strong correlation between the presence of gut and joint inflammation in SpA[6-10]. Therefore, some authors have suggested that joint abnormalities are the initial manifestation of IBD, and after several years, these patients later may develop florid intestinal abnormalities. On the other hand, some studies that have evaluated extraintestinal manifestations of patients with IBD have shown that 36%-46% of patients have at least one extraintestinal manifestation, and rheumatic abnormalities are the most frequent (22%-33%)[11,12]. Besides, rheumatic manifestations are significantly more common in patients with disease confined to the colon. For instance, some patient series with ulcerative colitis (UC) have reported a prevalence of joint involvement of 62%[13]. Several studies have evaluated the prevalence of seronegative SpA in patients with IBD: 18%-45% of patients with IBD fulfill the criteria for SpA; 3%-9.9% fulfill diagnostic criteria for ankylosing spondylitis (AS); around 14% develop one or more clinical manifestations of SpA without fulfilling diagnostic criteria, and some of these patients (up to 24%) have asymptomatic sacroiliitis[14-18].

IMMUNOPATHOGENESIS OF GUT AND JOINT INFLAMMATION

Immunologic alterations shared by patients with IBD and SpA

There have been interesting studies about the immunopathogenesis of IBD and SpA, which have shown alterations in key molecules that regulate the immune response in the gut of patients with SpA, and some of them are almost the same as those found in CD[19]. For instance E-cadherin, a transmembrane glycoprotein that mediates the intercellular adhesion of epithelial cells is expressed highly in the gut of patients with IBD[20] and in patients with SpA[21], and subclinical acute and chronic gut inflammation, even in those without macroscopic lesions, which indicates that the alteration in the regulation of these proteins may be an early event in the development of gut inflammation. Besides, E-cadherin is a ligand of α4β7 integrin in intraepithelial T cells. Two studies have shown increased expression of this integrin in T cell cultures from the gut mucosa of patients with AS[22] and CD[23]. Increased expression of this integrin has been found in patients without histological signs of gut inflammation, which suggests that there are common abnormalities in patients with SpA and IBD that precede clinical inflammation.

Other alterations that are common in both groups of diseases are those described in CD4⁺ T cells. Currently, four types of CD4⁺ T cells have been described: Th1 cells are identified as interferon γ (IFN-γ) producers; Th2 cells produce primarily interleukin (IL)-4, IL-5, IL-10 and IL-13; Th17 cells produce mainly IL-17A and they also produce IL-17F, IL-21, IL-22, granulocyte-monocyte colony-stimulator factor (GM-CSF), CCL-20, and potentially tumor necrosis factor (TNF) and IL-6. These cytokines have pro-inflammatory properties and they act on a broad range of cell types to induce the expression of several cytokines (TNF, IL-1β, IL-6, GM-CSF, G-CSF), chemokines (CXCL1, CXCL8, CXCL10), and metalloproteinases. On the other hand, regulatory T cells (Tregs) have a suppressor function; they influence the immune system by cell-to-cell contact and also via regulatory mechanisms that are still not fully elucidated. It is known that they are able to produce IL-10 and transforming growth factor (TGF)-β, and it is interesting that Th17 and Treg developmental programs are reciprocally interconnected. Upon T-cell receptor stimulation, a naïve T cell can be driven to express Foxp3 and become a Treg cell in the presence of TGF-β, but in the presence of TGF-β plus IL-6 or IL-21, the Treg developmental pathway is abrogated, and instead, T cells develop into Th17 cells[24]. Initial studies have shown Th1 predominance in intestinal mucosa of patients with IBD and SpA, however, recent studies have suggested that, in both groups of patients, Th17 cells may have an important role in initiation and perpetuation of autoimmune inflammation. One study that involved 499 patients with CD and 216 with UC has shown increased IL-17F mRNA expression in intestinal biopsies of patients compared to controls[25]. A recent study has shown an increased proportion of Th17 cells in patients with SpA[26] and increased IL-17, IL-6, TGF-β and IFN-γ levels in synovial fluid of patients with SpA, when compared with patients with rheumatoid arthritis[27]. Also, some authors have suggested that dysfunction of Tregs participates in the immunopathogenesis of these diseases, and they have proposed their use as therapeutic agents in IBD[24,28].

TNF-α is a pro-inflammatory cytokine that is produced mainly by macrophages and activated T cells. It is a key molecule in chronic inflammation of SpA and IBD. In the latter, the interaction between antigen-presenting cells (APCs) and intestinal bacterial flora contributes to the development of uncontrolled CD4⁺ cell activation, which leads to the release of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12, IL-23 and IL-17. In SpA, models of transgenic rats and clinical observations have suggested that pathogenic microorganisms and their interaction with APCs also have a crucial role in the initiation and perpetuation of the altered immune response that leads to joint and enthesis inflammation. Additionally, increased intestinal permeability has been found in patients with SpA and IBD. This fact could alter the innate immune response to bacterial antigens[29]. These discoveries have had important therapeutic implications for these groups of patients.

Other relevant molecules involved in the pathogenesis of both groups of diseases are the toll-like receptors (TLRs) that play an important role in the innate immune response against pathogenic microorganisms. Several studies have shown increased expression of TLR-4 and TLR-2 in APCs of patients with SpA[30,31] and in intestinal biopsies of patients with UC and CD[32-34]. The alterations in function and regulation of these molecules may have an important role in the initiation and perpetuation of chronic inflammation in these diseases[35]. There are studies that have correlated several mutations and genetic variations of these receptors with susceptibility for these diseases. The results are controversial, probably due to the heterogeneity of the patients and the ethnic groups that have been included in the studies[36-39].

Other immunopathogenic abnormalities in IBD and SpA

Abnormal responses to certain microorganisms have been described in patients with IBD or SpA; for instance, increased levels of the same serotypes of Klebsiella pneumoniae have been found more frequently in patients with IBD and SpA, compared with healthy controls and controls with celiac disease[40]. Besides, several studies have shown increased levels of antibodies against Klebsiella antigens, and against collagens type I, III, IV and V in patients with CD or AS. There are molecular similarities between Klebsiella nitrogenase and HLA-B27 genetic markers and between Klebsiella pullulanase and collagen fibers types I, III and IV. Therefore, several authors have proposed that there may be molecular mimicry between Klebsiella and human molecules that could participate in the initiation and perpetuation of these diseases[41], i.e. anti-Klebsiella IgA cross-reacts with HLA-B27 antigen, and antibodies to enteric bacteria are able to lyse lymphocytes from HLA-B27 patients with AS.

The participation of the HLA-B27 molecule in the immunopathogenesis of SpA has been well known since 1973 when Brewerton and Schlosstein detected its high prevalence in patients with AS, psoriatic arthritis (PsA), reactive arthritis and anterior uveitis[42]. Its functional relevance was demonstrated elegantly in 1990 by Hammer et al[43]; their group developed a transgenic rat with the human HLA-B27 molecule. These rats developed a multisystemic inflammatory disease that had several clinical and histopathological similarities to SpA and IBD[43]. An important finding was that these rats did not develop joint or gut inflammation when they were in a bacteria-free environment, which supports the theory of the participation of microorganisms in the pathogenesis of these diseases[44]. Some studies involving patients with IBD have shown an association of HLA-B27 molecule with the presence of sacroiliitis, spondylitis, enthesitis, peripheral arthritis, erythema nodosum, uveitis and oral ulcers[14].

Other genes have been associated with the clinical presentation of several arthropathies associated with IBD[45]. The Oxford Group has found an association of type 1 arthropathy (pauci-articular, self limited, with relapses) with HLA-DRB1*0103, HLA-B35 and HLA-B24, while type 2 arthropathy (polyarticular, progressive) is associated with HLA-B44 in British patients[46]. One study that evaluated Spanish patients has found an association of the mini-haplotype TNF a6B5 with the presence of joint manifestations in patients with UC[47]. Another study has found that a polymorphism of the gene CARD15 is associated with the presence of gut inflammation in patients with SpA, and the same polymorphism is over-represented in patients with CD[48].

On the other hand, there is evidence to suggest that, for patients with IBD, tobacco use and history of appendectomy are risk factors for developing extraintestinal manifestations, particularly seronegative SpA and dermatological manifestations such as erythema nodosum and pyoderma gangrenosum[49].

In summary, the autoimmune pathogenic mechanisms shared by IBD and SpA include genetic susceptibility to abnormal antigen presentation, aberrant recognition of self, the presence of autoantibodies against specific antigens shared by the colon and other extra-colonic tissues, and increased intestinal permeability. The response against microorganisms may have an important role through molecular mimicry and other mechanisms.

CLINICAL PRESENTATION OF THE RHEUMATIC MANIFESTATIONS OF IBD

The rheumatic manifestations of IBD have been divided into peripheral arthritis, and axial involvement, including sacroiliitis, with or without spondylitis, similar to the presentation of classic AS. There may be other periarticular manifestations such as enthesopathy, which is the involvement of tendinous insertions, tendonitis, periostitis, clubbing and granulomatous lesions in joints and bones. There may also be osteoporosis and osteomalacia secondary to IBD and to its treatment[50].

Peripheral arthritis

The frequency of peripheral arthritis in IBD ranges from 17% to 20%, and it is more common in CD[51]. In a retrospective study that included 1459 patients with IBD, peripheral arthritis was present in 6% of patients with UC and in 10% of patients with CD[52]. Another study has shown arthritis in 10%, enthesitis in 7%, and a history of arthritis in 29% in a group of patients with IBD[53].

The Oxford Group[52] has classified the peripheral arthritis associated with IBD (also called peripheral enteropathic arthropathy) without axial involvement, as pauci-articular or polyarticular arthropathy (Table 1). In the pauci-articular form, joint symptoms are usually acute and self-limited; the joint involvement is asymmetric and migratory, with participation of both large and small joints, and lower limbs are more affected. Many episodes last from 6 to 10 wk but relapses are frequent and they tend to coexist with IBD relapses; these patients have high frequencies of other extraintestinal manifestations such as erythema nodosum and uveitis. It is interesting that in 31% of these patients the arthropathy may appear even 3 years before the diagnosis of IBD is made. On the other hand, the polyarticular form tends to have a chronic course and it may be destructive; its course is independent of IBD exacerbations and the coexistence of other extraintestinal manifestations is rare, except for uveitis[50,54]. Enthesopathy, particularly affecting the Achilles tendon or plantar fascia insertion are common manifestations.

Table 1.

Classification of peripheral arthropathy associated with IBD

Type 1 (Pauci-articular)	Type 2 (Polyarticular)
Less than five joints	Five or more joints
Asymmetric involvement	Persistent inflammation for months or even years
Lower limbs more affected	May be erosive
Self limited episodes that last < 10 wk	Affects both large and small joints
Usually concomitant IBD relapse	It can be symmetric or asymmetric
High frequency of other extraintestinal manifestations	Clinical course is independent of IBD activity
	Associated with uveitis

IBD: Inflammatory bowel disease.

In most of the cases, intestinal symptoms precede or coexist with joint manifestations, but in some patients, arthritis precedes the gut manifestations, even by several years. In a prospective study that included 123 patients with SpA, 6% of the patients developed CD from 2 to 9 years after the first joint symptom. For UC, some studies have described a temporal relationship between arthritis and gut inflammation relapses[50]; there have been case reports of patients that have developed arthritis at the same time as ileal pouchitis after total proctocolectomy for UC activity. However, other studies have shown that colectomy has almost no effect on joint inflammation[50,55]. The most consistent finding is that colon involvement increases the susceptibility to peripheral arthritis.

There have been isolated case reports about patients that have presented with progressive, destructive monoarthritis with granulomatous synovial inflammation, and CD has been diagnosed when extension studies have been carried out as part of the diagnostic workup[56].

AS and other forms of axial involvement

Axial involvement is part of CD and UC, although it is more common in CD (5%-22%) than in UC (2%-6%), and in general, the prevalence is 10%-20% for sacroiliitis and 7%-12% for AS[51,57,58]. A study that included patients from a referral center has shown that 30% of the patients with IBD had inflammatory low back pain, 33% had abnormal Shober index, and 30% had unilateral or bilateral grade I or II sacroiliitis. In fact, 35% of the patients fulfilled the European Spondyloarthropathy Study Group criteria for SpA[53,59], and 10% fulfilled the criteria for AS. Other studies from referral centers have shown similar results and higher prevalence than for population studies, which probably reflects referral bias[13,17,53,58,60] (Table 2).

Table 2.

AS prevalence studies in patients with IBD

Author and referencenumber	n	Origin of patients	Diagnostic criteria	Prevalence (%)
				AS	SpA	Sacroiliitis (Rx or MRI)	Inflammatory low back pain	Articular manifestations
de Vlam et al[53]	103	Referral center	ESSG	10	35	30	30	39
Scarpa et al[13]	79	Referral center	New York	25			18	43
Salvarani et al[17]	160	Open population	ESSG	2 (CD)	18.1			32.5
				5.1 (UC)
Palm et al[58]	654	Open population	ESSG	6 (CD)	22	2	19
				2.6 (UC)
				3.7 Total
Wordsworth et al[60]	42	Referral center	ESSG	25 (CD)		36

Rx: Radiography; MRI: Magnetic resonance image; ESSG: European Spondyloarthropathy Study Group.

The clinical picture is virtually the same as the one for patients with AS without extra-articular manifestations. Axial symptoms usually precede gut symptoms; clinical course is totally independent of the intestinal manifestations and intestinal surgery does not alter the course of SpA. Ankylosing spondylitis associated with IBD can develop at any age, whereas idiopathic AS usually starts before 40 years of age. In idiopathic AS, males are more affected than females (ratio 2.5:1), while in AS associated with IBD, the male to female ratio is 1:1[61].

LABORATORY AND OTHER DIAGNOSTIC WORKUP

The most common laboratory abnormalities are: anemia due to chronic inflammation and intestinal bleeding, leukocytosis, thrombocytosis, elevated acute phase reactants such as C reactive protein, and erythrocyte sedimentation rate. Perinuclear anti-neutrophil cytoplasm antibodies are found in up to 60% of patients with UC and in some patients with CD, and they seem to be directed against lactoferrin autoantigens[62]. Antinuclear antibodies and rheumatoid factor are usually absent. Synovial fluid may be inflammatory but sterile.

Anti-Saccharomyces cerevisiae antibodies (ASCAs) were first described in patients with CD (both IgG and IgA isotypes). Several studies have confirmed their relevance as markers of CD. One multicenter study has shown that their presence in patients with IBD, who are negative for ANCA, has a positive predictive value of 94.2% for CD, and it is associated with severe clinical manifestations of this disease[63]. Another recent study has shown that the prevalence of ASCAs in patients with CD is 80.6%, and they have a sensitivity of 81%, specificity of 78%, positive predictive value of 45.5%, and negative predictive value of 95% when used as a single marker in patients with IBD[64]. One study that evaluated 87 SpA patients positive for HLA-B27 has found increased levels of IgA but not IgG ASCAs, particularly in patients with AS; although patients with increased levels of the antibody had no gastrointestinal symptoms. It remains unclear if these antibodies are associated with the development of IBD in patients with SpA, but this finding supports the etiopathogenic association of AS with IBD[65].

Sacroiliitis and spondylitis in IBD are associated with the presence of HLA-B27, although in lower frequencies than in AS (33% vs 71%). Besides, patients with AS without HLA-B27 have a higher risk of developing IBD than those with HLA-B27[53]. The Oxford study[52] has shown an association of pauci-articular arthritis with the presence of HLA-B27 (27% vs 7% in controls), HLA-B35 (32% vs 15%) and HLA-DRB1*0103 (33% vs 3%), while the polyarticular form was associated with HLA-B44 (62% vs 30%)[45]. Another study has shown that the presence of the shared epitope is associated with synovitis in patients with IBD without sacroiliitis[50,66].

Radiological studies of peripheral joints have shown changes of acute arthritis such as increased volume of soft tissue. Erosions are uncommon in patients with self-limited arthritis. Patients with persistent arthritis may develop joint erosion and, if the hips are affected, there may be also loss of joint space. Axial radiographs show typical AS changes, although some studies have suggested that asymmetric sacroiliitis frequency may be higher[67].

OTHER RHEUMATIC MANIFESTATIONS ASSOCIATED WITH IBD

Less frequently, IBD has been associated with Sjögren’s syndrome[68], rheumatoid arthritis[69], inflammatory myopathy and Takayasu arteritis[70,71], although these come from isolated case reports and no confirmed clinical or pathophysiological association can be made. There has been one study that has evaluated the prevalence of fibromyalgia and spread of musculoskeletal pain in patients with IBD, which has found equal frequencies to those in the general population[72]. In addition, it is advisable to evaluate IBD patients for osteoporosis if they have received high-dose steroids for long periods, and to implement prophylactic measures such as calcium and vitamin D supplements[73].

TREATMENT OF RHEUMATIC MANIFESTATIONS OF IBD

Treatment depends on the severity of the clinical picture. Patients with mild oligoarthritis usually respond to relative rest, physiotherapy and intra-articular steroid injections[74]. Most of the patients respond to nonsteroidal anti-inflammatory drugs because they control the symptoms and joint and enthesis inflammation, but they do not stop joint destruction, and they may have important side effects including exacerbation of IBD[75,76] and produce small intestine and colon ulcers[77]. Hence, they are recommended for patients with mild exacerbations, to control symptoms in arthritis flares, but their use must be limited to the minimal effective dose and time.

Sulfasalazine and 5-aminosalicylic acid are often recognized as useful for IBD, and are efficacious for moderate peripheral arthritis in SpA and IBD-associated arthritis, particularly in UC[78,79]. Their usefulness in CD is less clear. Some studies have shown promising results, others, no benefit at all, to control CD-associated arthritis[80-82]. These drugs have no effect in the progression of aggressive arthritis and their utility in axial involvement is marginal; also, they do not prevent the appearance of IBD in patients with SpA[83]. Their beneficial effect may be explained by their anti-inflammatory effects in the intestinal wall, by normalizing its permeability and preventing antigen entrance through an abnormal intestinal wall[84].

Immunosuppression with methotrexate, azathioprine, 6-mercaptopurine, cyclosporine and leflunomide has been successful in some patients with peripheral arthritis and other extraintestinal manifestations, although there are no controlled studies that have demonstrated their efficacy[74,85-88], and the evidence of their efficacy comes from uncontrolled studies or case reports.

The description of the pathogenic mechanisms of SpAs and IBD have relevant therapeutic implications for both groups of diseases. The initial observation that intestinal manifestations of patients with both SpA and IBD improve with TNF-α blocking agents has led to the use of these medications in patients with IBD, with favorable results, particularly with infliximab and adalimumab in CD[89]. Currently, infliximab is a first-line treatment for patients with active AS associated with IBD, and other TNF-α blocking agents such as certolizumab that have shown good results for patients with IBD, are promising[90,91].

Also, considering the pathogenic relationship between gut and joint inflammation in SpA, there are other agents with potential benefits in both diseases. Some of these include IL-10, IL-11, IL-6, intercellular adhesion molecule 1, mitogen-activated protein kinase and integrin (α4 and α4β7) blockade, as well as TLR modulation[92-95].

Some groups have proposed the use of probiotics for the treatment of patients with IBD and arthritis or AS. Their use is based on modulation of intestinal flora by bacteria and their products. The objective is to treat patients with persistent arthralgia in the early phases of the disease, before chronic damage is established, to improve the quality of life and have a positive influence on the natural course of the disease. Some interesting studies have demonstrated that these compounds improve experimental colitis in murine models and in patients with IBD. One of these models has shown that the anti-inflammatory effect depends on the probiotic DNA, in an IFN-mediated response induced by TLR9. Further studies should evaluate these and other mechanisms in animal models[96,97].

CONCLUSION

Rheumatic manifestations of IBD include peripheral arthritis, enthesitis and axial involvement, and they are present in up to 62% of patients with IBD. There is an important immunopathogenic relationship between gut and joint abnormalities in patients with IBD. TLR variants and abnormalities, altered function and balance of T-cell subpopulations and their production of pro-inflammatory cytokines, as well as integrin and E-cadherin dysfunction are partially responsible for such a relationship, and research in these areas will help to clarify the pathogenesis of these complex diseases. Medical treatment of rheumatic manifestations of IBD includes sulfasalazine and mesalamine, immunomodulators and TNF-α inhibitors. New treatments for IBD directed against pro-inflammatory cytokines and the regulation of the immune response may have long-term benefits for rheumatic manifestations.