CLINICAL REVIEW
Musculoskeletal Manifestations in Inflammatory Bowel Disease A Revisit in Search of Immunopathophysiological Mechanisms Tejas Sheth, MD,*w Capecomorin S. Pitchumoni, MD, FRCP(c), MACP, MACG, MPH, AGAF,*wz and Kiron M. Das, MD, PhD, FRCP, FACP, FACG, AGAFy8z
Abstract: Inflammatory bowel diseases are chronic inflammatory disorders of multiple organ systems, primarily involving the gut, with chronic relapsing and remitting course. Musculoskeletal involvement is the most common extraintestinal manifestation. Distinct cell-mediated and humoral immunopathophysiological mechanisms have been identified underlying gut and joint inflammation in patients with inflammatory bowel disease and arthritis. Genetic polymorphisms in genes coding for NOD2 and IL12/IL23 complex lead to impaired antigenic handling in the gut and local immune dysregulation. The gut-synovial axis hypothesis implicates both environmental and host factors acting as triggers to initiate inflammation in genetically predisposed individuals, leading to priming of Th1 and Th17 lymphocytes in the gut and subsequent homing to the synovial tissue. Similar to gut, antibody-dependent cell-mediated cytotoxicity and complement-mediated cell lysis may also contribute to the joint damage. Involvement of peripheral joints occurs in 2 distinct manners, one being oligoarticular asymmetric arthritis associated with active disease and the other being polyarticular symmetric involvement of small joints. The axial involvement may include asymptomatic sacroiliitis, inflammatory back pain, and ankylosing spondylitis, running an independent clinical course. Noninflammatory involvement of the musculoskeletal system may present as osteopenia, osteonecrosis, fibromyalgia, or myopathies, leading to significant impact on quality of life. Key Words: inflammatory bowel disease, extraintestinal manifestations, arthritis, ulcerative colitis, Crohn’s disease, NOD2, gutsynovial axis
(J Clin Gastroenterol 2014;48:308–317)
T
he term inflammatory bowel disease (IBD) describes chronic inflammatory disorders of the gastrointestinal tract driven by immune dysregulation and resulting in relapsing and remitting clinical course. The term IBD refers primarily to Crohn’s disease (CD) and ulcerative colitis (UC), but also encompasses atypical colitides, such as
From the *Department of Internal Medicine, St Peter’s University Hospital, Drexel University College of Medicine; zDepartment of Medicine, New York Medical College, Valhalla, NY; wRutgersRobert Wood Johnson Medical School and University Hospital; yDepartment of Medicine, Biochemistry and Molecular Biology, Rutgers-Robert Wood Johnson Medical School; 8Division of Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School and University Hospital; and zCrohn’s and Colitis Center of NJ, Rutgers-Robert Wood Johnson University Hospital, New Brunswick, NJ. The authors declare that they have nothing to disclose. Reprints: Kiron M. Das, MD, PhD, FRCP, FACP, FACG, AGAF, Clinical Academic Building, 125 Paterson Street, Suite 5100B, New Brunswick, NJ 08901-1962 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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collagenous colitis and lymphocytic colitis. The underlying immune dysregulation may target the whole body and not just the gastrointestinal tract; hence, 10% to 40% of patients with IBD may have extraintestinal manifestations (EIM), which can involve virtually any organ system (Table 1).1,2 There seems to be a direct relationship between the extent of colonic involvement and the presence of EIMs, as three fourths of patients with EIMs have extensive colitis on histopathology.1,3 In addition, the presence of one EIM is associated with a high likelihood of developing others. Musculoskeletal involvement is the most common EIM seen in patients with IBD; up to 30% of patients are affected.4 This article reviews the immunopathogenesis and musculoskeletal manifestations (MSMs) in inflammatory colitides, with special reference to IBD.
PATHOPHYSIOLOGY The pathogenesis of MSMs of IBD involves the “gutsynovial axis” hypothesis, which implicates both environmental and host factors acting as triggers to initiate inflammation in genetically predisposed individuals.
Genetic Predisposition In IBD, individuals with certain HLA alleles are at higher risk of developing EIMs. EIMs have been linked to carriage of HLA-A2, HLA-DR1, and HLA-DQw5 alleles in CD patients and to DRB1*0103, B27, and B58 alleles in UC patients.5 The experimental introduction of HLA-B27 and b2-microglobulin genes into a germ line of rats leads to the spontaneous development of gut inflammation involving primarily the colon. These animals also develop inflammatory involvement of peripheral and axial joints, male genital tract, and psoriasis-like skin and nail lesions in a pattern that closely resembles to the EIMs in IBD patients.6 This linkage suggests a common genetic predisposition for inflammation of the gut and the joints. A similar experimental model for studying the relationship between CD and spondyloarthropathies (SpAs) is the TNFDARE mouse model was used. This model involves 69 base pair deletions of TNF-a-AU-rich elements (AREs) leading to constitutional activation of TNF-a-mRNA and increased levels of TNF-a in hematopoietic and stromal cells. The mutant mice develop gut involvement similar to CD along with SpA-like sacroiliitis, enthesitis, and peripheral arthritis, suggesting ARE deletions as a novel pathologic mechanism underlying development of IBD and associated EIMs. The mutant mRNA loses its ability to be modulated by transcriptional factors such as Janus kinases (JAK) and p38, suggesting a pivotal role of ARE as a final executive element in the inflammatory cascade.7 J Clin Gastroenterol
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TABLE 1. Extraintestinal Manifestations in IBD
Common Extraintestinal Manifestations Musculoskeletal (refer to Table 2 for further details) Skin and mouth Reactive lesions: erythema nodosum, pyoderma gangrenosum, aphthous ulcers, vesiculopustular eruption, necrotizing vasculitis Specific lesions: fissures and fistulas, oral CD, drug rashes Nutritional deficiency: acrodermatitis enteropathica (Zn), purpura (vitamin C and K), glossitis (vitamin B), hair loss and brittle nail (protein) Associated diseases: vitiligo, psoriasis, amyloidosis, epidermolysis bullosa acquisita Hepatobiliary Specific complications: primary sclerosing cholangitis and bile duct carcinoma Associated inflammation: autoimmune chronic active hepatitis, pericholangitis, portal fibrosis and cirrhosis, granuloma in CD Metabolic: fatty liver, gallstones associated with ileal CD Ocular Uveitis (iritis), episcleritis, scleromalacia, corneal ulcers, retinal vascular disease Metabolic Growth retardation in children and adolescents, delayed sexual maturation Less common extraintestinal manifestations Blood and vascular: anemia due to iron, folate, and B12 deficiency or autoimmune hemolytic anemia, thrombocytopenic purpura, leukocytosis and thrombocytosis, thrombophlebitis and thromboembolism, arteritis and arterial occlusion Renal and genitourinary tract: urinary calculi (oxalate stones in ileal disease), local extension of CD involving ureter or bladder, amyloidosis, renal tubular damage with increased urinary retention of various enzymes, eg, b N-acetyl-D-glucosaminidase Neurological: neuropathy, myelopathy, myasthenia gravis, cerebrovascular disorders Bronchopulmonary: pulmonary fibrosis, vasculitis, bronchitis, acute laryngotracheitis, abnormal pulmonary function tests Cardiac: pericarditis, myocarditis, heart block Pancreas: acute pancreatitis, duodenal CD CD indicates Crohn’s disease. Reproduced from Das.1 With kind permission from Springer Science + Business Media B.V. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
MHC class II allele DRB1*0103 is frequently associated with UC: 8% of patients with UC carry this allele as opposed to 2% of healthy population.5 The presence of this allele predisposes to type 1 peripheral arthritis, an oligoarticular asymmetric involvement of large joints. Thirtyeight percent of patients with active UC or CD have been identified as carrying this allele. The same allele predisposes to the development of the reactive arthritis (also known as Reiter syndrome) occurring after episodes of Salmonella or Campylobacter enteritis.8 This suggests a common link in the pathogenesis of articular symptoms in these apparently different clinical entities related to gut inflammation. Type 2 peripheral arthritis is a polyarticular symmetric involvement primarily of small joints of the upper extremities. Patients with type 2 arthropathy have a strong association with HLA-B44.8 More than 90% of patients with ankylosing spondylitis (AS) are HLA-B27 positive and 25% to 78% of patients with IBD and AS are HLA-B27 positive. In addition, up to 60% of patients with AS have been found to have asymptomatic gut inflammation, 25% of them may develop overt IBD over time.6 In contrast, isolated sacroiliitis in IBD, however, is unrelated to HLA-B27. Asymptomatic sacroiliitis has been seen in up to 16% of patients with IBD6; with the use of MRI, however, the detection rate of sacroiliitis is now thought to be as high as 46%.4
Triggers Germ-free HLA-B27 transgenic rats do not develop gut or joint inflammation, suggesting that bacterial exposure is a prerequisite for the development of SpA in genetically predisposed IBD patients.4 Initial theory hypothesized that after absorption from gut, soluble bacterial antigens may translocate to blood stream and then to r
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synovium, initiating there an inflammatory response and the development of arthritis.9 However, there is little new evidence to support the concept of the actual viable microbial pathogens themselves circulating from the gut to the joint. In contrast, it seems likely that both bacterial antigens and reactive T-cell clones home to the joint.10
The Gut-Synovial Axis As discussed above, the genetic basis of gut-synovial interaction is well described. The molecular and biochemical links between intestinal and synovial inflammation have been extensively investigated as well.
Role of Cell-mediated Immune Responses Microbial handling in the gut and the development of desired local innate immunity is mediated primarily through binding of pathogen-associated molecular patterns and danger-associated molecular patterns (PAMPs and DAMPs), to their respective pattern recognition receptors located in subcellular components (Fig. 1).12 Local intestinal inflammation leads to cellular damage and in severe instances, to cellular apoptosis with proteolysis of subcellular components. Many of these nonpathogen-derived molecules act as initiators or perpetuators of inflammation; they are collectively known as alarmins or DAMPs. PAMPs, in contrast, are pathogen-associated moieties and are derived from intestinal bacteria. In the normal host, these factors maintain intestinal epithelial barrier function and innate immunity; in active IBD, their dysfunction augments the inflammatory state. Both of these factors act as the inducers of proinflammatory effects, seen in patients with active IBD.12 Intestinal epithelial cell (IEC) damage leads to barrier breakdown and contact of the gut flora with the www.jcge.com |
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submucosal antigen-presenting cells (APC). Bacterial cell wall muramyl dipeptide (MDP) is processed by NOD2 on the APC surface leading to Th1 and Th17 responses. Polymorphisms in the NOD2 gene modulate this response and lead to release of TNF-a. TNF-a in turn induces apoptosis of the IEC through its effect on TNF receptor 2 (TNFR2),11 and induces microvascular endothelial dysfunction and increased microvascular permeability. Increased expression of integrins a4b7 and aEb7 on the surface of lymphocytes leads to binding of ligand mucosal addressin cell adhesion molecule-1 (MadCAM-1), which is expressed on the high endothelial venules in Peyer’s patches
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and flat-walled venules in lamina propria, and to gut homing of the lymphocytes with subsequent transmigration across abnormally permeable vessels. The resultant generation of oxygen-free radicals and local hypoxia augment TNF-a-induced cellular apoptosis and increases the influx of bacterial pathogens into lamina propria, perpetuating a vicious cycle. Activated T cells and macrophages return to the systemic circulation through efferent lymphatics and are sequestered by the adhesion molecules such as b7 integrins, intercellular adhesion molecule-1 (ICAM-1/CD54), and vascular adhesion protein-1 (VAP-1) expressed by the synovial cells. This results in synovial homing of gut-primed
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cells and subsequent development of nuclear factor kB (NFkB)-induced inflammation.6,13 Identical T-cell clonal expansions have been demonstrated in the colonic mucosa and the synovium of patients with enterogenic SpA.14 Macrophages expressing a transmembrane scavenger receptor CD163 (clusters of differentiation 163) have been found in colonic lamina propria and in synovial lining in patients with SpA, with the number of such macrophages directly proportional to Creactive protein levels and erythrocyte sedimentation rate.15 CD163 + macrophages have also been found to be increased in gut and synovium of CD patients.16 It is possible that macrophages may undergo relocation to synovial tissue and there contribute to inflammation. In fact, using the Stamper-Woodruff assay it has been shown that macrophages exhibit selective binding with P-selectin molecules expressed by synovial endothelial cells and may act as transporters of processed antigens from gut to synovium.9 E-cadherin is a transmembrane glycoprotein responsible for intercellular adhesion of intestinal epithelial cells. E-cadherin/catenin complex is upregulated in gut mucosa of IBD patients, where it acts as a ligand for a4b7 integrin, responsible for gut homing of lymphocytes. An identical upregulation of the E-cadherin/catenin glycoprotein complex has been observed in acute and chronic active bowel inflammation of SpA patients, suggesting its role as a common pathogenic link.17
Autoimmunity in IBD, Role of Humoral Immune Responses Autoimmunity has been emphasized in the pathogenesis of UC (Fig. 2). IECs have distinct isoform of tropomyosin, isoform 5 (hTM5). hTMs are cytoskeletal microfilament proteins. Patients with UC have been found to have mucosal and serum autoantibodies directed specifically against human tropomyosin isoform 5 (hTM5, p40).18,19 T-cell response against hTM5 has also been demonstrated in UC.20 Peripheral blood lymphocytes from patients with UC secreted significant amount of IFN-g on exposure to hTM5 in vitro. The frequency of anti-hTM5 antibody has been shown to be increased in family members of patients with UC.21 Furthermore, these autoantibodies have been found to be pathogenic to colon epithelial cells suggesting hTM5 as a target.22 The destruction seems to be
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complement-mediated cytolysis. Deposition of IgG1 autoantibody against p40 autoantigen in the colonic mucosa of patients with active UC along with activated compliment component has been reported.23 Notably, hTM5 is also expressed in the biliary tract, skin, eyes, and joints in addition to colon epithelium, and may contribute as a target to the occurrence of EIMs in the IBD patient populations.1,24–26 Colonic epithelial protein (CEP), another protein molecule expressed on surface of colonic epithelial cells, acts as a chaperone for translocation of hTM5 to cell surface.25 CEP may also act as a target of antibody-mediated cytolysis.27 CEP carries structural similarity with epitopes present in uveal tract, biliary epithelium, and chondrocytes suggesting antigenic cross-reactivity as one of the pathophysiological mechanism for the EIMs.1,25,26,28 It is shown that arthritic patients with histologic changes of either acute or chronic gut inflammation in absence of clinical symptoms, when subjected to distal ileal and colonic biopsies, showed increased number of plasma cell populations and increased levels of IgA and IgG in acute ileitis, whereas increased levels of IgA, IgG, and IgM in chronic ileitis. These 2 distinct immunohistochemical patterns of antibodies population were identical to the patterns observed in patients with reactive arthritis and peripheral arthropathy in AS, respectively.29 It is well known that B cells after initial stimulation in lymphoepithelial structures such as Peyer’s patches in ileum, migrate as memory cells to secretary tissues all over the body including synovium.9 An expansion of CD27 + and CD27 switch memory B cells and IgG-secreting plasma cells has been demonstrated in the synovial fluid in patients with juvenile rheumatoid arthritis (RA). The study also demonstrated CD86 positivity in the switch memory B cells, speaking for their role as APCs acting locally in the synovium, thus providing a link between cellular and humoral process.30 The synovial tissue of patients with RA has been shown to have infiltration of naive B cells, memory B cells, and plasma cells; the later generated by locally activated memory B cells as evidenced by V-region gene analysis.31 Synovial extrafollicular germinal center development has been shown in patients with RA.32 These evidences support continuous activation of selected B-cell clones and plasma cells locally in the synovium of patients with inflammatory arthritis and complement-mediated destruction. The antigen
FIGURE 1. The gut-synovial axis: cellular immune responses. Increased production of TNF-a in the gut through tumor necrosis factor receptor 2 (TNFR2)-mediated signaling increases myosin light chain kinase (MLCK) expression leading to dysfunction of tight junction and induction of apoptosis of intestinal epithelial cells (IECs).11 Complement-mediated cell lysis also contributes to epithelial cell destruction (Fig. 2). Resulting intestinal mucosal barrier loss leads to penetration of intestinal bacteria and their products to submucosa. Bacterial cell wall component muramyl dipeptide (MDP), a pathogen-associated molecular patterns (PAMP), is processed by NOD2 on the surface of antigen-presenting cells (APC) in the submucosa. Apoptotic IECs also generate molecular patterns (DAMP) that can activate NOD2-mediated responses. NOD2-mediated processing leads to secretion of proinflammatory cytokines IL1b, IL12, and IL23 by the APC. IL23 and IL12 activate Th17 and Th1 responses, respectively (subset). The cytokine heterodimer of IL23 (IL23A and IL12B— also known as p40) binds with heterodimeric IL23 receptor (IL23R and IL23RB1) on the surface of naive Th17 cells, whereas the heterodimeric IL12 (IL12A and IL12B) binds with the heterodimer of IL12 receptor (IL23RB1 and IL12RB2) on the surface of naive Th1 cells. Thus, the pathways share a component of the cytokine complex (IL12B or p40) and its receptor counterpart (IL23RB1). Binding of IL23 and IL12 to the receptor complex leads to activation and phosphorylation of Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), which in turn engage and phosphorylate STAT proteins (signal transducer and activator of transcription). STAT3 and STAT4 translocate to the nucleus and activate transcription of a battery of inflammatory molecules, transforming naive T cells in to activated T cells. Activated T cells produce IL17A, IL17F, IL22, IL26, and TNF-a, all of which induce a local inflammatory state in the gut mucosa, leading to apoptosis of IECs and loss of the mucosa barrier, thus perpetuating the vicious cycle. TNF-a also induces microvascular endothelial dysfunction and expression of integrins on the surface of polymorphonuclear cells, lymphocytes, and endothelial cells leading to trafficking of inflammatory cells in the gut. The gut-primed T cells get access to systemic circulation and home to various extraintestinal organs including synovial membranes through selective recognition through a variety of adhesion molecules, inducing a similar inflammatory milieu in the joint. r
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FIGURE 2. The gut-synovial axis: humoral immune responses. The proposed mechanism as shown in this figure is based on some key references described in Brandtzaeg and colleagues.9,18–25 The human tropomyosin isoform 5 (hTM5) is a cytoskeletal microfilament protein present in colonic epithelial cells in close association with a colonic epithelial cell protein (CEP) and in extracolonic organs including skin, eyes, biliary epithelium, and joints.1,24,25 T-cell activation to hTM5 has also been reported in ulcerative colitis.20 This may lead to production of IFN-g and IL4, which may lead to stimulation of B cells. B cells transform in to plasma cells leading to production of hTM5-specific antibodies both locally in the submucosa and in the circulation.18,19 The antibodies bind with hTM5 on surface of colonic epithelial cells and fix complement leading to complement-induced lysis of the cells.22 Alternatively, the antibodies also engage natural killer cells bearing the receptors for Fc fragment of the antibody molecules, leading to antibody-dependent cell-mediated cytotoxicity (ADCC).22,23 The hTM5-specific antibodies through systemic circulation may get access to joints, leading to similar set of events causing joint inflammation and damage. Specific B-cell homing may also be involved in this process.9
directly responsible for such activation has not been isolated; however it may be hypothesized that similar to UC, hTM5 or CEP can locally act as a trigger for the proliferation of memory B cells primed in the gut in patients with IBD. Further studies are needed to demonstrate reactivity between synovial tissue isolated from patients with IBD with joint symptoms and antibodies directed against hTM5 and/or CEP located in the joint tissue.1,24,26
IBD Genetic Loci and Their Association With Arthropathy Of the >100 susceptibility IBD genes identified, only 2 (NOD2 and IL23R) contribute significantly to clinical IBD risk, NOD2 accounting for 20% of overall susceptibility in CD.33 All other loci cause only a marginal increase in the disease penetrance (RR < 1.5).34
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Role of NOD2 NOD2 or CARD15 was the first susceptibility gene identified for CD. The protein product (NOD2) is expressed on the surface of the APCs: macrophages and lymphocytes. It is also expressed on the surface of Paneth cells and epithelial cells of the gastrointestinal mucosa.34 NOD2 ligand, an MDP, is a ubiquitous molecule present as a cell wall component in many gram-positive and gram-negative bacteria. Upon activation by the ligand, NOD2 has been shown to engage transcription factor NFkB pathway by recruitment of RIP kinase 2 (receptor-interacting protein 2). This leads to the induction not only of a proinflammatory state, but also serves as a positive regulator of immune defense in the gut.35 Mutations in the leucine-rich repeat domain of NOD2, which is responsible for microbial sensing, are associated with a disturbed cellular response to MDP and lipopolysaccharides leading to abnormal intracellular r
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persistence of antigens and predisposition to CD. Presence of NOD2 mutations also predispose to the phenotype of stricturing disease and ileal involvement.34,36,37 NOD2-mediated NFkB-dependent inflammatory reaction has also been suggested to be an important pathogenic process responsible for joint inflammation in patients with SpAs.6 NOD2 has been shown to be expressed by fibroblasts and macrophages in the synovium of RA patients, predominantly at sites of invasion into articular cartilage and both initiate and perpetuate inflammation in RA. Its expression is induced by lipopolysaccharide and TNF-a. Toll-like receptors act synergistically with NOD2 in the production of IL-6 and IL-8 through p38 and NFkB.38 Furthermore, NOD2/CARD15 plays an important role in pathogenesis of psoaritic arthritis, providing additional support to the common pathogenetic link.39 Uveitis, a prominent clinical feature in patients with AS, is also a common EIM in patients with IBD. Gain of function mutations in NOD2 result in autosomal-dominant Blau syndrome, which is characterized by severe iritis and uveitis in addition to inflammatory arthritis,40 suggesting NOD2 as a common link between joint, gut, and ocular inflammation. There is no established association between carriage of NOD2 variants and development of AS or SpAs in IBD population. However, patients with SpA who carry NOD2 variants are more likely to develop chronic subclinical gut inflammation as compared with other SpA patient (OR = 5.8) and general population (OR = 2.9).41
Role of IL23/IL12 Signaling Complex Activation of Th17 and Th1 cells is mediated through IL23 and IL12 signaling, respectively (Subset Fig. 1). In both the pathways, the cytokine heterodimer binds to the heterodimeric receptor activating downstream signaling by Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) and leading to engagement and activation of signal transducer and activator of transcription (STAT) proteins (STAT3 and STAT4 for Th17 and Th1 response, respectively).42 STATs translocate to the nucleus to activate transcription of inflammatory molecules IL17A, IL17F, IL22, IL6, and TNF-a eliciting Th17 response. The IL23 and IL12 heterodimers share components cytokines (IL12B, also known as p40) and their receptors (IL12RB1).6,34 IBD and many EIMs have been directly linked to variants in the genes of the signaling complex.34,43 As such, these molecules represent potential therapeutic targets to halt the ongoing intestinal inflammation.44 Patients with moderate-to-severe CD resistant to TNF antagonists have been shown to benefit from Ustekinumab, a fully humanized monoclonal antibody against IL12/IL23.45,46 Arg381Gln variant of IL23R is protective against CD; presence of the allele reduces the risk of CD by 3-fold.34 Interestingly, the same polymorphism has also been shown to be protective against AS, suggesting another common molecular overlap in the pathogenesis of the gut inflammation and SpA.4
Role of TNF-a The IEC rather than being mere “bystander cells” may, in fact, be the source of TNF-a production, the initiating event in the chronic inflammation in CD.47 It has been shown that experimental TNFRI (TNF-a receptor I) expression in mesenchymal cells results in both spondyloarthritic and intestinal phenotypes, indicating the r
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Musculoskeletal Manifestations in IBD
TABLE 2. Musculoskeletal Manifestations in IBD
Salient Features Peripheral arthropathies Type 1 Oligoarticular, asymmetric peripheral arthritis Type 2 Polyarticular, symmetric peripheral arthritis Arthralgia Pain without swelling or without erythema arthritis Enthesitis Pain and swelling at the tendon insertion site Dactylitis Pain and swelling of the entire digit Axial arthropathies Inflammatory Chronic back pain without back pain radiologic findings Isolated Imaging showing erosion or sacroiliitis sclerosis of SI joints Ankylosing Combination of inflammatory spondylitis back pain and imaging studies showing bilateral sacroiliitis grade Z2 or unilateral sacroiliitis grades 3-4 Other Fibromyalgia Generalized body pain, tender syndrome points Osteopenia BMD T-score r 1.0 Osteoporosis BMD T-score r 2.5 Osteonecrosis Marrow infarction Myopathy Multifactorial in etiology Orbital myositis Inflammation of extraocular muscles Gastrocnemius Gastrocnemius muscle myalgia involvement syndrome
Prevalence (%) 3.6-649 2.5-449 5.3-1649,50 6-504,51 2-413 17-2252 16-464,6 1-11.44
3-3.753 32-3654 7-1554 < 0.555 Rare Rare Rare
BMD indicates bone mineral density; IBD, inflammatory bowel disease; SI, sacroiliac.
mesenchymal cell as the primary and sufficient target, and TNF-a as the common cellular molecule in the gut-synovial axis.48
MSMs Table 2 summarizes MSMs in patients with IBD. The arthritis in patients with IBD can involve primarily either the peripheral (appendicular) skeleton or the axial skeleton.13 Two different types of inflammatory peripheral arthritis have been described in association with idiopathic IBD.49,56 Type 1 peripheral arthritis, the most common arthritis, is seen equally in men and women; children are affected as often as adults. There is an increased prevalence of HLAB27 antigen (23%) in these patients.56 The arthritis is acute in onset, migratory, and usually asymmetric. It is oligoarticular and usually involves 3 months, (4) association with morning stiffness, and (5) improvement after exercise. Four of the 5 factors are needed to make the diagnosis of IBP based on this criteria. The observed prevalence of IBP in IBD patients is 17% to 22%.52
AS AS is the prototypical SpA; it is characterized by sacroiliitis, spondylitis, and enthesitis (Fig. 3B). The modified New York criteria are the most widely used criteria to define AS in patients with IBD; AS is defined if radiologic criterion (bilateral sacroiliitis grade Z2 or unilateral sacroiliitis grades 3 to 4) is present with at least 1 of the 3 clinical criteria which are: (1) low back pain and stiffness for >3 months, improve with exercise and not relieved by rest; (2) limitation of motion of lumbar spine in both the sagittal and frontal planes; and (3) restriction of chest expansion relative to normal values corrected for age and sex.64 Using the modified New York criteria, the prevalence of AS in IBD varies from 1% to 11.4%.4 There is no correlation between localization or extent of the intestinal inflammation and presence of AS.13 AS associated with IBD does not have sex predisposition and is more weakly associated with HLA-B27 than sporadic AS (60% as compared with >90% in sporadic AS).8
Other Manifestations Osteonecrosis (ON) refers to cell death in osseous components, both hematopoietic fat marrow and osteocytes. The prevalence of ON in IBD patient is reported to be
Musculoskeletal Manifestations in Inflammatory Bowel Disease A Revisit in Search of Immunopathophysiological Mechanisms Tejas Sheth, MD,*w Capecomorin S. Pitchumoni, MD, FRCP(c), MACP, MACG, MPH, AGAF,*wz and Kiron M. Das, MD, PhD, FRCP, FACP, FACG, AGAFy8z
Abstract: Inflammatory bowel diseases are chronic inflammatory disorders of multiple organ systems, primarily involving the gut, with chronic relapsing and remitting course. Musculoskeletal involvement is the most common extraintestinal manifestation. Distinct cell-mediated and humoral immunopathophysiological mechanisms have been identified underlying gut and joint inflammation in patients with inflammatory bowel disease and arthritis. Genetic polymorphisms in genes coding for NOD2 and IL12/IL23 complex lead to impaired antigenic handling in the gut and local immune dysregulation. The gut-synovial axis hypothesis implicates both environmental and host factors acting as triggers to initiate inflammation in genetically predisposed individuals, leading to priming of Th1 and Th17 lymphocytes in the gut and subsequent homing to the synovial tissue. Similar to gut, antibody-dependent cell-mediated cytotoxicity and complement-mediated cell lysis may also contribute to the joint damage. Involvement of peripheral joints occurs in 2 distinct manners, one being oligoarticular asymmetric arthritis associated with active disease and the other being polyarticular symmetric involvement of small joints. The axial involvement may include asymptomatic sacroiliitis, inflammatory back pain, and ankylosing spondylitis, running an independent clinical course. Noninflammatory involvement of the musculoskeletal system may present as osteopenia, osteonecrosis, fibromyalgia, or myopathies, leading to significant impact on quality of life. Key Words: inflammatory bowel disease, extraintestinal manifestations, arthritis, ulcerative colitis, Crohn’s disease, NOD2, gutsynovial axis
(J Clin Gastroenterol 2014;48:308–317)
T
he term inflammatory bowel disease (IBD) describes chronic inflammatory disorders of the gastrointestinal tract driven by immune dysregulation and resulting in relapsing and remitting clinical course. The term IBD refers primarily to Crohn’s disease (CD) and ulcerative colitis (UC), but also encompasses atypical colitides, such as
From the *Department of Internal Medicine, St Peter’s University Hospital, Drexel University College of Medicine; zDepartment of Medicine, New York Medical College, Valhalla, NY; wRutgersRobert Wood Johnson Medical School and University Hospital; yDepartment of Medicine, Biochemistry and Molecular Biology, Rutgers-Robert Wood Johnson Medical School; 8Division of Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School and University Hospital; and zCrohn’s and Colitis Center of NJ, Rutgers-Robert Wood Johnson University Hospital, New Brunswick, NJ. The authors declare that they have nothing to disclose. Reprints: Kiron M. Das, MD, PhD, FRCP, FACP, FACG, AGAF, Clinical Academic Building, 125 Paterson Street, Suite 5100B, New Brunswick, NJ 08901-1962 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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collagenous colitis and lymphocytic colitis. The underlying immune dysregulation may target the whole body and not just the gastrointestinal tract; hence, 10% to 40% of patients with IBD may have extraintestinal manifestations (EIM), which can involve virtually any organ system (Table 1).1,2 There seems to be a direct relationship between the extent of colonic involvement and the presence of EIMs, as three fourths of patients with EIMs have extensive colitis on histopathology.1,3 In addition, the presence of one EIM is associated with a high likelihood of developing others. Musculoskeletal involvement is the most common EIM seen in patients with IBD; up to 30% of patients are affected.4 This article reviews the immunopathogenesis and musculoskeletal manifestations (MSMs) in inflammatory colitides, with special reference to IBD.
PATHOPHYSIOLOGY The pathogenesis of MSMs of IBD involves the “gutsynovial axis” hypothesis, which implicates both environmental and host factors acting as triggers to initiate inflammation in genetically predisposed individuals.
Genetic Predisposition In IBD, individuals with certain HLA alleles are at higher risk of developing EIMs. EIMs have been linked to carriage of HLA-A2, HLA-DR1, and HLA-DQw5 alleles in CD patients and to DRB1*0103, B27, and B58 alleles in UC patients.5 The experimental introduction of HLA-B27 and b2-microglobulin genes into a germ line of rats leads to the spontaneous development of gut inflammation involving primarily the colon. These animals also develop inflammatory involvement of peripheral and axial joints, male genital tract, and psoriasis-like skin and nail lesions in a pattern that closely resembles to the EIMs in IBD patients.6 This linkage suggests a common genetic predisposition for inflammation of the gut and the joints. A similar experimental model for studying the relationship between CD and spondyloarthropathies (SpAs) is the TNFDARE mouse model was used. This model involves 69 base pair deletions of TNF-a-AU-rich elements (AREs) leading to constitutional activation of TNF-a-mRNA and increased levels of TNF-a in hematopoietic and stromal cells. The mutant mice develop gut involvement similar to CD along with SpA-like sacroiliitis, enthesitis, and peripheral arthritis, suggesting ARE deletions as a novel pathologic mechanism underlying development of IBD and associated EIMs. The mutant mRNA loses its ability to be modulated by transcriptional factors such as Janus kinases (JAK) and p38, suggesting a pivotal role of ARE as a final executive element in the inflammatory cascade.7 J Clin Gastroenterol
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Musculoskeletal Manifestations in IBD
TABLE 1. Extraintestinal Manifestations in IBD
Common Extraintestinal Manifestations Musculoskeletal (refer to Table 2 for further details) Skin and mouth Reactive lesions: erythema nodosum, pyoderma gangrenosum, aphthous ulcers, vesiculopustular eruption, necrotizing vasculitis Specific lesions: fissures and fistulas, oral CD, drug rashes Nutritional deficiency: acrodermatitis enteropathica (Zn), purpura (vitamin C and K), glossitis (vitamin B), hair loss and brittle nail (protein) Associated diseases: vitiligo, psoriasis, amyloidosis, epidermolysis bullosa acquisita Hepatobiliary Specific complications: primary sclerosing cholangitis and bile duct carcinoma Associated inflammation: autoimmune chronic active hepatitis, pericholangitis, portal fibrosis and cirrhosis, granuloma in CD Metabolic: fatty liver, gallstones associated with ileal CD Ocular Uveitis (iritis), episcleritis, scleromalacia, corneal ulcers, retinal vascular disease Metabolic Growth retardation in children and adolescents, delayed sexual maturation Less common extraintestinal manifestations Blood and vascular: anemia due to iron, folate, and B12 deficiency or autoimmune hemolytic anemia, thrombocytopenic purpura, leukocytosis and thrombocytosis, thrombophlebitis and thromboembolism, arteritis and arterial occlusion Renal and genitourinary tract: urinary calculi (oxalate stones in ileal disease), local extension of CD involving ureter or bladder, amyloidosis, renal tubular damage with increased urinary retention of various enzymes, eg, b N-acetyl-D-glucosaminidase Neurological: neuropathy, myelopathy, myasthenia gravis, cerebrovascular disorders Bronchopulmonary: pulmonary fibrosis, vasculitis, bronchitis, acute laryngotracheitis, abnormal pulmonary function tests Cardiac: pericarditis, myocarditis, heart block Pancreas: acute pancreatitis, duodenal CD CD indicates Crohn’s disease. Reproduced from Das.1 With kind permission from Springer Science + Business Media B.V. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
MHC class II allele DRB1*0103 is frequently associated with UC: 8% of patients with UC carry this allele as opposed to 2% of healthy population.5 The presence of this allele predisposes to type 1 peripheral arthritis, an oligoarticular asymmetric involvement of large joints. Thirtyeight percent of patients with active UC or CD have been identified as carrying this allele. The same allele predisposes to the development of the reactive arthritis (also known as Reiter syndrome) occurring after episodes of Salmonella or Campylobacter enteritis.8 This suggests a common link in the pathogenesis of articular symptoms in these apparently different clinical entities related to gut inflammation. Type 2 peripheral arthritis is a polyarticular symmetric involvement primarily of small joints of the upper extremities. Patients with type 2 arthropathy have a strong association with HLA-B44.8 More than 90% of patients with ankylosing spondylitis (AS) are HLA-B27 positive and 25% to 78% of patients with IBD and AS are HLA-B27 positive. In addition, up to 60% of patients with AS have been found to have asymptomatic gut inflammation, 25% of them may develop overt IBD over time.6 In contrast, isolated sacroiliitis in IBD, however, is unrelated to HLA-B27. Asymptomatic sacroiliitis has been seen in up to 16% of patients with IBD6; with the use of MRI, however, the detection rate of sacroiliitis is now thought to be as high as 46%.4
Triggers Germ-free HLA-B27 transgenic rats do not develop gut or joint inflammation, suggesting that bacterial exposure is a prerequisite for the development of SpA in genetically predisposed IBD patients.4 Initial theory hypothesized that after absorption from gut, soluble bacterial antigens may translocate to blood stream and then to r
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synovium, initiating there an inflammatory response and the development of arthritis.9 However, there is little new evidence to support the concept of the actual viable microbial pathogens themselves circulating from the gut to the joint. In contrast, it seems likely that both bacterial antigens and reactive T-cell clones home to the joint.10
The Gut-Synovial Axis As discussed above, the genetic basis of gut-synovial interaction is well described. The molecular and biochemical links between intestinal and synovial inflammation have been extensively investigated as well.
Role of Cell-mediated Immune Responses Microbial handling in the gut and the development of desired local innate immunity is mediated primarily through binding of pathogen-associated molecular patterns and danger-associated molecular patterns (PAMPs and DAMPs), to their respective pattern recognition receptors located in subcellular components (Fig. 1).12 Local intestinal inflammation leads to cellular damage and in severe instances, to cellular apoptosis with proteolysis of subcellular components. Many of these nonpathogen-derived molecules act as initiators or perpetuators of inflammation; they are collectively known as alarmins or DAMPs. PAMPs, in contrast, are pathogen-associated moieties and are derived from intestinal bacteria. In the normal host, these factors maintain intestinal epithelial barrier function and innate immunity; in active IBD, their dysfunction augments the inflammatory state. Both of these factors act as the inducers of proinflammatory effects, seen in patients with active IBD.12 Intestinal epithelial cell (IEC) damage leads to barrier breakdown and contact of the gut flora with the www.jcge.com |
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submucosal antigen-presenting cells (APC). Bacterial cell wall muramyl dipeptide (MDP) is processed by NOD2 on the APC surface leading to Th1 and Th17 responses. Polymorphisms in the NOD2 gene modulate this response and lead to release of TNF-a. TNF-a in turn induces apoptosis of the IEC through its effect on TNF receptor 2 (TNFR2),11 and induces microvascular endothelial dysfunction and increased microvascular permeability. Increased expression of integrins a4b7 and aEb7 on the surface of lymphocytes leads to binding of ligand mucosal addressin cell adhesion molecule-1 (MadCAM-1), which is expressed on the high endothelial venules in Peyer’s patches
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and flat-walled venules in lamina propria, and to gut homing of the lymphocytes with subsequent transmigration across abnormally permeable vessels. The resultant generation of oxygen-free radicals and local hypoxia augment TNF-a-induced cellular apoptosis and increases the influx of bacterial pathogens into lamina propria, perpetuating a vicious cycle. Activated T cells and macrophages return to the systemic circulation through efferent lymphatics and are sequestered by the adhesion molecules such as b7 integrins, intercellular adhesion molecule-1 (ICAM-1/CD54), and vascular adhesion protein-1 (VAP-1) expressed by the synovial cells. This results in synovial homing of gut-primed
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cells and subsequent development of nuclear factor kB (NFkB)-induced inflammation.6,13 Identical T-cell clonal expansions have been demonstrated in the colonic mucosa and the synovium of patients with enterogenic SpA.14 Macrophages expressing a transmembrane scavenger receptor CD163 (clusters of differentiation 163) have been found in colonic lamina propria and in synovial lining in patients with SpA, with the number of such macrophages directly proportional to Creactive protein levels and erythrocyte sedimentation rate.15 CD163 + macrophages have also been found to be increased in gut and synovium of CD patients.16 It is possible that macrophages may undergo relocation to synovial tissue and there contribute to inflammation. In fact, using the Stamper-Woodruff assay it has been shown that macrophages exhibit selective binding with P-selectin molecules expressed by synovial endothelial cells and may act as transporters of processed antigens from gut to synovium.9 E-cadherin is a transmembrane glycoprotein responsible for intercellular adhesion of intestinal epithelial cells. E-cadherin/catenin complex is upregulated in gut mucosa of IBD patients, where it acts as a ligand for a4b7 integrin, responsible for gut homing of lymphocytes. An identical upregulation of the E-cadherin/catenin glycoprotein complex has been observed in acute and chronic active bowel inflammation of SpA patients, suggesting its role as a common pathogenic link.17
Autoimmunity in IBD, Role of Humoral Immune Responses Autoimmunity has been emphasized in the pathogenesis of UC (Fig. 2). IECs have distinct isoform of tropomyosin, isoform 5 (hTM5). hTMs are cytoskeletal microfilament proteins. Patients with UC have been found to have mucosal and serum autoantibodies directed specifically against human tropomyosin isoform 5 (hTM5, p40).18,19 T-cell response against hTM5 has also been demonstrated in UC.20 Peripheral blood lymphocytes from patients with UC secreted significant amount of IFN-g on exposure to hTM5 in vitro. The frequency of anti-hTM5 antibody has been shown to be increased in family members of patients with UC.21 Furthermore, these autoantibodies have been found to be pathogenic to colon epithelial cells suggesting hTM5 as a target.22 The destruction seems to be
Musculoskeletal Manifestations in IBD
complement-mediated cytolysis. Deposition of IgG1 autoantibody against p40 autoantigen in the colonic mucosa of patients with active UC along with activated compliment component has been reported.23 Notably, hTM5 is also expressed in the biliary tract, skin, eyes, and joints in addition to colon epithelium, and may contribute as a target to the occurrence of EIMs in the IBD patient populations.1,24–26 Colonic epithelial protein (CEP), another protein molecule expressed on surface of colonic epithelial cells, acts as a chaperone for translocation of hTM5 to cell surface.25 CEP may also act as a target of antibody-mediated cytolysis.27 CEP carries structural similarity with epitopes present in uveal tract, biliary epithelium, and chondrocytes suggesting antigenic cross-reactivity as one of the pathophysiological mechanism for the EIMs.1,25,26,28 It is shown that arthritic patients with histologic changes of either acute or chronic gut inflammation in absence of clinical symptoms, when subjected to distal ileal and colonic biopsies, showed increased number of plasma cell populations and increased levels of IgA and IgG in acute ileitis, whereas increased levels of IgA, IgG, and IgM in chronic ileitis. These 2 distinct immunohistochemical patterns of antibodies population were identical to the patterns observed in patients with reactive arthritis and peripheral arthropathy in AS, respectively.29 It is well known that B cells after initial stimulation in lymphoepithelial structures such as Peyer’s patches in ileum, migrate as memory cells to secretary tissues all over the body including synovium.9 An expansion of CD27 + and CD27 switch memory B cells and IgG-secreting plasma cells has been demonstrated in the synovial fluid in patients with juvenile rheumatoid arthritis (RA). The study also demonstrated CD86 positivity in the switch memory B cells, speaking for their role as APCs acting locally in the synovium, thus providing a link between cellular and humoral process.30 The synovial tissue of patients with RA has been shown to have infiltration of naive B cells, memory B cells, and plasma cells; the later generated by locally activated memory B cells as evidenced by V-region gene analysis.31 Synovial extrafollicular germinal center development has been shown in patients with RA.32 These evidences support continuous activation of selected B-cell clones and plasma cells locally in the synovium of patients with inflammatory arthritis and complement-mediated destruction. The antigen
FIGURE 1. The gut-synovial axis: cellular immune responses. Increased production of TNF-a in the gut through tumor necrosis factor receptor 2 (TNFR2)-mediated signaling increases myosin light chain kinase (MLCK) expression leading to dysfunction of tight junction and induction of apoptosis of intestinal epithelial cells (IECs).11 Complement-mediated cell lysis also contributes to epithelial cell destruction (Fig. 2). Resulting intestinal mucosal barrier loss leads to penetration of intestinal bacteria and their products to submucosa. Bacterial cell wall component muramyl dipeptide (MDP), a pathogen-associated molecular patterns (PAMP), is processed by NOD2 on the surface of antigen-presenting cells (APC) in the submucosa. Apoptotic IECs also generate molecular patterns (DAMP) that can activate NOD2-mediated responses. NOD2-mediated processing leads to secretion of proinflammatory cytokines IL1b, IL12, and IL23 by the APC. IL23 and IL12 activate Th17 and Th1 responses, respectively (subset). The cytokine heterodimer of IL23 (IL23A and IL12B— also known as p40) binds with heterodimeric IL23 receptor (IL23R and IL23RB1) on the surface of naive Th17 cells, whereas the heterodimeric IL12 (IL12A and IL12B) binds with the heterodimer of IL12 receptor (IL23RB1 and IL12RB2) on the surface of naive Th1 cells. Thus, the pathways share a component of the cytokine complex (IL12B or p40) and its receptor counterpart (IL23RB1). Binding of IL23 and IL12 to the receptor complex leads to activation and phosphorylation of Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), which in turn engage and phosphorylate STAT proteins (signal transducer and activator of transcription). STAT3 and STAT4 translocate to the nucleus and activate transcription of a battery of inflammatory molecules, transforming naive T cells in to activated T cells. Activated T cells produce IL17A, IL17F, IL22, IL26, and TNF-a, all of which induce a local inflammatory state in the gut mucosa, leading to apoptosis of IECs and loss of the mucosa barrier, thus perpetuating the vicious cycle. TNF-a also induces microvascular endothelial dysfunction and expression of integrins on the surface of polymorphonuclear cells, lymphocytes, and endothelial cells leading to trafficking of inflammatory cells in the gut. The gut-primed T cells get access to systemic circulation and home to various extraintestinal organs including synovial membranes through selective recognition through a variety of adhesion molecules, inducing a similar inflammatory milieu in the joint. r
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FIGURE 2. The gut-synovial axis: humoral immune responses. The proposed mechanism as shown in this figure is based on some key references described in Brandtzaeg and colleagues.9,18–25 The human tropomyosin isoform 5 (hTM5) is a cytoskeletal microfilament protein present in colonic epithelial cells in close association with a colonic epithelial cell protein (CEP) and in extracolonic organs including skin, eyes, biliary epithelium, and joints.1,24,25 T-cell activation to hTM5 has also been reported in ulcerative colitis.20 This may lead to production of IFN-g and IL4, which may lead to stimulation of B cells. B cells transform in to plasma cells leading to production of hTM5-specific antibodies both locally in the submucosa and in the circulation.18,19 The antibodies bind with hTM5 on surface of colonic epithelial cells and fix complement leading to complement-induced lysis of the cells.22 Alternatively, the antibodies also engage natural killer cells bearing the receptors for Fc fragment of the antibody molecules, leading to antibody-dependent cell-mediated cytotoxicity (ADCC).22,23 The hTM5-specific antibodies through systemic circulation may get access to joints, leading to similar set of events causing joint inflammation and damage. Specific B-cell homing may also be involved in this process.9
directly responsible for such activation has not been isolated; however it may be hypothesized that similar to UC, hTM5 or CEP can locally act as a trigger for the proliferation of memory B cells primed in the gut in patients with IBD. Further studies are needed to demonstrate reactivity between synovial tissue isolated from patients with IBD with joint symptoms and antibodies directed against hTM5 and/or CEP located in the joint tissue.1,24,26
IBD Genetic Loci and Their Association With Arthropathy Of the >100 susceptibility IBD genes identified, only 2 (NOD2 and IL23R) contribute significantly to clinical IBD risk, NOD2 accounting for 20% of overall susceptibility in CD.33 All other loci cause only a marginal increase in the disease penetrance (RR < 1.5).34
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Role of NOD2 NOD2 or CARD15 was the first susceptibility gene identified for CD. The protein product (NOD2) is expressed on the surface of the APCs: macrophages and lymphocytes. It is also expressed on the surface of Paneth cells and epithelial cells of the gastrointestinal mucosa.34 NOD2 ligand, an MDP, is a ubiquitous molecule present as a cell wall component in many gram-positive and gram-negative bacteria. Upon activation by the ligand, NOD2 has been shown to engage transcription factor NFkB pathway by recruitment of RIP kinase 2 (receptor-interacting protein 2). This leads to the induction not only of a proinflammatory state, but also serves as a positive regulator of immune defense in the gut.35 Mutations in the leucine-rich repeat domain of NOD2, which is responsible for microbial sensing, are associated with a disturbed cellular response to MDP and lipopolysaccharides leading to abnormal intracellular r
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persistence of antigens and predisposition to CD. Presence of NOD2 mutations also predispose to the phenotype of stricturing disease and ileal involvement.34,36,37 NOD2-mediated NFkB-dependent inflammatory reaction has also been suggested to be an important pathogenic process responsible for joint inflammation in patients with SpAs.6 NOD2 has been shown to be expressed by fibroblasts and macrophages in the synovium of RA patients, predominantly at sites of invasion into articular cartilage and both initiate and perpetuate inflammation in RA. Its expression is induced by lipopolysaccharide and TNF-a. Toll-like receptors act synergistically with NOD2 in the production of IL-6 and IL-8 through p38 and NFkB.38 Furthermore, NOD2/CARD15 plays an important role in pathogenesis of psoaritic arthritis, providing additional support to the common pathogenetic link.39 Uveitis, a prominent clinical feature in patients with AS, is also a common EIM in patients with IBD. Gain of function mutations in NOD2 result in autosomal-dominant Blau syndrome, which is characterized by severe iritis and uveitis in addition to inflammatory arthritis,40 suggesting NOD2 as a common link between joint, gut, and ocular inflammation. There is no established association between carriage of NOD2 variants and development of AS or SpAs in IBD population. However, patients with SpA who carry NOD2 variants are more likely to develop chronic subclinical gut inflammation as compared with other SpA patient (OR = 5.8) and general population (OR = 2.9).41
Role of IL23/IL12 Signaling Complex Activation of Th17 and Th1 cells is mediated through IL23 and IL12 signaling, respectively (Subset Fig. 1). In both the pathways, the cytokine heterodimer binds to the heterodimeric receptor activating downstream signaling by Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) and leading to engagement and activation of signal transducer and activator of transcription (STAT) proteins (STAT3 and STAT4 for Th17 and Th1 response, respectively).42 STATs translocate to the nucleus to activate transcription of inflammatory molecules IL17A, IL17F, IL22, IL6, and TNF-a eliciting Th17 response. The IL23 and IL12 heterodimers share components cytokines (IL12B, also known as p40) and their receptors (IL12RB1).6,34 IBD and many EIMs have been directly linked to variants in the genes of the signaling complex.34,43 As such, these molecules represent potential therapeutic targets to halt the ongoing intestinal inflammation.44 Patients with moderate-to-severe CD resistant to TNF antagonists have been shown to benefit from Ustekinumab, a fully humanized monoclonal antibody against IL12/IL23.45,46 Arg381Gln variant of IL23R is protective against CD; presence of the allele reduces the risk of CD by 3-fold.34 Interestingly, the same polymorphism has also been shown to be protective against AS, suggesting another common molecular overlap in the pathogenesis of the gut inflammation and SpA.4
Role of TNF-a The IEC rather than being mere “bystander cells” may, in fact, be the source of TNF-a production, the initiating event in the chronic inflammation in CD.47 It has been shown that experimental TNFRI (TNF-a receptor I) expression in mesenchymal cells results in both spondyloarthritic and intestinal phenotypes, indicating the r
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Musculoskeletal Manifestations in IBD
TABLE 2. Musculoskeletal Manifestations in IBD
Salient Features Peripheral arthropathies Type 1 Oligoarticular, asymmetric peripheral arthritis Type 2 Polyarticular, symmetric peripheral arthritis Arthralgia Pain without swelling or without erythema arthritis Enthesitis Pain and swelling at the tendon insertion site Dactylitis Pain and swelling of the entire digit Axial arthropathies Inflammatory Chronic back pain without back pain radiologic findings Isolated Imaging showing erosion or sacroiliitis sclerosis of SI joints Ankylosing Combination of inflammatory spondylitis back pain and imaging studies showing bilateral sacroiliitis grade Z2 or unilateral sacroiliitis grades 3-4 Other Fibromyalgia Generalized body pain, tender syndrome points Osteopenia BMD T-score r 1.0 Osteoporosis BMD T-score r 2.5 Osteonecrosis Marrow infarction Myopathy Multifactorial in etiology Orbital myositis Inflammation of extraocular muscles Gastrocnemius Gastrocnemius muscle myalgia involvement syndrome
Prevalence (%) 3.6-649 2.5-449 5.3-1649,50 6-504,51 2-413 17-2252 16-464,6 1-11.44
3-3.753 32-3654 7-1554 < 0.555 Rare Rare Rare
BMD indicates bone mineral density; IBD, inflammatory bowel disease; SI, sacroiliac.
mesenchymal cell as the primary and sufficient target, and TNF-a as the common cellular molecule in the gut-synovial axis.48
MSMs Table 2 summarizes MSMs in patients with IBD. The arthritis in patients with IBD can involve primarily either the peripheral (appendicular) skeleton or the axial skeleton.13 Two different types of inflammatory peripheral arthritis have been described in association with idiopathic IBD.49,56 Type 1 peripheral arthritis, the most common arthritis, is seen equally in men and women; children are affected as often as adults. There is an increased prevalence of HLAB27 antigen (23%) in these patients.56 The arthritis is acute in onset, migratory, and usually asymmetric. It is oligoarticular and usually involves 3 months, (4) association with morning stiffness, and (5) improvement after exercise. Four of the 5 factors are needed to make the diagnosis of IBP based on this criteria. The observed prevalence of IBP in IBD patients is 17% to 22%.52
AS AS is the prototypical SpA; it is characterized by sacroiliitis, spondylitis, and enthesitis (Fig. 3B). The modified New York criteria are the most widely used criteria to define AS in patients with IBD; AS is defined if radiologic criterion (bilateral sacroiliitis grade Z2 or unilateral sacroiliitis grades 3 to 4) is present with at least 1 of the 3 clinical criteria which are: (1) low back pain and stiffness for >3 months, improve with exercise and not relieved by rest; (2) limitation of motion of lumbar spine in both the sagittal and frontal planes; and (3) restriction of chest expansion relative to normal values corrected for age and sex.64 Using the modified New York criteria, the prevalence of AS in IBD varies from 1% to 11.4%.4 There is no correlation between localization or extent of the intestinal inflammation and presence of AS.13 AS associated with IBD does not have sex predisposition and is more weakly associated with HLA-B27 than sporadic AS (60% as compared with >90% in sporadic AS).8
Other Manifestations Osteonecrosis (ON) refers to cell death in osseous components, both hematopoietic fat marrow and osteocytes. The prevalence of ON in IBD patient is reported to be
