Extraintestinal manifestations (EIM) of inflammation are common among patients with inflammatory bowel disease (IBD), many of which have distinct etiologies and treatment approaches. In the past decade, there has been a significant expansion of treatment modalities for IBD, with distinct mechanisms of action that may allow for targeting of multiple organ systems with a single agent. We review common neurologic, dermatologic, ocular, and musculoskeletal EIMs associated with IBD, and identify opportunities to address EIMs together with IBD using specific agents or therapeutic classes in order to optimally personalize treatment toward both bowel and extraintestinal inflammation.
Extraintestinal manifestations in patients with inflammatory bowel disease (IBD) can significantly impact health-related quality of life. Advances in pathophysiology knowledge and immunomodulatory targeted therapies bring diverse treatment options for IBD and inflammatory manifestations outside the bowel which should be considered when choosing the most appropriate approach for treating both intestinal and extraintestinal manifestations of IBD. This review provides an overview of treatment approaches of IBD and extra intestinal presentations of neurological, ocular, cutaneous, and musculoskeletal manifestations.
NEUROLOGICAL MANIFESTATIONS
Neurological extraintestinal manifestations are relatively rare in IBD. Multiple Sclerosis (MS), optic neuritis (ON) and transverse myelitis (TM) are chronic, inflammatory, demyelinating and neurodegenerative diseases, which have a heterogeneous, multifactorial, immune-mediated background caused by complex gene–environment interactions. As MS is the most common disease, most studies between IBD and CNS have been focused on MS.
Anti-TNFα therapy has been putatively associated with demyelinating syndromes.1,2 The mechanism for which anti-TNFα might potentially cause demyelination in patients with rheumatological disease and IBD is still not fully understood. Current hypotheses include an increased influx of peripheral autoreactive T cells into the CNS, dysregulation of myelin repair, downregulation of interleukin-10 and upregulation of interleukin-12 and interferon γ; and possible increase in the risk of an underlying latent infections by anti-TNFα which could lead to demyelination.6,7
Consequently, TNF inhibitors should be avoided in patients with MS or other demyelinating diseases. Some advocate that this restriction should be applied as well to first-degree relatives of patients with MS given an increased risk of developing MS, with a sibling relative risk being as high as 18 to 36.8
In patients with MS or high risk of developing demyelinating diseases, recommendations for IBD treatment depend on the type of IBD (e.g. Crohn’s disease (CD) or ulcerative colitis (UC)). For moderate to severe CD, natalizumab may be appropriate due to its effectiveness in both CD and in MS. Natalizumab is a humanized monoclonal antibody which targets the lymphocyte adhesion molecule α4β1 integrin, disrupting the interaction of α4β1 integrin with vascular adhesion molecule (VCAM) -1 and interfering with the migration of the peripheral lymphocytes from blood vessels into the CNS and into the gut lamina propria, hence its beneficial effects for both MS and CD. It is FDA approved for the treatment of relapsing – remitting MS and for CD. However, uptake of natalizumab has been limited by increased risks of progressive multifocal leukoencephalopathy (PML) through reactivation of John Cunningham (JC) virus at a rate of approximately 1 in 1000 among individuals demonstrating antibody reactivity to JC virus, a ubiquitous virus present in large proportions of the population.9 Thus, individuals with CD initiating natalizumab should not receive concomitant immunomodulators, and steroids should be tapered off within 6 months of drug initiation. Furthermore, monitoring for JC virus every 6 months is warranted while on natalizumab maintenance therapy, with shared decision-making discussions to stop therapy for patients who seroconvert while on treatment.
Sphingosine 1-phosphate (S1P) receptor modulators are approved as disease-modifying treatments for MS and UC based on a mechanism of limiting lymphocyte trafficking to the CNS and to the gut by trapping activated lymphocytes in lymph nodes. Ozanimod is currently approved for the treatment of both relapsing and remitting MS, as well as for moderately to severely active UC in adults. Thus, ozanimod may be an appropriate treatment option for those with UC, who also have or are at-risk for MS.
Nonspecific white matter lesions have also been described in patients with IBD without presenting concomitant CNS degenerative diseases. It has been proposed that asymptomatic white matter lesions may be correlated with anxiety and disease duration, and that these findings may serve as a biomarker of neuropsychiatric comorbidities of CD.10 These lesions are generally asymptomatic, although their pathogenesis is unknown. Several mechanisms have been proposed for their etiology including thromboembolism, immunologic abnormalities, drug side effects, malabsorption, and infections.11,12
OCULAR
Nearly 5-7% of patients with IBD experience ocular inflammation, most commonly episcleritis, scleritis or non-infectious uveitis (NIU).
Episcleritis, or inflammation of the episclera, is the most frequent ocular EIM. It is associated with active intestinal inflammation, and usually responds to topical steroids. On the other hand, scleritis, the inflammation of the sclera, is more challenging to treat, it usually requires nonsteroidal anti-inflammatory drugs, systemic steroids or immunosuppressants. If not controlled, scleritis can lead to necrotizing scleritis, anterior scleritis and posterior scleritis with secondary potential vision loss.14 In contrast, uveitis, the inflammation of the iris, ciliary body, and choroids, is less frequently associated with IBD flares but may precede a diagnosis of IBD by months or years. Although ophthalmological manifestations are present in any type of IBD, they are more common in CD patients.
Infliximab and adalimumab, both anti-tumor necrosis factor (TNF)-α antibodies, are frequently used first-line in patients with ocular manifestations of scleritis or uveitis. Infliximab is effective in the treatment of NIU unresponsive to other drugs, with approximately 82% of patients achieving clinical remission in a median time of 127 days. For patient with uveitis, brain magnetic resonance imaging (MRI) is indicated to screen for demyelination before the commencement of TNFα inhibitors. TNF-alpha inhibitors were shown to significantly reduce relapses, and to control scleral inflammation both rapidly and with a long-lasting effects.15,16
Most recently, therapies targeting interleukin (IL) 23 and Janus kinase inhibitor (JAK) inhibitors have emerged as treatment options for ocular EIMs. Ustekinumab, a monoclonal antibody against human IL-12/IL-23 p40 subunit, has been described in case reports for the successful treatment of non-infectious uveitis including a patient with psoriatic arthritis and psoriasis, and 2 patients with CD, including 1 with comorbid MS.17,18
Tofacitinib, a nonselective small molecule JAK inhibitor approved for UC, has been used successfully in patients with severe refractory juvenile idiopathic arthritis (JIA)-associated uveitis,19,20 but further studies are needed to show the safety and efficacy of JAK inhibitors in larger cohorts.
SKIN MANIFESTATIONS
Cutaneous extraintestinal manifestations have been described in up to 15% of patients with IBD, often preceding their IBD diagnosis and not necessarily linked with IBD disease activity.
Erythema nodosum (EN), affecting up to 15% of those with IBD and pyoderma gangrenosum (PG), affecting up to 5% of those with IBD are the most common skin manifestations in those with CD or UC.21 It is important to note that while PG is associated with IBD, EN may be associated with a variety of conditions such as infection, medications, sarcoidosis, pregnancy, IBD, autoimmune diseases, vaccination, malignancy, and miscellaneous causes.22 PG is also linked with some degree of colonic inflammation, in up to 50% of patients underlying active disease is present, and often requires multiple therapies to achieve complete healing.23
There is an association between psoriasis and IBD, with a risk in UC patients 1.6 times higher than in the general population. Paradoxically, psoriasis can also be triggered in up to 5% of patients using anti-TNF drugs,24 and it may present in atypical locations, including new scaly and dry plaques that may be confused for eczema; therefore requiring a high suspicion by the medical provider for medication side effects. Paradoxical psoriasis may be treated with topical steroids or oral methotrexate, but if severe may require discontinuation of anti-TNF medication.
The IL23/IL17 axis plays a critical role in the pathogenesis of skin EIMs. IL-23 stimulates the production of IL-17, an essential proinflammatory cytokine, mainly secreted by CD4+ helper T cells (Th17); therefore, biologic therapies targeting IL-23 in IBD may play a significant role in improving cutaneous inflammation such as psoriasis.26 In a similar vein, the expression of TNFα and its receptors are increased in PG and EN lesions in skin suggesting a mechanistic explanation for the effectiveness of anti-TNF therapy for these conditions.
Anti-TNFα agents, especially infliximab and adalimumab may thus be effective for some cutaneous manifestations and IBD including psoriasis and PG, and they can also be considered as sparing agents to avoid long-term side effects from systemic corticosteroids.26 Biologics against IL-23 can also be considered in patients with IBD and psoriasis, PG or EN. Considering the role of IL23 in the pathophysiology of skin inflammation, biologics such as ustekinumab, which targets IL12/23 and is approved for moderate to severely active CD and UC; and risankizumab, a humanized immunoglobulin G1 antibody targeting the p19 subunit of IL-23 approved for moderate to severe CD, may be appropriate therapeutic options for patients with IBD and concomitant psoriasis, EN, or PG.
MUSCULOSKELETAL
Musculoskeletal involvement is the most common extraintestinal manifestations in IBD. Arthritis may affect up to 46% of patients with IBD, and its prevalence decreases with age. Patients with IBD and concomitant musculoskeletal symptoms are typically seronegative for rheumatoid factor (RF) and anti-citrullinated peptide antibodies. Seronegative spondyloarthropathies (SpA) include ankylosing spondylitis, reactive arthritis, and psoriatic arthritis (PsA). Rheumatoid arthritis (RA) has also been linked with IBD population.
| CD | UC | MS | Scleritis | NIU | EN | PG | PsA | RA | SpA | |
| Anti-TNF | + | + | x | + | + | (+) | (+) | + | + | + |
| Anti IL12/23 | + | + | (+) | (+) | (+) | + | ||||
| Anti IL-23 | + | + | (+) | (+) | (+) | + | ||||
| JAK inhibitors | + | + | (+) | (+) | (+) | + | + | + | ||
| Natalizumab | + | + | ||||||||
| Sphingosine 1-phosphate | + | + | ||||||||
| Anti IL17A | x | + | + |
Musculoskeletal conditions associated with IBD can be mainly divided into axial and peripheral arthritis (PA). Although both are present in patients with UC and CD, they are more commonly seen in CD sub-population; and while peripheral arthritis is typically correlated with active intestinal inflammation, axial arthritis is generally independent of it.
Patients with peripheral arthritis may respond to a course of nonsteroidal anti-inflammatory drugs (NSAIDs), but chronic NSAIDs use is discouraged in patients with IBD given the possibility of intestinal ulcer development and disease exacerbation; COX-2 inhibitors have been proposed as an acceptable first line treatment option for up to 14 days.27,28
Corticosteroids, on the other hand, are well known for their anti-inflammatory effects and are used in IBD as well as for peripheral arthropathies pains and flares, however they are generally ineffective for the treatment of axial arthritis and should be limited in use due to systemic side-effects.
Sulfasalazine may be effective for peripheral and axial inflammatory arthritis, but it may be more effective in UC and peripheral arthritis than in CD. Although methotrexate has not shown efficacy in axial arthropathy either, when treating PA and CD patients, it has provided clinical improvement and may be used to achieve higher levels of anti-TNFs.29
When biologic treatments need to be considered, anti-tumor necrosis factors including infliximab and adalimumab continue to be the first line treatment as they have shown significant efficacy in both peripheral and axial arthropathy. Additional therapeutic considerations like IL12/23 and JAK inhibitors can be alternative approaches depending on the specific rheumatologic diagnosis, PsA, RA, or SpA. (Table 1.)
Ustekinumab, has shown to be effective for peripheral arthritis, including PsA, enthesitis and dactylitis, however it does not seem to be effective for treatment of axial arthropathies as SpA nor RA.30
Jak inhibitors are fast acting, oral medications, only available after not responding to TNF blockers due to safety considerations, and are effective for the treatment of SpA, RA and PsA.
Upadacitinib, a JAK inhibitor with high selectivity for JAK1 is approved for moderate to severe CD and UC as well as for moderate to severe RA, psoriatic arthritis, ankylosing spondylitis and non-radiographical axial spondyloarthropathy. Its efficacy has been demonstrated as a monotherapy with similar efficacy that combining upadacitinib with methotrexate.31,32 Tofacitinib acts by preferentially inhibiting JAK1 and JAK3, with reduced inhibition for JAK2 and tyrosine kinase 2, it is used for moderate to severe UC as well as RA, PsA and active ankylosing spondylitis.32,33
Monoclonal IgG4 antibodies directed against IL-17A such as secukinumab and ixekizumab; or against IL-17 receptor, brodalumab, are highly effective for psoriasis, enthesitis and peripheral arthritis. However, they have not only shown to be ineffective in IBD but are associated with exacerbation and new onset of IBD and colitis and its use in patients with MSK manifestations is thus not recommended.34
Summary
IBD may present with a single or multiple extraintestinal manifestations. EIMs may affect any organ system and are chronic inflammatory diseases capable of causing a major debilitating comorbidity if left untreated or partially treated. Detailed consideration of EIMs needs to be taken into account when deciding which biologic to use when co-treating IBD and EIMs.
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