Arthritis related to inflammatory bowel disease: Treatment and prognosis

INTRODUCTION — 

Arthritis is a recognized extraintestinal manifestation of inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis. IBD-related arthritis is a type of spondyloarthritis (SpA), and its management is similar to the treatment of other forms of SpA; however, therapy for arthritis must be coordinated with therapy for gastrointestinal manifestations of IBD.

The treatment of IBD-related arthritis is presented here. The clinical manifestations, diagnosis, and differential diagnosis of IBD-related arthritis are presented separately. (See "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)

The management of IBD in children and adults is also reviewed in detail elsewhere:

●(See "Overview of the management of Crohn disease in children and adolescents".)

●(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

●(See "Management of mild to moderate ulcerative colitis in children and adolescents".)

●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

OVERVIEW OF THERAPY — 

For arthritis related to inflammatory bowel disease (IBD), the goal of treatment is controlling inflammation in the joints and gastrointestinal tract to minimize symptoms and the risk of irreversible joint damage. Care must be coordinated carefully between gastroenterology and rheumatology.

The general approach to the treatment of IBD-related arthritis is similar to that for other forms of spondyloarthritis (SpA) and depends on whether or not the patient has active IBD (algorithm 1):

●Inactive IBD – In patients with inactive IBD and related arthritis, initial therapy consists of a short course of nonsteroidal antiinflammatory drugs (NSAIDs). Selected patients may also receive adjunctive therapies, such as intraarticular glucocorticoid injections for limited peripheral arthritis and/or physical therapy for axial arthritis. (See 'Initial treatment' below.)

Patients with persistent symptoms despite or intolerance of NSAIDs are treated with systemic immunosuppression, with the choice of therapy guided by the specific location of the arthritis (algorithm 2). Specifically, patients with isolated peripheral arthritis are started on selected conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), while those with axial disease are typically started on monoclonal tumor necrosis factor (TNF) inhibitors. (See 'Treatment of persistent or refractory disease' below.)

●Active IBD – In patients with active IBD and related arthritis, treatment is focused on targeting the gastrointestinal manifestations and may also involve short-term use of NSAIDs. (See 'Treatment of patients with active inflammatory bowel disease' below.)

Direct evidence to support the use of specific therapies in IBD-related arthritis is extremely limited and mostly consists of case series and a few other observational studies. Our approach is generally aligned with expert opinion on the management of patients with coexisting SpA and IBD [1]. In addition, there are substantial indirect data derived from treatment of patients with various forms of peripheral and axial SpA, including psoriatic arthritis (PsA), and, in children, psoriatic juvenile idiopathic arthritis (psJIA) and enthesitis related arthritis (ERA).

PRETREATMENT CONSIDERATIONS — 

Septic arthritis should be excluded in patients with presumed arthritis related to inflammatory bowel disease (IBD), especially before using intraarticular glucocorticoids and/or systemic immunosuppression. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children" and "Septic arthritis in adults".)

When we are considering starting systemic immunosuppression (eg, systemic glucocorticoids, disease-modifying antirheumatic drugs [DMARDs]), we screen for latent infections (eg, hepatitis B and C, tuberculosis) and ensure that patients have received any indicated prophylactic vaccinations. The approach to vaccination in immunocompromised patients with IBD-related arthritis is the same as that for patients with other types of inflammatory arthritis, which is described in detail elsewhere. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults" and "Juvenile idiopathic arthritis: Immunizations and complications", section on 'Immunizations'.)

TREATMENT OF PATIENTS WITH INACTIVE INFLAMMATORY BOWEL DISEASE

Initial treatment — For patients with quiescent inflammatory bowel disease (IBD), we give a short course (two weeks) of a nonsteroidal antiinflammatory drug (NSAID) and consider adjunctive therapies, such as intraarticular glucocorticoid injections for limited peripheral arthritis and/or physical therapy for axial arthritis (algorithm 1).

NSAIDs for most patients — A short course of NSAIDs is often used as initial therapy for patients with inactive IBD, as it can provide relatively rapid symptom relief and does not carry the risk of infection associated with immunosuppressive options. NSAID therapy should be initiated collaboratively in consultation with the patient's gastroenterologist since there is limited evidence that NSAIDs may exacerbate preexisting IBD [2-7].

●NSAID selection, dosing, and monitoring – In patients who have quiescent IBD, we suggest initial therapy with a cyclooxygenase 2 (COX-2) selective NSAID rather than a disease-modifying antirheumatic drug (DMARD). We typically administer a two-week course. Any COX-2 selective NSAID may be effective at antiinflammatory doses (eg, celecoxib 100 mg twice daily) (table 1). If a COX-2 selective NSAID is not available, an alternative option is to use a nonselective NSAID (eg, naproxen, ibuprofen) together with a proton pump inhibitor (eg, omeprazole 20 mg daily) for gastroprotection. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Proton pump inhibitors'.)

Information about contraindications, adverse effects, and drug monitoring for NSAIDs is provided separately. (See "Overview of COX-2 selective NSAIDs" and "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse effects on the distal small bowel and colon".)

●Evidence – Despite the risk of flare, both nonselective and COX-2 selective NSAIDs can be used with good efficacy and tolerance in the author's experience and are recommended as first-line therapy by experts [1]. We typically use COX-2 selective agents since there are limited data suggesting good tolerance of COX-2 selective NSAIDs for patients with IBD, especially when used for short periods of time [5,6]. As an example, one study randomly assigned 222 adults with quiescent ulcerative colitis to receive the COX-2 selective NSAID celecoxib (200 mg twice daily) or placebo to treat musculoskeletal pain (eg, arthralgia or arthritis) and performed endoscopy at baseline and after two weeks [5]. The two patient groups had similar rates of disease exacerbations (3 to 4 percent) and bowel-related adverse events (11 percent). There are no published studies examining the efficacy or tolerance of nonselective NSAIDs for IBD-related arthritis.

Evidence to support the use of NSAIDs as initial therapy of many other forms of spondyloarthritis (SpA) in children and adults is discussed in detail elsewhere:

•(See "Spondyloarthritis in children", section on 'NSAIDs for most patients'.)

•(See "Psoriatic juvenile idiopathic arthritis: Management and prognosis", section on 'NSAIDs for most patients'.)

•(See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Initial drug therapy with NSAIDs'.)

•(See "Treatment of psoriatic arthritis".)

●Response to NSAIDs – If a patient develops signs or symptoms of active IBD while using an NSAID, we temporarily or permanently discontinue this medication. If patients have persistent symptoms of IBD-related arthritis despite the initial NSAID trial and have tolerated the NSAID well, we generally switch to another two-week course of an alternative NSAID. As with the initial NSAID trial, we often prescribe a COX-2 selective NSAID, although a nonselective NSAID with a proton pump inhibitor is an alternative option.

Adjunctive therapies for selected patients

Intraarticular glucocorticoids for limited peripheral arthritis — Patients with a limited number of swollen joints (ie, ≤3) amenable to arthrocentesis may benefit from intraarticular glucocorticoid injections in addition to NSAIDs as part of their initial treatment approach. Intraarticular glucocorticoids should not be used unless septic arthritis has been excluded as an alternative diagnosis. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children" and "Septic arthritis in adults".)

The procedure, dosing of glucocorticoids, and monitoring for complications are the same in IBD-related arthritis as in other types of inflammatory arthritis and are detailed elsewhere, with dosing provided in the table (table 2). (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?" and "Joint aspiration and injection in adults: Indications and technique".)

While there are no trials examining the use of intraarticular glucocorticoids in IBD-related arthritis, they are included in the approach used by experts [1] and, in the author's experience, may reduce the need for systemic therapy.

Physical therapy for axial arthritis — We refer all patients with axial symptoms to a physical therapist for instruction in back exercises. Exercise is a cornerstone for the long-term management of axial arthritis and helps maintain flexibility and posture. While data to directly support the use of physical therapy in patients with IBD-related arthritis are very limited, it is recommended by experts for other forms of axial SpA in adults and children [8,9] and is useful in the author's clinical experience. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Initial therapy'.)

Treatment of persistent or refractory disease — If patients with quiescent IBD cannot tolerate NSAIDs or have persistent or recurrent arthritis despite the measures outlined above, then we escalate to systemic immunosuppression (algorithm 2). The optimal type of immunosuppression depends on the extent of arthritis. Patients with isolated peripheral arthritis can try a conventional synthetic DMARD (csDMARD; eg, sulfasalazine [SSZ] or methotrexate [MTX]), while those with axial involvement often receive a monoclonal tumor necrosis factor (TNF) inhibitor. Systemic or local glucocorticoids may be effective as bridging therapy in patients with debilitating peripheral arthritis. Management of refractory disease depends on the previous therapies; patients with peripheral arthritis typically add or switch to a TNF inhibitor, while those with axial arthritis may try a second type of TNF inhibitor.

Peripheral arthritis

●Persistent peripheral arthritis despite NSAIDs – For patients who do not have axial arthritis and who have persistent peripheral arthritis despite initial therapy (eg, NSAIDs with or without local glucocorticoid injections), we suggest adding SSZ rather than another csDMARD or biologic DMARD (bDMARD). Our approach is outlined in the algorithm (algorithm 2), with drug dosing for adults in the table (table 3). If SSZ is inadequate or poorly tolerated, we typically start MTX; other options include azathioprine (AZA) or 6-mercaptopurine (6-MP). The same approach is used when patients cannot tolerate NSAID therapy. If patients are tolerating NSAIDs, we typically continue the NSAID with the csDMARD. (See 'csDMARDs' below.)

In patients who have both axial and peripheral arthritis that is refractory to NSAIDs, we use a TNF inhibitor since csDMARDs are typically ineffective for axial manifestations. (See 'Axial arthritis' below.)

Since csDMARDs typically take months to be fully effective, glucocorticoids are sometimes added for peripheral arthritis that persists despite NSAIDs, especially in the presence of severe symptoms or functional impairment. Local glucocorticoid injection may be beneficial in patients with one or two affected joints that are amenable to injection, while a short course of oral glucocorticoids or an intramuscular injection is used for patients with more widespread disease. (See 'Glucocorticoids as bridging therapy' below.)

There is very limited evidence to support one type of immunosuppression over another for treatment of IBD-related arthritis that is refractory to NSAIDs. The preference for SSZ and MTX over other csDMARDs is due to evidence that these agents may treat both IBD and peripheral SpA. By contrast, AZA and 6-MP are both use to treat IBD but not SpA. The preference for SSZ is also supported by expert opinion [1] and by the authors' clinical experience.

●Refractory peripheral arthritis despite csDMARDs – In patients with peripheral joint disease that is refractory to a three-month trial of csDMARDs, we suggest adding a monoclonal TNF inhibitor rather than another csDMARD or an alternative bDMARD. In patients who have an inadequate response to a three-month trial of a first TNF inhibitor, we generally try switching to a second monoclonal TNF inhibitor. (See 'Tumor necrosis factor inhibitors' below.)

Patients who cannot tolerate or do not respond to TNF inhibitors may benefit from alternative DMARDs. (See 'Other DMARDs' below.)

Axial arthritis

●Persistent axial arthritis despite NSAIDs – In patients with persistent axial arthritis despite initial therapy with NSAIDs, we suggest adding a monoclonal TNF inhibitor rather than a csDMARD. The same approach is used when patients cannot tolerate NSAID therapy. If patients are tolerating NSAIDs, we typically continue the NSAID with the TNF inhibitor. Our approach is outlined in the algorithm (algorithm 2), with drug dosing for adults in the table (table 3). (See 'Tumor necrosis factor inhibitors' below.)

TNF inhibitors are favored over csDMARDs in axial IBD-related arthritis because csDMARDs (eg, SSZ, MTX) are generally ineffective for axial disease in other forms of SpA. The preference for TNF inhibitors over other bDMARDs is supported by expert opinion [1] and by the authors' clinical experience.

●Refractory axial arthritis despite TNF inhibitors – In patients who have an inadequate response to a three-month trial of a first TNF inhibitor, we generally try switching to a second monoclonal TNF inhibitor. Therapeutic alternatives to TNF inhibitors for treatment of refractory axial arthritis are similar to those outlined for refractory peripheral arthritis. (See 'Other DMARDs' below.)

Enthesitis and dactylitis — The management of persistent enthesitis and dactylitis in the setting of IBD is similar to the management of these conditions in patients with other forms of peripheral SpA. After NSAIDs, we typically treat enthesitis and/or dactylitis with a monoclonal TNF inhibitor (see 'Axial arthritis' above). Adjunctive therapy with heel orthoses can be beneficial and a prolonged course of physical therapy may be required.

Direct evidence to support the use of various treatment strategies for enthesitis and dactylitis in IBD-related arthritis is extremely limited. An open-label study of infliximab in 24 patients with Crohn disease and associated arthritis noted improvement in enthesitis [10]. The treatment of enthesitis and dactylitis in other forms of SpA is discussed elsewhere:

●(See "Psoriatic juvenile idiopathic arthritis: Management and prognosis", section on 'Dactylitis'.)

●(See "Treatment of peripheral spondyloarthritis", section on 'Enthesitis'.)

●(See "Treatment of peripheral spondyloarthritis", section on 'Dactylitis'.)

Available therapies — Dosing of available therapies is summarized in the table (table 3) and discussed in more detail below.

csDMARDs

●Sulfasalazine – We start SSZ at a dose of 1000 mg daily (split into two doses a day). Every two weeks, we increase the daily dose by 1000 mg until arthritis symptoms improve, up to a maximum daily dose of 3000 mg (split into two to three doses daily). A trial of at least 12 weeks is required to adequately assess efficacy. More information about the dosing, monitoring, adverse effects, and contraindications to SSA and its use in other forms of arthritis and IBD is provided separately. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

SSZ is an azo-bonded combination of 5-aminosalicylic acid, which lowers colonic prostaglandin E and alters gut flora, and sulfapyridine, which appears to be antiarthritic [11]. Evidence supporting the use of SSZ in SpA and IBD in children and adults is discussed elsewhere:

•(See "Spondyloarthritis in children", section on 'bDMARD for most patients'.)

•(See "Treatment of peripheral spondyloarthritis", section on 'Resistant to initial therapy'.)

•(See "Overview of the medical management of mild (low risk) Crohn disease in adults", section on '5-aminosalicylates'.)

•(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Alternative therapy'.)

●Methotrexate – The approach to MTX dosing and administration in IBD-related arthritis is the same as that used in other types of SpA. The usual initial dose is 10 mg once weekly; the dose is then increased in 2.5 to 5 mg increments every one to two weeks until joint inflammation is controlled or a maximum dose of 25 mg weekly is reached. Orally administered MTX is adequately absorbed, even in patients with active IBD [12]. However, subcutaneous injections of MTX provide higher drug bioavailability, especially at doses greater than 15 mg, and may also help alleviate gastrointestinal adverse effects (eg, nausea). We provide folic acid supplementation for all patients taking methotrexate (eg, folic acid 1 mg daily). More information about the dosing, monitoring, adverse effects, and contraindications to MTX are provided separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major adverse effects of low-dose methotrexate".)

Evidence supporting the use of MTX in other types of SpA is described elsewhere:

•(See "Polyarticular juvenile idiopathic arthritis: Treatment and prognosis", section on 'Methotrexate'.)

•(See "Treatment of peripheral spondyloarthritis", section on 'Resistant to initial therapy'.)

•(See "Treatment of peripheral psoriatic arthritis", section on 'Methotrexate'.)

●Azathioprine/6-mercaptopurine – 6-MP is the active metabolite of AZA. The approach to dosing and monitoring of AZA in patients with IBD-related arthritis is the same as that used for patients with other rheumatic diseases and IBD, which is described separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

While data are very limited to support the use of AZA or 6-MP in patients with IBD-related arthritis, experts have proposed this as a potential therapy [13]. Data on their use in treating IBD are presented separately:

•(See "Medical therapies for Crohn disease in children and adolescents", section on 'Aminosalicylates'.)

•(See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Maintenance of remission'.)

•(See "Overview of the medical management of mild (low risk) Crohn disease in adults", section on '5-aminosalicylates'.)

•(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Subsequent therapy'.)

Tumor necrosis factor inhibitors — We use adalimumab (originator or biosimilar), certolizumab, golimumab, or infliximab (originator or biosimilar) according to the dosing regimens employed for other forms of SpA and in IBD. We generally do not favor the use of etanercept since it is not effective for IBD [14,15]. A summary of key differences in drug design and administration between TNF inhibitors is provided in the table (table 4). Dosing of TNF inhibitors for IBD and IBD-related arthritis may be higher than that typically used for other forms of inflammatory arthritis. We typically use the following initial doses of TNF inhibitors for adults with IBD-related arthritis:

●Adalimumab – 40 mg by subcutaneous injection every other week

●Certolizumab pegol – Initial: 400 mg by subcutaneous injection, repeat dose two and four weeks after initial dose; maintenance: 200 mg every two weeks or 400 mg every four weeks

●Golimumab – 50 mg by subcutaneous injection once a month (loading doses may also be used in patients with active gut inflammation)

●Infliximab – 5 mg/kg by intravenous infusion at zero, two, and six weeks, followed by 5 mg/kg every eight weeks thereafter

The choice of TNF inhibitor should be made in collaboration between the rheumatologist and gastroenterologist and may be determined in part by regulatory, cost, or insurance restrictions, which may be affected by the specific IBD diagnosis (ie, whether the patient has Crohn disease or ulcerative colitis). These factors also influence the decision to use a biosimilar TNF inhibitor in this clinical setting.

●Contraindications and adverse effects – The presence of active infection is an absolute contraindication to the use of TNF inhibitors. This is a particular concern in fistulizing Crohn disease where patients may develop abscesses. There should be an ongoing dialogue between the gastroenterologist and the rheumatologist when considering bDMARDs in such a patient.

The risks and adverse effects of TNF inhibitors are described in detail separately:

•(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

•(See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

•(See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

•(See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

●Evidence – The preference for TNF inhibitors over other bDMARDs is supported by expert opinion [1] and by the authors' clinical experience. While both TNF and JAK inhibitors are effective in axial SpA and IBD, the cumulative experience is greater with TNF inhibitors for longer-term safety and efficacy [16]. Furthermore, a number of small case series and other observational studies have supported the use of TNF inhibition in patients with IBD-related arthritis, including the following [10,17-19]:

•In a prospective study of 153 adults with active Crohn disease that was refractory to other therapy (defined as taking glucocorticoids, AZA, 6-MP, and/or MTX), a 12-week course of infliximab lead to a significant improvement in arthralgia and/or arthritis [18]. Of the 59 patients who had arthralgia or arthritis at baseline, 46 percent had no symptoms at follow-up.

•In another prospective study, 24 adults with active arthritis related to Crohn disease received infliximab for 12 to 18 months [10]. Compared with 12 patients who were treated with nonbiologic therapies (eg, glucocorticoids, AZA, MTX, antibiotics), patients taking infliximab had a more rapid improvement in peripheral arthritis and greater improvement in enthesitis.

Whether TNF inhibitor therapy has any long-term benefit in reducing the progression of IBD-related spondylitis remains to be determined. However, there is a growing consensus that early, sustained TNF inhibitor therapy in axial SpA can modify radiographic progression over time. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Effects of treatment on radiographic progression'.)

Most of the evidence to support the use of TNF inhibitors in IBD-related arthritis is extrapolated from studies in other forms of SpA, which are summarized elsewhere:

•(See "Spondyloarthritis in children", section on 'bDMARD for most patients'.)

•(See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'TNF inhibitors'.)

•(See "Treatment of peripheral psoriatic arthritis", section on 'TNF inhibitors for most patients'.)

Other DMARDs — Other DMARDs are sometimes used to treat patients with refractory IBD-related arthritis or those with contraindications to other therapies. Options include the following:

●Interleukin 12/23 inhibitors – The IL-12/23 inhibitor ustekinumab and the IL-23 inhibitor risankizumab are used to treat both Crohn disease and psoriatic arthritis. These agents may be more effective for patients with IBD-related arthritis who only have peripheral disease, and they are generally not effective for the treatment of axial SpA in adults [20,21]. Evidence supporting the use of IL-12/23 or IL-23 inhibitors in patients with peripheral SpA or IBD is provided elsewhere. (See "Medical management of moderate to severe Crohn disease in adults", section on 'Anti-interleukin (IL) antibody therapy' and "Management of moderate to severe ulcerative colitis in adults", section on 'Anti-interleukin (IL) antibody-based therapy' and "Treatment of peripheral psoriatic arthritis", section on 'Ustekinumab'.)

●Janus kinase inhibitors – Janus kinase (JAK) inhibitors appear to be effective for both axial and peripheral manifestations of SpA. Tofacitinib and upadacitinib have been approved by US Food and Drug Administration (FDA) for certain types of SpA and ulcerative colitis. Evidence supporting the use of JAK inhibitors in patients with IBD or SpA is provided elsewhere. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Janus kinase (JAK) inhibitors' and "Treatment of psoriatic arthritis", section on 'Axial disease resistant to initial tumor necrosis factor inhibitor'.)

When patients have refractory disease despite a TNF-inhibitor, we evaluate for possible subclinical IBD activity:

●(See "Management of mild to moderate ulcerative colitis in children and adolescents", section on 'Determination of response to therapy'.)

●(See "Overview of the management of Crohn disease in children and adolescents", section on 'Assessment of disease activity'.)

●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Monitoring during remission'.)

●(See "Overview of the medical management of mild (low risk) Crohn disease in adults", section on 'Monitoring during remission'.)

Glucocorticoids as bridging therapy

●Intraarticular glucocorticoids – For intraarticular glucocorticoids, the procedure, dosing, and monitoring for complications are the same in IBD-related arthritis as other types of inflammatory arthritis and are detailed elsewhere. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?" and "Joint aspiration and injection in adults: Indications and technique".)

●Systemic glucocorticoids – For systemic glucocorticoids, we use either an intramuscular injection of methylprednisolone (80 to 120 mg) or a short course of oral glucocorticoids (initially 20 mg daily of prednisone or its equivalent, followed by a two-week taper). We avoid the use of long-term systemic glucocorticoids because of the infection-related risks already imposed by IBD. Adverse effects of systemic glucocorticoids are discussed in detail separately. (See "Major adverse effects of systemic glucocorticoids".)

TREATMENT OF PATIENTS WITH ACTIVE INFLAMMATORY BOWEL DISEASE — 

When patients have active inflammatory bowel disease (IBD) as well as related arthritis, the focus of treatment is to optimize control of the underlying gastrointestinal manifestations in collaboration with the patient's gastroenterologist. IBD may be active clinically (eg, diarrhea, weight loss, abdominal pain) or subclinically (ie, asymptomatic patients with evidence of ongoing intestinal inflammation on imaging or laboratory studies). Based on the author's experience, improvement in gastrointestinal inflammation often leads to concomitant improvement in arthritis (see "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases", section on 'Type I arthropathy'). Researchers have hypothesized that the relationship between arthritis and intestinal inflammation in IBD may be related to the exposure of the immune system to local bacteria when there is mucosa inflammation. More information on the role of intestinal inflammation and the gut microbiome in the pathogenesis of spondyloarthritis is discussed in detail separately. (See "Pathogenesis of spondyloarthritis", section on 'The gut mucosa, gut microbiome, and IL-17A'.)

●Choosing a treatment regimen – When patients have active clinical or subclinical IBD, we prioritize the treatment of gastrointestinal disease (algorithm 1). In general, we use agents that are effective for both gastrointestinal and articular manifestations of IBD, rather than ones that only target gastrointestinal manifestations. Examples of agents that have some supportive data for treating IBD and inflammatory arthritis include systemic glucocorticoids, sulfasalazine (SSZ), methotrexate (MTX), azathioprine (AZA), 6-mercaptopurine (6-MP), tumor necrosis factor (TNF) inhibitors, interleukin 12/23 (IL-12/23) inhibitors, and janus kinase (JAK) inhibitors [13,17,18,22-25]. Some of these agents treat axial arthritis (eg, TNF and JAK inhibitors), while others do not. (See 'Axial arthritis' above.)

Some agents used to treat gastrointestinal manifestations of IBD may be ineffective for or, less commonly, exacerbate related arthritis. This underscores the importance of selecting agents carefully in order to streamline therapy and reduce the cumulative risk of multiple immunosuppressive medications. Aminosalicylates (eg, mesalamine) are useful for controlling intestinal inflammation but appear to have no direct antiinflammatory effect on the synovium [13]. Vedolizumab is effective for treating gastrointestinal manifestations of IBD but is ineffective for treating the arthritis and, based on one case series, may induce or flare axial or peripheral arthritis in some patients [26].

●Adjunctive therapies

•NSAIDs – When patients with active IBD require nonsteroidal antiinflammatory drugs (NSAIDs), a short trial of a low-dose cyclooxygenase 2 (COX-2) selective NSAID (eg, celecoxib 100 mg twice daily for one to two weeks) may be considered in collaboration with the patient's gastroenterologist; however, patients should be monitored closely for worsening IBD symptoms. (See 'NSAIDs for most patients' above.)

•Other therapies – Patients with peripheral arthritis affecting a limited number of joints that are amenable to injection may benefit from the addition of intraarticular glucocorticoids. Those with axial disease also typically receive physical therapy. (See 'Adjunctive therapies for selected patients' above.)

The treatment of IBD is discussed in detail separately:

●(See "Overview of the management of Crohn disease in children and adolescents".)

●(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

●(See "Medical management of moderate to severe Crohn disease in adults".)

●(See "Management of mild to moderate ulcerative colitis in children and adolescents".)

●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

●(See "Management of moderate to severe ulcerative colitis in adults".)

SPECIAL POPULATIONS

Children — Our approach to treating inflammatory bowel disease (IBD)-related arthritis in children is generally the same as that outlined above for adults. However, there may be relatively less safety data for some agents used to treat refractory disease. As an example, we may reserve janus kinase (JAK) inhibitors for patients who do not tolerate other options due to the limited amount of data in children.

Pregnant patients — Certain immunosuppressive therapies, such as methotrexate (MTX), are contraindicated in patients who are pregnant or who are considering pregnancy. Nonsteroidal antiinflammatory drugs (NSAIDs) should generally be avoided after the 20^th week of gestation. Other medications, such as sulfasalazine (SSZ), azathioprine (AZA), and certolizumab, have good safety profiles during pregnancy. More information on the use of NSAIDs and immunosuppressive therapy during pregnancy and lactation is provided elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Patients with comorbid uveitis — Patients with IBD may develop comorbid uveitis or other forms of eye inflammation (eg, episcleritis, scleritis) (see "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Ocular disease'). There is significant overlap in the types of immunosuppressive therapies used for both IBD-related arthritis and uveitis (eg, glucocorticoids, MTX, AZA). However, certain types of biologic disease-modifying antirheumatic drugs (bDMARDs) may be preferable over others when a patient with refractory IBD-related arthritis also has uveitis. As an example, tumor necrosis factor (TNF) inhibitors (with the exception of etanercept) are commonly used to treat uveitis, while interleukin 12/23 (IL-12/23) inhibitors are generally not effective for uveitis. The treatment of noninfectious uveitis is described in detail elsewhere. (See "Uveitis: Treatment".)

Patients with comorbid psoriasis — Psoriasis has been associated with both Crohn disease and ulcerative colitis (see "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Psoriasis'). Many treatments for IBD-related arthritis are also effective for psoriasis. However, glucocorticoids have been associated with flares of psoriasis when they are tapered and are often avoided in patients with psoriasis [27]. Furthermore, some types of conventional synthetic DMARDs (csDMARDs) used to treat IBD-related arthritis may also treat psoriasis (eg, MTX), while others do not (eg, SSZ, AZA). Most bDMARDs used to treat IBD-related arthritis would also treat comorbid psoriasis (eg, TNF, IL-12/23, and JAK inhibitors). The treatment of psoriasis is discussed separately. (See "Psoriasis in children: Management of chronic plaque psoriasis" and "Chronic plaque psoriasis in adults: Overview of management".)

MONITORING OF THERAPY — 

Monitoring of patients after initiation of therapy follows the same approach as in other forms of spondyloarthritis (SpA), with the caveat that management should be done in collaboration with the patient's gastroenterologist. The monitoring of SpA in children and of peripheral and axial SpA in adults is discussed in detail separately:

●(See "Psoriatic juvenile idiopathic arthritis: Management and prognosis", section on 'Assessing response to treatment'.)

●(See "Treatment of peripheral spondyloarthritis", section on 'Monitoring'.)

●(See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Evaluation and monitoring'.)

Routine monitoring for patients taking certain types of medications for inflammatory arthritis is summarized in the table (table 5). Therapeutic drug monitoring (eg, target drug trough concentrations and levels of anti-drug antibodies) is often done for patients with Crohn disease or ulcerative colitis who are taking tumor necrosis factor (TNF) inhibitors, which is discussed in detail elsewhere. (See "Dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults" and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

PROGNOSIS — 

The long-term outcomes of patients with arthritis related to inflammatory bowel disease (IBD) are commonly defined more by the course of the IBD than the arthritis. The musculoskeletal prognosis appears to mirror that seen in other forms of spondyloarthritis (SpA) in the absence of IBD, although it has not been formally evaluated. The course of the peripheral arthritis often fluctuates and typically is nonerosive and nondeforming. Axial arthritis may be complicated by progressive spondylitis.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Spondyloarthritis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Juvenile idiopathic arthritis (The Basics)" and "Patient education: Ankylosing spondylitis (The Basics)" and "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (The Basics)" and "Patient education: Physical activity for people with arthritis (The Basics)" and "Patient education: Ulcerative colitis in adults (The Basics)" and "Patient education: Crohn disease in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Arthritis (Beyond the Basics)" and "Patient education: Axial spondyloarthritis, including ankylosing spondylitis (Beyond the Basics)" and "Patient education: Arthritis and exercise (Beyond the Basics)" and "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs) (Beyond the Basics)" and "Patient education: Sulfasalazine and the 5-aminosalicylates (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)" and "Patient education: Ulcerative colitis (Beyond the Basics)" and "Patient education: Crohn disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview of therapy – Arthritis related to inflammatory bowel disease (IBD) is a type of spondyloarthritis (SpA). The goal of treatment is controlling inflammation in both the joints and gastrointestinal tract; care must therefore be coordinated carefully between gastroenterology and rheumatology. The general approach to the treatment depends on whether or not the patient has active IBD. (See 'Overview of therapy' above.)

●Pretreatment considerations – Septic arthritis should be excluded in patients with presumed arthritis related to IBD, especially before using intraarticular glucocorticoids and/or systemic immunosuppression. (See 'Pretreatment considerations' above.)

●Treatment of patients with inactive IBD

•Initial treatment – For patients with quiescent IBD and active arthritis, initial therapy consists of a short course (two weeks) of a nonsteroidal antiinflammatory drug (NSAID) and, in selected patients, adjunctive intraarticular glucocorticoid injections and physical therapy (algorithm 1). (See 'Initial treatment' above.)

-NSAIDs for most patients – In patients who have quiescent IBD, we suggest initial therapy with a cyclooxygenase 2 (COX-2) selective NSAID rather than a disease-modifying antirheumatic drug (DMARD) (Grade 2C). We typically administer a two-week course. Any COX-2 selective NSAID may be effective at antiinflammatory doses (eg, celecoxib 100 mg twice daily) (table 1). If a COX-2 selective NSAID is not available, an alternative option is to use a nonselective NSAID (eg, naproxen, ibuprofen) together with a proton pump inhibitor (eg, omeprazole 20 mg daily) for gastroprotection. (See 'NSAIDs for most patients' above.)

NSAIDs must be initiated collaboratively in consultation with the patient's gastroenterologist since there is limited evidence that they may exacerbate IBD. We discontinue NSAIDs if a patient develops signs or symptoms of active IBD during treatment. If patients have persistent symptoms of IBD-related arthritis despite the initial NSAID trial and have tolerated the NSAID well, we generally switch to another two-week course of an alternative NSAID.

-Intraarticular glucocorticoids for limited peripheral arthritis – Patients with ≤3 swollen joints amenable to arthrocentesis may benefit from the addition of intraarticular glucocorticoid injections. Intraarticular glucocorticoids should not be used unless septic arthritis has been excluded as an alternative diagnosis. (See 'Intraarticular glucocorticoids for limited peripheral arthritis' above.)

-Physical therapy for axial arthritis – We refer all patients with axial symptoms to a physical therapist for instruction in back exercises to help maintain spine flexibility and posture. (See 'Physical therapy for axial arthritis' above.)

•Treatment of persistent or refractory disease – Patients with persistent symptoms despite or intolerance of NSAIDs are treated with systemic immunosuppression, with the choice of therapy guided by the specific location of the arthritis (algorithm 2 and table 3). (See 'Treatment of persistent or refractory disease' above.)

-Peripheral arthritis – For patients who do not have axial arthritis and who have persistent peripheral arthritis despite initial therapy (eg, NSAIDs with or without local glucocorticoid injections), we suggest adding sulfasalazine (SSZ) rather than another conventional synthetic DMARD (csDMARD) or biologic DMARD (bDMARD) (Grade 2C). If SSZ is contraindicated or poorly tolerated, we typically use methotrexate (MTX); other options include azathioprine (AZA) or 6-mercaptopurine (6-MP). (See 'Peripheral arthritis' above and 'csDMARDs' above.)

Adjunctive glucocorticoids are sometimes added for patients with severe symptoms or functional impairment, either through intraarticular injections for those with limited joint involvement (≤3 joints) or systemic routes for those with more widespread disease. (See 'Glucocorticoids as bridging therapy' above.)

In patients with peripheral joint disease that is refractory to a three-month trial of csDMARDs, we suggest adding a monoclonal tumor necrosis factor (TNF) inhibitor rather than another csDMARD or an alternative bDMARD (Grade 2C). (See 'Tumor necrosis factor inhibitors' above.)

-Axial arthritis – In patients with persistent axial arthritis despite initial therapy with NSAIDs, we suggest adding a monoclonal TNF inhibitor rather than a csDMARD (Grade 1B). (See 'Axial arthritis' above and 'Tumor necrosis factor inhibitors' above.)

In patients who have an inadequate response to a three-month trial of a first TNF inhibitor, we generally switch to a second monoclonal TNF inhibitor.

-Enthesitis and dactylitis – After NSAIDs, patients with persistent enthesitis and/or dactylitis are generally started on a monoclonal TNF inhibitor. (See 'Enthesitis and dactylitis' above.)

●Treatment of patients with active IBD – In patients with active IBD and related arthritis, treatment is focused on targeting the gastrointestinal manifestations. In general, we use agents that are effective for both gastrointestinal and articular manifestations of IBD, rather than ones that only target gastrointestinal ones. A short trial of a low-dose COX-2 selective NSAID (eg, celecoxib 100 mg twice daily for one to two weeks) may also be considered in collaboration with the patient's gastroenterologist. (See 'Treatment of patients with active inflammatory bowel disease' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter H Schur, MD, and Filip van den Bosch, MD, PhD, who contributed to earlier versions of this topic review.