Once the primary care physician suspects IBD, the patient may be referred to a specialist, who will request a colonoscopy (if there is direct access to endoscopies, the colonoscopy may be requested and the patient referred to the specialist once the diagnosis has been confirmed). The form of referral from PC to Gastroenterology is highly heterogeneous, depending on where the PC physician works. There is no uniformity in accessibility to testing, in the way of establishing contact with specialised care, or in waiting times. All of this creates a barrier to the referral and follow-up of these patients, as well as significant dissatisfaction on the part of the primary care practitioners.32

Open access to specialised care is preferred by both patients with IBD and primary care physicians, and it has been found that personal acquaintance between primary care physicians and gastroenterologists increases the quality of care. Both these areas should therefore be objectives for improvement, as it is essential to acquainted, at least nominally, with the IBD gastroenterologists and how to access the region's IBD reference units.

In the GETECCU IUC programme, one of the indicators for the accreditation of the units consists of having a priority appointment circuit from PC to the IBD units for both recently diagnosed patients and flare-ups of activity.33

In the computer age, e-consultation is a good option. The primary care physician makes an e-consultation addressed to the gastroenterologist through the patient's electronic medical records and the recipient evaluates the case, determining the need for further information or tests by the primary care physician, establishing the diagnostic approach, referral to the IBD unit, consultation with other specialities, or the start of a particular treatment. All of this is done electronically or by arranging a face-to-face appointment for the patient within a time frame appropriate to the severity of the disease.34 To achieve this, it is essential that GPs submit a summary of the case, which is easy to read, and which allows patients to be filtered and prioritised appropriately. If e-consultation is not available, communication can be established by email or telephone, although this method is much more complicated due to accessibility issues. Lastly, contact can be made through the usual referral circuits, using the official form with normal or priority referral, although this involves the familiar problems of lack of interaction between healthcare professionals, excessive delays, inappropriate referrals, poor patient control or healthcare professional dissatisfaction, both in primary care and specialised care.

There are different formulations of mesalazine available, both for oral and rectal use. Clinical trials have not demonstrated differences in efficacy or safety with the different oral formulations, so patient preferences should be taken into account when choosing tablets or microgranules.35 The appropriate oral mesalazine dose for induction of remission in patients with mild/moderate UC flare-up is 2.4 g/day, with >3 g/day, in a single daily dose, being optimal.36 Topical mesalazine may be administered via suppositories, foam or rectal suspension (enemas). The choice of one or another depends on the extent of the disease: the rectal suspension can reach up to the splenic flexure, the foam reaches the sigmoid colon/descending colon, while suppositories reach no further than the rectum. In ulcerative proctitis the first-line indication in the flare-up is a suppository of 1 g/24 h, before going to bed, possibly increasing to 3 g per week for maintenance, depending on tolerance.26 For better adherence, there are explanatory videos about the use of topical mesalazine on the website (GEducaEII) https://www.youtube.com/watch?v=oWyfExo8Zj8&t=271s.

Mesalazine is generally well tolerated. The most frequently reported adverse effects are mild, and consist of abdominal pain, nausea and vomiting. There are no differences in safety between the use of low or high doses of mesalazine, and annual monitoring of renal function and liver enzymes is recommended.37

There are two types of corticosteroids: systemic oral corticosteroids, with high bioavailability and significant toxicity; and topical oral corticosteroids, with low systemic availability. The usual dose for the management of a moderate IBD flare-up is 1 mg/kg/day (or 40−60 mg/day) of oral prednisone (or equivalent). Weaning off systemic steroids, once remission is achieved, is usually done reducing by 10 mg each week until reaching 20 mg/day, and then by 5 mg a week. Steroids should not be stopped abruptly in patients who have been on treatment for more than 7–10 days. Topical oral corticosteroids include budesonide, indicated for inducing remission of mild/moderate flare-ups of ileal CD, at doses of 9 mg/day in a single dose and with a progressive decrease once remission is achieved, and beclomethasone dipropionate, indicated in mild/moderate flare-ups of UC, at a dose of 5 mg per day for one month (sometimes they can be used 10 mg/day for one month and 5 mg for a further 2–4 weeks).28,29 Lack of response to full-dose corticosteroids is known as being refractory to corticosteroids. Corticosteroid dependence occurs when corticosteroids cannot be reduced to under 10 mg/day of prednisone or 3 mg/day of budesonide without recurrence of symptoms, in the first three months of treatment, or when a clinical relapse occurs within three months of discontinuing corticosteroids.38 In these cases, an alternative treatment must be sought to avoid the excessive use of corticosteroids, and they should never be considered as maintenance therapy in patients with IBD, given that they have a significant number of side effects, including high blood pressure, water retention, moon face, acne, hirsutism, stretch marks, glucose intolerance, insomnia, emotional lability, infections, cataracts, glaucoma, adrenal atrophy, growth retardation in children, and loss of bone mineral density. Monitoring of blood glucose and blood pressure levels is recommended in patients with previous diabetes mellitus and hypertension. Special attention should be paid to patients with underlying psychiatric disorders, in case steroids unbalance them. The effect of steroids on bone mineral density should be monitored, and it is recommended that they always be co-administered with calcium and vitamin D supplements.39

Thiopurine immunosuppressants: azathioprine and mercaptopurine. These are indicated in corticosteroid dependence, and concomitantly with anti-TNF drugs, to prevent immunogenicity. The dose of azathioprine is 2.5−3 mg/kg/day in a single dose (which can be divided if there is poor tolerance). Exposure to sunlight should be limited and high sun protection should be used routinely due to its association with non-melanoma skin cancer. From the start of treatment, a slight decrease in the number of leucocytes (lymphocytes) may occur and the mean corpuscular volume may increase. Adverse effects are very common and lead to withdrawal in 15%–20% of patients (Table 6). Recommendations for analyses during follow-up include monitoring with blood count and liver profile at two weeks, one month, then every three months in the first year, and every four to six months for the duration of the treatment period.40

Methotrexate. This can be used subcutaneously on a weekly basis in steroid-dependent CD or in combination with anti-TNF drugs. It is used much less often than thiopurines. Adverse effects include increased infections, risk of teratogenicity, which renders it contraindicated in women and men who want to have children (it should be withdrawn three months in advance if there is a wish for pregnancy), hepatotoxicity and lung toxicity, with risk of pulmonary fibrosis. For monitoring, a monthly blood tests are recommended for the first three months and subsequently every three to four months, with a liver elastography every two years from the fifth year on.29

These are indicated for the induction and maintenance of remission, corticosteroid resistance, corticosteroid dependence, perianal disease or extraintestinal manifestations, especially when other approaches have not been sufficient. Biologic drugs are classified according to their mechanism of action (Table 7). Before starting a biologic drug, the vaccination schedule should be updated and tuberculosis screening should be performed (Mantoux and/or Interferon Gamma Release Assay [IGRA]). IGRA screening is recommended every 12–24 months during treatment.

Adverse effects with anti-TNF treatments include infections (especially in combination therapy with immunosuppressants), hypersensitivity reactions after the infusion, injection site reactions in subcutaneous administration, arthralgia, autoimmune hepatitis, and the appearance of paradoxical reactions such as induced psoriasis or lupus-like phenomena. New biologics, such as vedolizumab, ustekinumab, risankizumab and mirikizumab, have provided a better safety profile with mild side effects, such as headache, nausea, arthralgia, pharyngitis, fatigue and pruritus, which rarely lead to discontinuation of treatment. Biologic drugs have no significant drug interactions.41

These are small, chemically synthesised molecules that inhibit JAK receptors, which modulate various inflammatory and immune responses. Three JAK inhibitors are currently approved: tofacitinib, filgotinib, and upadacitinib; the first two for UC, and the third for UC and CD. They are indicated for patients with moderate to severe activity with insufficient response, loss of response or intolerance to conventional treatment or a biologic medication. Latent tuberculosis should be ruled out before and during treatment. An increased risk of herpes zoster has been documented, owing to which vaccination with two doses of the inactivated recombinant vaccine Shingrix® is recommended, if possible, before starting treatment. In patients over the age of 65, with high vascular risk or history of cancer, it can be used as an alternative if other biologic therapies fail. During follow-up, patients should be monitored for possible cytopenias, especially lymphopenia and lipid metabolism.42

The safest and most effective contraceptive option is long-acting reversible contraception, which may include a hormonal or non-hormonal intrauterine device or a contraceptive implant. This is preferable to oral contraception, as active inflammation of the bowel, resection or rapid intestinal transit may reduce its effectiveness. If oral contraceptives need to be used, we would use a contraceptive with low doses of oestrogen, given the risk of venous thromboembolism, or a contraceptive that only contains progestogens. There is no contraindication for emergency contraception.46,47

IBD frequently affects patients of reproductive age; consequently, information on aspects such as fertility, genetic risk or the influence of the disease on pregnancy is important. Women with IBD have the same fertility rate as age-matched controls, although it may decrease in active disease or with a history of previous pelvic surgery. Reduced desire for motherhood due to fear of transmitting the disease or the effect of treatments, lack of sexual desire or dyspareunia may also have an influence.48 Regarding assisted reproductive therapy or egg freezing, there are no data to suggest that IBD medications have any effect, or that the hormones used in treatment act on the disease.49 Children of parents with IBD have a genetic predisposition to develop the disease. If one parent suffers from CD or UC, the probability is 5% and 3% respectively, and if both parents have it, 30%.46

Preconception visits and prior counselling are associated with better pregnancy outcomes. It is important for the patient to know that she should be in remission, ideally for three to six months, before conception. This reduces the risk of flare-ups during pregnancy and postpartum, as well as the risks of miscarriage, low birth weight and premature birth.50 In conjunction with the patient's gastroenterologist, a plan should be established for treatment to maintain the disease inactive and that can be taken during pregnancy. The patient needs to be aware of the risks of discontinuing the prescribed medication, and adherence should be reinforced by primary care. Most medications can be used, except methotrexate, which should be discontinued three months before, in both females and males. Corticosteroids would be indicated in the short term in a flare-up. Biologic drugs can be used throughout pregnancy.47 The use of JAK inhibitors is discouraged due to lack of safety studies. In cases where a pregnancy is considered high risk, a multidisciplinary approach should be taken.46 The usual analytical and ultrasound tests of the pregnancy programme will be requested, incorporating disease monitoring parameters, such as FC, and taking into account that patients with IBD have a higher risk of suffering from iron or vitamin B12 deficiency. During pregnancy, the flu, pneumococcus and hepatitis B vaccines are recommended if there are risk factors, and the diphtheria, tetanus and whooping cough vaccines are recommended between weeks 28 and 36 (ideally at week 32). SARS-CoV-2 vaccination is also recommended during pregnancy or breastfeeding.51

Patients may have a vaginal delivery unless they have active perineal disease, in which case a caesarean section is usually recommended to reduce the risk of injury.47 Breastfeeding should be advised, and the same drugs that are permitted during pregnancy may be administered. If the mother has received biologic therapy during pregnancy, live virus vaccines should be avoided during the first 12 months.51

These are the most common EIM. They belong to the group of spondyloarthritis (SpA); they are divided into axial and peripheral forms, and may appear before or after the diagnosis of IBD.56 It is essential to establish referral criteria, predominantly clinical, between PC, Gastroenterology and Rheumatology (Table 9).57

Erythema nodosum is the most common cutaneous EIM. It is characterised by the presence of red or purple subcutaneous nodules, 1–5 cm in size, on the extensor surfaces of limbs; the pretibial region is the most common, and they may be painful. The clinical course is usually associated with flare-ups, and the treatment is that for IBD, in addition to rest and analgesia.59

Pyoderma gangrenosum is characterised by the appearance of a pustule or nodule on the skin that quickly transforms into a purple-edged ulcer, which can spread due to a pathergy phenomenon (Fig. 2). It usually appears on the lower limbs or at the edges of the stoma. It may have a course independent of that of IBD, and early referral to dermatology is recommended. Treatment is with topical tacrolimus, corticosteroids or biologic drugs.60

Figure 2.

Pyoderma gangrenosum.

Hidradenitis suppurativa is a disease that affects the folliculopilosebaceous units in different locations, with a variable course, from mild forms with papules, pustules and inflammatory nodules, to severe cases with deep abscesses, cutaneous fistulas and scar formation.61 Patients with IBD (more common in CD) tend to be younger, smokers, and with other associated comorbidities.62 The diagnosis is clinical, and the course is recurrent. In mild stages, topical 15% resorcinol (two applications per day), intralesional corticosteroids (triamcinolone acetonide or betamethasone) and topical clindamycin may be useful. In moderate/severe cases, clindamycin and rifampicin (300 mg of each drug every 12 h for 10 weeks), adalimumab or oral acitretin are indicated. Routine surgical drainage is not recommended. Pain management can include local dry cold, lidocaine 5%, diclofenac gel 1% and abscess drainage.

There are other less common disorders, such as Sweet syndrome and cutaneous metastatic CD.58

Lastly, there are the skin manifestations associated with or induced by the treatments used in IBD. These include non-melanoma skin tumours associated with thiopurine drugs (in these patients it is recommended to limit exposure to the sun and to use sun protection routinely) and anti-TNF-induced eczema and paradoxical psoriasis.59

The most common eye EIM are dry eye, blepharitis, episcleritis and anterior uveitis (Fig. 3). Scleritis and intermediate/posterior uveitis are less common, but potentially more serious, and constitute an ophthalmological emergency. Uveitis in CD is usually bilateral, associated with SpA, more common in females, and may present with red eye, eye pain, blurred vision, photophobia and headache. Treatment for uveitis will depend on the type and activity of the IBD. Corticosteroid drops is the initial treatment for anterior uveitis, while intravitreal or systemic corticosteroids should be used for intermediate, posterior or panuveitis. Anti-TNF agents are indicated when eye inflammation persists or there is IBD activity. Complications associated with the use of corticosteroids include cataracts, ocular hypertension and glaucoma.63

Figure 3.

Episcleritis and uveitis.

In patients with IBD, it is common to detect elevated liver enzymes and in 5%–16%, this can be persistent. In these cases, patients should be assessed for viral, autoimmune, metabolic or drug-related causes. Metabolic dysfunction-associated steatotic liver disease is considered the most common and with the highest risk of cardiovascular diseases (CVD), and screening and prevention from primary care is important, regardless of the presence or absence of other classic CVD factors.64

PSC is the most common IBD-specific liver disease (2%), particularly with extensive colonic involvement, and almost 75% of patients with PSC have an associated IBD.65 It is characterised by inflammation, fibrosis and destruction of the bile duct, producing cholestasis, stricture of the bile ducts and liver fibrosis, which can progress to cirrhosis. It is usually asymptomatic in early stages. In advanced stages, it may present with itching, asthenia, jaundice and pain in the right hypochondrium, which may be intermittent and confused with flare-ups of activity. A common finding is a chronic, 3- to 5-fold increase in alkaline phosphatase levels. Diagnosis is made by MR cholangiopancreatography ± liver biopsy. PSC progresses independently of IBD, giving it a worse prognosis. Treatment includes bezafibrate as first line, and cholestyramine resin for biliary pruritus and ursodeoxycholic acid (15−20 mg/kg/day) to improve the liver profile, but these drugs do not modify disease outcome.66 PSC increases the risk of colorectal cancer fourfold in patients with IBD, and an annual screening colonoscopy is recommended. It also increases the risk of gallbladder cancer, and an annual abdominal ultrasound is therefore recommended.55

Drug-induced liver damage can affect 10% of patients treated with methotrexate and 3–15% of patients treated with azathioprine. Azathioprine hepatotoxicity is usually dose-dependent and resolves by reducing or withdrawing the drug, although it can also cause more serious damage, such as veno-occlusive disease, peliosis hepatis and nodular regenerative hyperplasia.67

Chronic inflammation in IBD is considered an independent cardiovascular risk factor and is associated with early atherosclerosis, thrombotic events and rhythm disturbances, especially atrial fibrillation. It is important to detect and optimise cardiovascular risk factors. An electrocardiogram should be requested in patients with a flare-up of activity and tachycardia, to rule out atrial fibrillation.68

Patients with IBD, particularly during the active phase of the disease, have twice the risk of developing deep vein thrombosis (DVT), owing to which it is essential to institute early prophylaxis during medical hospital admissions or admission for major surgery. If a thrombotic event occurs, anticoagulation with low molecular weight heparin should be started, followed by oral anticoagulation for at least three months (unless there is a prior episode, in which case maintaining it indefinitely should be considered).69 It is important that the patient receive information from PC about the risk factors for DVT, including long distance travel and oestrogen oral contraceptives.

Diabetes mellitus has a higher prevalence in patients with IBD and is considered a risk factor for the development of complications.70 The prevalence of overweight/obesity appears to be similar or slightly higher, with a harmful effect on IBD, as adipose tissue is capable of producing proinflammatory cytokines. A consensus document on the management of obesity in patients with IBD has recently been published.71

Respiratory involvement tends to be uncommon, but includes inflammation of the airways, parenchymal involvement, pulmonary embolisms and respiratory complications caused by medication (sulfasalazine, 5-aminosalicylates, methotrexate, azathioprine or anti-TNF agents).

An increased risk of bronchiectasis, interstitial lung disease and granulomatous lung disease has been found in patients with IBD.55

Anaemia is the most common manifestation, and patients should be checked periodically in view of the impact on quality of life. It can be multifactorial, with iron deficiency and anaemia of chronic disease being the most prevalent causes in IBD, followed by vitamin B12 and folic acid deficiency, and adverse effects of medication. In the presence of inflammation, the criterion for anaemia of chronic disease is ferritin >100€µg/l and a transferrin saturation index <20%. With hypoalbuminaemia, ferritin may be falsely normal. Patients with iron deficiency anaemia should receive iron therapy until haemoglobin and iron deposition reach normal levels. Oral iron is recommended in patients with mild anaemia and no clinical activity, and intravenous iron is recommended in patients with moderate/severe anaemia with clinical activity or previous intolerance to oral iron. Iron levels should be monitored every 3–6 months the first year after supplementation. Leucopenia and thrombocytopenia may occur associated with the use of immunosuppressants.72

The most common is peripheral and sensory neuropathy, which is usually due to vitamin B12 deficiency or prolonged treatment with metronidazole. Demyelinating diseases may worsen, and are a contraindication to the use of anti-TNF agents.55

In exceptional cases, aminosalicylates can cause intestinal nephritis, so kidney function should be monitored regularly. There is an increased risk of kidney stones (7–10%), especially in CD. Renal amyloidosis is a rare but serious complication associated with CD; its most common manifestation is proteinuria.73

Patients with IBD are at a high risk of vitamin and mineral deficiencies (especially vitamin D, vitamin B12, iron, calcium and zinc). The location, extension or surgical resection will specifically affect some of these deficiencies (vitamin B12, the terminal ileum; iron and calcium, the small intestine). Flare-ups need to be controlled, a balanced diet recommended, and deficiencies corrected according to individual abnormalities. Monitoring of blood levels is recommended every 6–12 months, including acute phase reactants, albumin, iron deficiency profile (especially in the case of anaemia), folic acid (especially if the patient takes sulfasalazine or methotrexate), vitamin B12 (if there is resection or involvement of the ileum) and ions (calcium, phosphorus, magnesium and potassium) in the case of chronic diarrhoea.55

In IBD, there is an increased risk of osteopenia, osteoporosis (15%) and fractures (40%) compared to the general population. Factors that influence the reduction in bone mineral density include systemic inflammation, the use of corticosteroids, CD, smoking, malabsorption of vitamin D and calcium, little physical activity and malnutrition. Screening bone densitometry is recommended in patients with risk factors (Table 10), and if normal, the recommendation is to repeat after 2–3 years. Treatment includes hygiene and dietary measures. Calcium and vitamin D should be supplemented in patients on treatment with corticosteroids, with osteopenia or at risk of low bone mineral density. In the case of a high risk of fracture or worsening, bisphosphonates may be useful.74

Approximately one third of patients with IBD have symptoms of anxiety or depression and sleep disturbances, increasing to 60–80% during flare-ups, with a greater possibility of relapse and poorer quality of life. In children and adolescents, the disease has a negative impact on their day-to-day activities and those of their parents.76 From PC, it is important to assess in an open and empathetic way how IBD can affect the psychological sphere, identifying the associated psychological comorbidities, referring to Mental Health where necessary, and introducing the figure of the social worker to resolve legal issues and provide information regarding the social resources available.77

IBD is associated with a high prevalence of sexual dysfunction. The chronic and intermittent nature of the disease, its clinical manifestations such as abdominal pain, faecal incontinence and perianal disease, surgery and stomas and affective disorders can all have an impact on sexual health. A position statement has recently been published on sexuality and IBD.78

Fatigue has a prevalence of 40−60% in inactive disease and 80% in active disease. It negatively affects health-related quality of life, regardless of disease activity. It is important to rule out nutritional deficiencies (iron and vitamins) and to explore comorbidities such as pain, anxiety and sleep disorders. A complete and balanced diet should be recommended, as well as gradual aerobic physical exercise of moderate intensity.79