Ulcerative colitis K51.9

In Germany, about 150,000 people are affected by ulcerative colitis. For most patients, the disease begins during schooling or vocational training and continues throughout life. Ulcerative colitis is a chronic inflammatory disease of the colon mucosa, which manifests itself primarily in the distal rectum. After its onset in the rectum (proctitis), it spreads continuously proximally.

The clinical classification (Silverberg MS et al. 2005) is based on the spread type:

• E1 Proctitis: Limited to the rectum (distal to the rectosigmoidal junction)
• E2 Left-sided colitis: Infestation up to the left flexure
• E3 Extended colitis: extension beyond the left flexure to pancolitis

Several score systems are available for the macroscopic-endoscopic classification of ulcerative colitis, such as the partial Mayo-Score:

• Mayo 0: normal findings or inactive disease
• Mayo I, mild colitis: erythema, slightly brittle mucosa, reduced vascular drawing
• Mayo II, moderate colitis: distinct erythema, erosions, vascular pattern disappeared
• Mayo III, severe colitis: ulcerations, spontaneous bleeding

The incidence of ulcerative colitis in Germany is about 4/100 000 inhabitants/year. The prevalence is assumed to be about 90/100 000 inhabitants/year. Incidence and prevalence do not seem to have changed in recent decades, although an increase is observed worldwide. Within Europe, however, there is a north-south divide, with the highest incidence in Iceland (24.3/100 000) and the lowest in Portugal (1.7/100 000). The risk of disease for siblings of patients with CU is 15 times higher than for the general population (Vermeire S 2006). However, the lifetime risk of developing ulcerative colitis for first-degree relatives is only about 5%. This is important information for patients in family planning. Familial cases of ulcerative colitis seem to affect the female sex more, and the age of onset of the disease seems to be lower.

The exact triggers and mechanisms are only partially known. Apparently, several extrinsic and intrinsic factors interact in the triggering process.

m:w=1:1; in terms of age-specific incidence, the highest rate is in the group of 25-35 year-olds (approx. 4.5/100 000). A second frequency peak is found in the age group > 55 years.

The natural course of ulcerative colitis is characterized by episodes of disease relapses alternating with phases of remission. The main symptoms are bloody-mucus diarrhoea, possibly fever, anaemia; furthermore, sometimes cramp-like pain in the left lower abdomen (usually before defecation). A simple but still valid clinical definition of severe colitis was established by Truelove and Witts as early as 1954:

• > 6 bloody diarrhoea/d and at least one of the following criteria:
• BSG > 30 mm/h
• Tachycardia > 90/min
• Haemoglobin < 10.5 g/dl
• Temperature > 37,8 °C

The remission is characterized by the combination

• max. 3 formed, bloodless bowel movements/d and
• of an endoscopically unremarkable mucosa.

Extraintestinal symptoms (about 30% of patients):

• eyes (7%): iritis, episcleritis, conjunctivitis
• Joints: Arthritis, ankylosing spondylarthritis
• Liver: Primary sclerosing cholangitis, fatty liver
• Ulcerative colitis in children:
• Children with ulcerative colitis usually exhibit typical symptoms such as anaemia (84%), chronic diarrhoea (74%) and abdominal pain, mainly in the form of tenesmus (62%). (Sawczenko A et al. 2003) The most common extraintestinal symptom is arthropathy (10%). Skin manifestations are rather rare in children. In the case of chronic (> 2 weeks) or recurrent diarrhoea, clarification should also be carried out without blood admixtures.

Skin changes and changes in the mucous membranes close to the skin in ulcerative colitis (10%):

• Pyoderma gangraenosum (also atpic localized e.g. nose)
• pyostomatitis vegetans
• Erythema nodosum
• Aphthae
• Vasculitis
• Dermatosis, acute febrile neutrophils (Sweet syndrome)
• Purpura
• furunculoid, nodular or multiform skin changes
• cheilitis granulomatosa
• Alopecia areata (also universal forms as Alopecia areata totalis)
• Kindler Syndrome

Endoscopically, ulcerative colitis presents as a continuous inflammation of varying severity spreading from the rectum to the oral cavity. The spectrum ranges from low activity with brittle, granular mucosa with reduced vascular drawing and possibly mild erythema to severe activity in the form of (confluent) ulcers and spontaneous, predominantly petechial haemorrhages. The transition from inconspicuous to inflamed mucosa is typically a sharp line. After anal, the inflammation typically increases in severity. In the case of prolonged severe activity, pseudopolyps may occur.

The endoscopic activity correlates well with the severity of the inflammation. To assess activity, endoscopic visualization of the right transverse colon is usually sufficient. Especially in severe colitis, further prophylaxis should be avoided because of the risk of perforation and worsening of the flare. Long-term disease activity may result in structural damage of varying degrees.

The spectrum ranges from individual scarred areas of mucous membrane to the complete loss of homologation with a rigid colon resembling a bicycle inner tube

Note: In everyday clinical practice, the question regularly arises at what points in the course of the patient's life the endoscopy should be performed.

• Before initiating or changing therapy, the inflammatory activity should be objectified and the response to therapy should be monitored endoscopically.
• Patients with pure ulcerative proctitis do not appear to have an increased risk of developing colorectal carcinomas. All other patients should be endoscopically examined regularly from the 8th year after the first manifestation of the disease.
• If there is no inflammatory activity, monitoring colonoscopies should be performed at intervals of 3 years. In case of relevant inflammation, annual colonoscopies are recommended. If PSC is present at the same time, annual colonoscopies are necessary from the time of diagnosis of PSC - or in case of sufficient suspicion.

Transabdominal ultrasound: method with the advantage of non-invasivity. Inflammations in the area of the colon can be detected with a sensitivity of up to 90%. In the hands of a trained examiner, both the activity of the disease and the extent of the disease can be reliably determined. In severe ulcerative colitis there is moderate wall thickening (usually 4-6 mm) with preserved wall stratification and hyperperfusion limited to the mucosa. An echoric environmental reaction should rather remind of Crohn's disease, but is possible in severe colitis and especially in toxic megacolon and must then be understood as an alarm signal.

CT and MRI: Supplementary sectional imaging procedures such as computed tomography and magnetic resonance imaging are generally used for differential diagnosis of Crohn's disease. If ulcerative colitis has been chronically active for many years, scarring caused structural damage to the colonic wall can be seen as a loss of home-trition (so-called "bicycle inner tube phenomenon"). This can be detected sonographically as well as by computer and MR-tomography.

X-ray with double contrast enema: loss of homophoria ("bicycle inner tube" phenomenon) "collar button fulcera".

Serological laboratory values may be normal, especially in mild to moderate ulcerative colitis and/or distal colitis. In proctitis, the C-reactive protein correlates with the extent of the disease and clinical activity. In patients with severe disease activity, SPA elevations and anemia are found.

Faecal stool markers, especially calprotectin, lactoferrin, lysozyme, PMN-elastase, can be used as markers of clinical inflammatory activity in ulcerative colitis. Calprotectin has the highest sensitivity (Herrlinger et al. 2004)

Stool cultures are necessary for the differentiation and diagnosis of self-limiting infectious colitis stool cultures.

Histopathology: The initial diagnosis should be made on at least 2 step biopsies from the ileum and from all colon sections including the rectum. Histopathology: Diffuse panmucosal chronic inflammation (lymphocytes and plasma cells) in combination with a disturbance of the crypt architecture/crypt atrophy, plasmocytosis in the basal mucosal stroma Paneth-cell metaplasia distal to the right colonic flexure, reduction of the number of goblet cells or the mucin content of the single cells, continuous distribution of the inflammatory and structural mucosal changes, decreasing gradient from distal to proximal.

The histopathological evaluation of inflammatory activities in ulcerative colitis is based on the extent of tissue infiltration by segment-nucleated neutrophil granulocytes as well as damage to the intestinal epithelium, the extent of cryptitic lesions and cryptitic abscesses and the extent of erosive and ulcerative lesions. The utility of histopathology for predicting recurrence and assessing adequate control of inflammation has implications for therapeutic management and reduction of neoplasia risk (Winther KV et al 2004; Lutgens MW et al 2008).

The diagnosis of ulcerative colitis is based on the detection of a characteristic combination of clinical, laboratory, endoscopic, radiological and pathomorphological findings. There is no gold standard for diagnosis. Pathohistological diagnosis is also based on the synoptic assessment of a combination of characteristics, mainly concerning the type and distribution of inflammatory infiltrates and changes in the mucosal architecture. The individual histological findings are not specific in themselves and may also occur in other forms of inflammatory bowel disease (Kucharzik T et al. 2019).

Normal findings in the histopathology of mucosal biopsies exclude active ulcerative colitis! The initial diagnosis should be made on at least 2 step biopsies from the ileum and from all colon sections including the rectum.

Note: If an exact assignment to the entities ulcerative colitis or Crohn's disease is not possible, the clinical picture is listed under the diagnosis "indeterminate colitis" (Inflammatory Bowel Disease unclassified (Silverberg).

• Infectious colitis caused by Campylobacter spp, Escherichia coli (enteroinvasive strains), Clostridium difficile toxin A and B
• Enteritis regionalis (Crohn's disease - K50.9)
• Self-limiting infectious colitis (microbiological pathogen diagnostics at initial diagnosis and on onset of the disease): Entamöba histolyticum; Balantidium coli, Giardia, schistosomiasis (bilharziosis) Antibiotic-associated pseudomembranous colitis (A047.4)
• Non-infectious colitis (ischaemic colitis, radiation colitis, microscopic colitis)
• Food allergies
• Gluten Sensitive Enteropathy
• Irritable bowel syndrome (K58.9)
• NSAR-associated colitis (medical history important, possibly course; usually discontinuous pattern of colitis; colonoscopy and sonography or sectional imaging for further clarification)
• Ischemic colitis (older patients, course; usually discontinuous pattern of colitis; colonoscopy and sonography or sectional imaging for further clarification)

Growth disorders in childhood

Weight loss

Recurrent, partly massive bleeding

Toxic colon dilatation (toxic megacolon) with high lethality (30%)

Colorectal carcinoma: Occurs mostly after the 10th year of illness. A significant proportion of colorectal carcinomas can also occur before the 8th year of illness (Winther KV et al. 2004). In one study it could be shown that 22 % of patients with ulcerative colitis had already developed the disease before the start of regular monitoring colonoscopies (Lutgens MW et al. 2008). The cumulative colorectal carcinoma risk within a 10-year period is 1 %, within a 20-year period 3 %, within a 30-year period 7 % (Annese V et al. 2013).

The development of carcinoma in chronic ulcerative colitis often occurs without a preliminary polyp stage at the base of an intraepithelial neoplasia (IEN)

Rare late complication: Amyloidosis

A causal, drug therapy for ulcerative colitis is not yet available. Proctocolectomy is a curative therapy option, but it is associated with considerable defect formation and often functional limitations. All drug therapies are aimed at modifying the immunological response. The therapeutic decision depends on the activity of the disease, the localisation, the course, the previous therapeutic modalities and possible complications or extraintestinal manifestations.

Ulcerative proctitis: The standard therapy for proctitis consists of topical therapy with 5-ASA suppositories (1 g/d). Mesalazine foams or enemas are considered equivalent (recommended daily dose ≥ 2 g/d; therapy is best administered at night). However, compared to suppositories, they are often less well tolerated by patients. In case of lack of improvement, topical 5-ASA therapy should be combined with oral 5-ASA therapy (dose ≥ 3 g/d) or a topical corticosteroid (e.g. budesonide 2 mg/d, hydrocortisone acetate 100 mg/d, or beclometasone 3 mg/d). Oral 5-ASA monotherapy should not be used primarily because it is inferior to topical therapy. If patients do not tolerate topical therapy, oral 5-ASA therapy can be tried with ≥ 3 g/d.

• Therapy-refractory course of ulcerative proctitis: Extension of therapy according to recommendations for left-sided colitis (Cave: overtreatment). A proctocolectomy will be necessary only rarely and in exceptional cases. The functional outcome is usually a deterioration of the quality of life, especially since proctitis alone does not appear to increase the risk of colon cancer.

Left-sided colitis: If the course is uncomplicated, initial therapy with topical mesalazine foams or enemas in a dose of 2-4 g/d - (therapy is best performed at night). Combined 5-ASA therapy is increasingly used as standard therapy for left-sided colitis: oral administration (recommended minimum dose > 3 g/d) and enemas (recommended dose at least 1 g/d). Response to therapy with discontinuation of hematochezia should be within 14 days. If this effect does not occur, systemic steroid therapy should be initiated. Different regimens are used, the minimum starting dose should be 40 mg prednisolone equivalent (typically 1 mg/kg body weight) at ≥. The duration of therapy should not be less than 4 weeks with a sneak-out regimen due to an increased relapse rate. Note: Daily doses ≤ 15 mg prednisolone equivalent are considered ineffective in active ulcerative colitis. Note: It is very important to evaluate the clinical response on days 7-10, as a steroid-refractory course is present if taken correctly and there is no response, which requires a rapid change in therapy.

• Alternative: as an alternative to systemic steroid therapy in the event of failure of 5-ASA therapy, the administration of budesonide 9 mg as a multi-matrix system (budesonide MMX) may be considered. The special galenics result in a continuous release of budesonide throughout the colon. At a daily dose of 9 mg budesonide MMX, approx. 30 % of patients achieve clinical remission after 8 weeks of therapy, comparable to patients receiving 5-ASA.

Extensive colitis: Extensive colitis with mild to moderate disease activity should be treated by combined 5-ASA administration in the same way as left-sided colitis. The same recommendations regarding dose and frequency of application apply.

• Alternatively, if this therapy fails or if rapid therapeutic success is required, the indication for therapy with systemic steroids is analogous to left-sided colitis.

Severe ulcerative colitis Patients with severe colitis as defined by Truleove and Witts are usually at acute risk and usually require hospital admission and immediate therapy: The general consensus is an intravenous steroid therapy with 1 mg/kg bw prednisolone as an i.v. bolus 1 ×/d. Higher steroid doses are not more effective, lower doses are less effective. The success of the therapy should be assessed on day 3 and the duration of therapy should be limited to 7-10 d. It has been shown that longer therapy does not promise any advantage in the event of a lack of response (25-34% of patients).

• Alternative in case of resistance to therapy: alternative immunosuppressive therapy or emergency surgery. Remark: additionally a multimodal therapy concept is necessary. Early consultation with the surgeon! If there is no response on day 3 of an intravenous steroid therapy, therapy alternatives in the form of colectomy or a medicinal second line therapy (Ciclosporin, Tacrolimus, TNF-α-antibodies) should be discussed with the patient at an early stage.
• Alternatively, in steroid-refractory, non-severe relapsing ulcerative colitis: Outpatients with moderately active (criteria not met according to Trulove & Witts) but steroid-refractory ulcerative colitis should be treated with an anti-TNF-α inhibitor , vedolizumab or tofacitinib for remission induction. A combination therapy of infliximab and azathioprine seems to be superior to a monotherapy with these drugs in the induction of remission.
• Alternatively, in steroid-refractory, severe relapses of ulcerative colitis: Severe, extensive ulcerative colitis is a potentially life-threatening situation (hospital admission necessary). If there is no response to the intravenous steroid therapy even on days 7-10, the further procedure must be coordinated in interdisciplinary exchange with the visceral surgery colleagues (proctocolectomy vs. drug therapy). As second line therapy the national and European guidelines recommend: Ciclosporin A, Tacrolimus or Infliximab.

Ulcerative colitis with steroid-dependent course: Corticosteroids must not be used to maintain remission due to considerable long-term side effects. Thiopurines, TNF-α antibodies, vedolizumab and tofacitinib are effective alternatives. TNF-α antibodies or vedolizumab are used for relapse activity under azathioprine therapy (2-2.5 mg/kg daily dose over at least 12 weeks); alternatively:tofacitinib.

Maintenance of remission in ulcerative colitis: most patients experience a recurrence within 12 months. In this respect, remission-maintaining therapy is recommended for all patients (current ECCO guideline) with the aim of achieving steroid-free remission.

• Remission maintenance of proctitis: 5-ASA suppositories (recommended daily dose 1 g, effective minimum dose 3 g/week) should be used.
• Maintenance of remission in left-sided colitis: 5-ASA enemas (recommended daily dose at least 1 g) should be used either as monotherapy or in combination with oral 5-ASA . If adherence is poor, oral maintenance therapy with 5-ASA at a dosage of > 1.5 g/d is also possible.
• Maintain remission in extensive colitis even after systemic corticosteroid therapy: The first choice is oral 5-ASA at a minimum dose of 1.5 g/d . If a relapse occurs under this therapy regime, the dose is increased and a combination therapy (topical and oral) is administered. The duration of the 5-ASA therapy, independent of the application method, should be at least 2 years.
  • Alternatively, remission maintenance by continuous therapy with mesalazine.
• Maintenance of remission in extensive colitis with thiopurines: If remission with tacrolimus or ciclosporin is achieved in severe steroid-refractory colitis, thiopurines can also be used to maintain remission. The therapy should be carried out for at least 2 years.
• Maintenance of remission with anti-TNF-α inhibitors: In all approval studies of Infliximab, Adalimumab, Golimumab, Vedolizumab and Tofacitinib, response and remission to induction therapy as well as maintenance of remission after 1 year were examined. All biologicals and tofacitinib proved to be statistically significantly superior to placebo in terms of remission maintenance. In simplified terms, any biological therapy that led to a response or remission should be continued to maintain remission. Duration of therapy: Current recommendations are for anti-TNF-α inhibitors at least two years. Tofacitinib has only been approved since the end of 2018. The clinical experience is still limited.

Surgical therapy: The standard surgical procedure for refractory or complicative ulcerative colitis is laparoscopic proctocolectomy with ileoanal pouch. The operation should be performed as a two- or three-stage operation. Approximately 15-35 % of patients with ulcerative colitis will have to undergo proctocolectomy during their lifetime. However, especially young patients will be advised to undergo surgery because of the longer life expectancy and the associated higher probability of later severe dysplasia.

There are three main indications for proctocolectomy:

• Therapy-refractory colitis
• Detection of (high-grade) dysplasia or colon carcinoma associated with colitis
• Emergency indication (toxic colon, refractory colonic bleeding, colitis-related free colon perforation).

Stenoses in confirmed ulcerative colitis are often caused by a stenosing carcinoma, so that proctocolectomy should also be performed. If the proctocolectomy is performed due to dysplasia or malignoma, an annual endoscopic check of the pouch is recommended.

Surgery as an emergency indication: Emergency proctocolectomies are still associated with high morbidity (27-51%) and mortality (5-8%). Therapy-refractory bleeding is an emergency indication for surgery: vital threatening colon bleeding with the necessity of transfusion of > 4 red blood cell concentrates in 24 h. The most severe form of acute, severe colitis is toxic megacolon. It can take a life-threatening course. This situation is defined by a septic clinical picture with dilatation of the transverse colon to > 5.5 cm. In the context of severe inflammatory activity, free colon perforation may occur. This is treated by emergency colectomy, leaving the rectum intact.

The average life expectancy of all patients with ulcerative colitis corresponds to the life expectancy of the normal population. However, due to disease-related complaints, there may be:

• Absenteeism at work or school
• Restrictions on social activities
• Reduction of the quality of life.

• Psyllium: Plantago ovata can be used in a complementary way in remission-preserving treatment. 102 patients with ulcerative colitis in remission were assigned to three groups and received either flea seed, flea seed in combination with mesalazine or mesalazine alone. After 12 months, there was no difference between the treatment with mesalazine and that with flea seed. Only the butyrate concentration in the stool of patients who had received flea seed was better. There were no serious adverse effects (Fernandez-Banares F et al. 1999) There are drugs approved in Germany for Plantago ovata.
• Curcumin: Studies of curcumin complementary to an aminosalicylate therapy have shown positive results in remission induction and maintenance of remission. Curcumin is not available as a drug in Germany. A systematic review of complementary and alternative procedures for the treatment of chronic inflammatory bowel disease identified two RCTs that evaluated the effects of curcumin in the treatment of ulcerative colitis. In a prospective randomized, double-blind, placebo-controlled multicenter study, 2 × 1 g/d curcumin complementary to sulfasalazine or mesalazine was investigated in the remission-maintaining therapy of ulcerative colitis over a period of 6 months (22 patients in the verum group) (Hanai H et al. 2006). There was a significant group difference in terms of recurrence frequency, CAI and an endoscopic index in favour of the verum group at the end of therapy. Curcumin is superior in the therapy of ulcerative colitis. There were no differences in terms of side effects. Curcumin is only offered in Germany as a food supplement and is not available as a drug.
• Myrrh, camomile blossom extract and coffee charcoal (Caffee carbo): A combination of myrrh, camomile blossom extract and coffee charcoal can be used in a complementary way in remission-maintaining treatment. A systematic review of complementary and alternative methods for the treatment of chronic inflammatory bowel disease identified a high-quality clinical study on the efficacy and safety of myrrh, camomile blossom extract and coffee charcoal in remission-maintaining treatment of ulcerative colitis in 96 patients. The study found evidence that therapy with myrrh, camomile blossom extract and coffee charcoal is not inferior to standard therapy with mesalazine in remission-maintaining therapy and is very well tolerated. A follow-up questionnaire study as well as a large cohort study on this issue confirmed these indications (Langhorst J et al. 2016). In Germany there is an approved traditional drug for myrrh, camomile flower extract and coffee charcoal (Myrrhinil intest®).
• Pomegranate extract: In 78 patients with ulcerative colitis and moderate disease activity, the effect of pomegranate extract in combination with standard therapy was evaluated compared to placebo with standard therapy. Conclusions are that pomegranate extract can be used because it had positive effects on disease activity and individual symptoms, but not beyond a placebo effect. Adverse effects were mild and moderate and did not differ between groups (Kamali M et al. 2015)
• Frankincense preparation: A systematic review identified two non-randomized studies evaluating the effect of Boswellia serrata (frankincense preparation) compared to sulfasalazine. Both groups showed positive effects in terms of histology and stool parameters without significant group differences. Side effects included heartburn, nausea, loss of appetite and pain in the upper abdomen. Boswellia serrata is only offered in Germany as a dietary supplement and is not available as a drug (Gupta I et al. 2001).
• Wheatgrass juice: An RCT that tested the effect of wheatgrass juice compared to placebo juice in 24 patients with ulcerative colitis showed that the patients in the experimental group had significantly lower disease activity, less rectal bleeding and less abdominal pain after four weeks. No serious side effects occurred (Ben-Arye E et al. 2002).
• Evening primrose seed oil: A systematic review of complementary and alternative procedures for the treatment of chronic inflammatory bowel disease identified an RCT that evaluated the effect of evening primrose oil in 43 patients with ulcerative colitis compared to olive and omega-3 oil. Evening primrose oil was found to be superior only in terms of stool consistency. No undesirable side effects were recorded (Greenfield SM et al. 1993).
• Japanese whisker: Another RCT on the efficacy of sophora (extract of the Japanese whisker as a capsule) compared to mesalazine in 126 patients with ulcerative colitis showed indications that therapy with sophora might not be inferior to standard therapy with mesalazine. No relevant side effects occurred (Tong ZQ et al. 2010).
• Blueberry extracts: An open pilot study shows that the intake of a blueberry preparation consisting of dried fruits and juice concentrate could have a positive effect on disease activity (Biedermann L et al. 2013). However, high-quality RCTs are needed to confirm this.
• Further unconventional methods cannot be recommended due to the insufficient data available.

Transdermally applied nicotine: In randomized placebo-controlled clinical trials in patients with active ulcerative colitis, transdermal nicotine was shown to produce additional beneficial effects in the treatment of active ulcerative colitis in combination with standard therapy (Sandborn WJ et al. 1997). However, the administration of transdermal nicotine leads to frequent and sometimes severe side effects, especially in lifelong nonsmokers.

see also under microbiological therapy

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