Inflammatory bowel disease and lupus: A systematic review of the literature

Abstract

Coexistence of systemic lupus erythematosus (SLE) should be considered in patients with inflammatory bowel disease (IBD) and complex extraintestinal manifestations and the diagnosis of IBD could be established either before or after the diagnosis of SLE. Differential diagnosis of concomitant SLE and IBD is difficult and should always exclude infectious conditions, lupus-like reactions, visceral vasculitis and drug-induced lupus.

The underlying mechanism by which 5-ASA/sulphasalazine induces SLE or lupus-like syndromes is not clear and high awareness for possible predictive factors is demanded for early prevention.

In most cases the symptoms from drug-induced lupus have been reversible after the discontinuation of the drug and response to steroids is favorable. Treatment of patients co-diagnosed with SLE and IBD may include corticosteroids, immunosupressants and hydroxychloroquine.

In severe lupus and IBD patients cyclophosphamide pulse may be of benefit while infliximab may be beneficiary in patients with lupus nephritis. However, the role TNFalpha plays in humans with SLE and IBD is controversial and data on the likely effects of blocking TNFalpha on anti-DNA autoantibody production is always of interest.

CD, Crohn's disease, UC, ulcerative colitis, IBD, inflammatory bowel disease, SLE, systemic lupus erythematosus

Lupus, Systemic lupus erythematosus, Crohn's disease, Inflammatory bowel disease, Ulcerative colitis, Vasculitis

1 Introduction

Inflammatory bowel disease (IBD) is a chronic recurrent disease characterized by intestinal mucosal inflammation and includes ulcerative colitis (UC) and Crohn's disease (CD). Almost one fourth of IBD patients suffer from extra-intestinal manifestations, including oligoarticular or polyarthicular non-deforming peripheral arthritis, spondylitis or sacroilitis, episcleritis or uveitis, erythema nodosum, pyoderma gangrenosum, sclerosing cholangitis and thromboembolic events. On the other hand, systemic lupus erythematosus (SLE) is an autoimmune disorder occurring predominantly in women during reproductive years. It is a multisystem disease with numerous clinical manifestations such as skin rashes, photosensitivity, oral ulcers, arthritis, serositis, renal, neurologic and hematologic disorders. The characteristic immunologic findings include the presence of antinuclear antibodies (ANAs), anti-DNA, anti-Sm and anti-phospholipid antibodies.

The coexistence of the IBD and SLE is rare. The coexistence of clinical features of both diseases in a patient represents a diagnostic challenge. In fact, it is not known whether IBD and SLE co-occur by chance or by real association and no data on incidence/prevalence of IBD and SLE co-occurrence is available.

After reviewing systematically the literature using all terms relevant to IBD and lupus, we present the gastrointestinal features of SLE, the lupus-like syndrome caused by drugs used in IBD as well as the coexistence of SLE with IBD and the treatment that can be used in both entities.¹

2 Systemic lupus erythematosus and gastrointestinal involvement

Gastrointestinal symptoms are common in systemic lupus erythematosus (SLE) patients, and more than half of them are caused by adverse reactions to medications and viral or bacterial infections. Gastrointestinal manifestations may overshadow other aspects of the disease and mimic any type of abdominal condition. Lupus mesenteric vasculitis is the most common cause, followed by protein-losing enteropathy, acute pancreatitis, serositis (peritonitis) intestinal pseudo-obstruction and other rare comorbidities such as celiac disease and inflammatory bowel disease (IBD).² In an extensive review of the gastrointestinal and hepatic manifestations of systemic lupus erythematosus only about 10% of patients with autoimmune hepatitis had lupus and up to 4.7% of patients with SLE had chronic active hepatitis.³

Some of the more potentially dangerous gastrointestinal complications of SLE occur in the small and large intestines secondary to small-vessel vasculitis. This may progress to ischemic enteritis and to bowel infarction with bleeding or perforation and peritonitis. Clinical presentation is variable and the definite diagnosis of vasculitis may be difficult to establish because of its insidious and intermittent behavior that is common prior to the acute event. Abdominal pain, nausea and vomiting are frequent manifestations of gastrointestinal vasculitis.⁴ The exact incidence of lupus vasculitis in the gastrointestinal tract is hard to determine. The prevalence of intestinal vasculitis has been reported to range from 0.2 to 53% of patients with SLE but clinically apparent bowel vasculitis occurs in about 2% of SLE patients. Vasculitis in SLE may involve any part of the gastrointestinal tract from esophagus to colon though there is a tendency for the vasculitis to affect the distribution of superior mesenteric artery. It is quite rare and almost always accompanied by evidence of active disease in other organs, although occasionally it may be the presenting feature of the disease. Lupus enteritis unlike CD and UC, may be complicated by perforation even when the disease appears to be well controlled.⁵ Thrombosis of mesenteric vessels associated with the antiphospholipid syndrome can give rise to mesenteric ischemia and bowel infarction. No specific autoantibody is identified as being associated with this SLE-related gastroenteropathy.⁵ The peritoneum is the least likely of the serosal linings to be affected in SLE. Symptoms include rebound tenderness, fever, nausea, vomiting and diarrhea leading frequently in surgical intervention.

Imaging studies are helpful in diagnosing SLE-related gastroenteropathies. Early nondiagnostic radiographic findings include thumbprinting, pseudoobstruction and segmental bowel dilatation. Abdominal CT and arteriography may be more helpful with diagnosis but a negative arteriogram does not exclude disease because vasculitis generally involves small arteries.⁶

Abdominal CT scan may show thickened small bowel loops with contrast enhancement consistent with small bowel ischemia. However, small bowel thickening is not a specific finding for intestinal vasculitis and may be also associated with hypoalbuminemia, IBD and gastroenteritis.⁷

Colon involvement in systemic lupus erythematosus at barium enema is depicted as the “collar button” type of penetrating ulcers and at endoscopy the multiple round- or oval-shaped discrete ulcers, the so-called “punched-out” ulcers with pale mucosa can be found. Differential diagnosis with ulcerative colitis ulcers in patients with SLE-related colon involvement is sometimes very difficult. To be more confident in a definite diagnosis a panel of imaging, endoscopic and histological information may be needed. In lupus cases colon involvement at endoscopy and/or radiology is remarkably segmental with focal non-perimetrical distributed ulcerations and biopsies keep in general the architectural structure of the mucosa with a remarkable absence of cell typical in chronic inflammatory conditions.⁸

Therapy of lupus vasculitis may include high-dose corticosteroids (prednisone 1–2 mg/kg/day) or pulse therapy with methylprednisolone 1 g/day for 3 days and azathioprine/6-mercaptopurine. Intestinal rest with parenteral nutrition, prokinetics and antibiotics may be of help.³ Cyclophosphamide pulse therapy 0.75–1 g/m² may be used in refractory cases.⁹

3 Concomitant diagnosis of IBD and SLE

Concomitant diagnosis of IBD and SLE is rare and IBD may occur either before or after SLE diagnosis (Table 1). Although a chance occurrence cannot be excluded it is possible that both conditions share some genetic or immunological defects. However, data on common genetic susceptibility between SLE and CD is controversial.¹⁰,¹¹ In addition, certain medications used for treating IBD may cause drug-induced lupus.

According to a referral center study the overall prevalence of concomitant ulcerative colitis (UC) diagnosis is 0.4% of SLE patients. The concurrence of SLE and Crohn's disease (CD) is even more rare.⁴

Only few cases of SLE-related to UC have been reported so far, and numbers of SLE related CD are even less including some cases with presumable co-existence of the two diseases.

The majority of those patients have excellent response to steroids combined with hydroxychloroquine or/and azathioprine. However, some patients with CD may have life-threatening gastrointestinal bleeding and some may need high dosage methylprednisolone for maintenance therapy. The prognosis of SLE-related IBD is usually good.

4 Crohn's disease and lupus

The concurrence of SLE and CD is rare. There are very few case reports of the co-existence of these two diseases while data regarding common genetic susceptibility between SLE and CD is controversial.⁴ A study did not find evidence that the Crohn's disease-associated mutations on CARD15 contributed to SLE susceptibility.¹⁰ A pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15 (908R) IBD risk allele may have a strong effect on risk of SLE.¹¹

In total nine cases¹²–²⁰ of CD and SLE and one with CD and subacute cutaneous lupus erythematosus²¹ have so far been described, all in young individuals. One of these cases was complicated with massive lower gastrointestinal bleeding,¹³ in another one rheumatoid arthritis with SLE, Sjögren's syndrome and CD were co-existing¹² and finally one case was of familial CD with three family members affected.²⁰

In the majority of these cases CD was the preceding diagnosis. However, in some cases CD diagnosis also followed¹⁶,¹⁸ SLE diagnosis. Two of the eight cases were complicated by lupus nephritis¹⁸,¹⁹ and one of them showed favorable renal response to infliximab.¹⁹

There have been two additional reports²²,²³ of patients with presumed coexistence of SLE and CD, although pathologic information was not available. The first was a report of a 20-year-old man who presented with acute abdominal pain, anemia, leukopenia, and an abnormal urinary sediment.²² A localized area of non-specific ileitis was found at laparotomy. Patient also demonstrated a false-positive test for syphilis, circulating anticoagulant, abnormal serum proteins, and cryoglobulins. No definite diagnosis of either Crohn's disease or SLE could be made. The second report describes a 35-year-old man with an established diagnosis of SLE with pleuritis, arthralgia, hematuria and proteinuria, and positive lupus cells who developed abdominal pain and was found to have two areas of edema and red-purple discoloration in the distal ileum associated with narrowing of the lumen.²³

The differentiation of CD from SLE gastrointestinal involvement may be difficult. In fact, cases with inflammatory bowel diseases like CD could show similar clinical signs and symptoms to SLE, and in some cases of CD might fulfill some of the classification of criteria for SLE.²⁴,²⁵

Gastrointestinal symptoms, laboratory studies, and radiographic findings may appear similar between the two diseases. The correct diagnosis has important treatment and prognostic implications.

Furthermore, diagnosis of such rare cases needs always to exclude relative co morbidities or overlapping features of similar pathogenic entities and always requires a plan for optimal management of both systemic diseases.

Two cases in SLE patients that mimic IBD have been also reported. One case of a patient with strongyloidiasis²⁶ and one of CMV infection mimicking CD of the terminal ileum.²⁷ In this case, ganciclovir therapy was effective in resolving his symptoms and normalizing his ileal mucosa.

The presence of phospholipid-binding antibodies could be a sign of vascular alterations that are potentially thrombogenic per se, and their predictive value with respect to the specific inflammatory syndrome of Crohn's disease is an important phenomenon.²⁷ Two cases with antiphospholipid syndrome manifested by ischemic stroke²⁸ and thrombosis²⁹ in Crohn's disease have been reported. There may be a possible association between antiphospholipid syndrome and hypercoagulable state in Crohn's disease.

5 Ulcerative colitis and lupus

The association between UC and SLE is rare. Since Brown et al.³⁰ reported the first UC and SLE case in 1956, Dubois and Tuffaneli reported that the incidence of UC in 520 cases of SLE was 0.4% (only two cases)³¹ and in October 1975 Tsuchiya et al.⁸ reported that they had found so far 35 cases of SLE with UC reported in the literature including their own case. Our thorough search in the literature resulted in eleven additional cases from 1988 until today.³²–⁴⁰ Another patient from this list developed hypocomplementemic urticarial vasculitis syndrome, a year prior to the onset of ulcerative colitis. Ten years later, primary sclerosing cholangitis and the antiphospholipid syndrome developed concomitantly.⁴⁰

In these series, one case of patient with small bowel perforation due to concomitant non-Hodgkin-lymphoma occurred.³⁴ The same list includes three cases of lupus nephritis.³⁵,³⁶ Among those three cases, one was with diffuse proliferative lupus nephritis³⁶ and two with chronic glomerulonephritis and mild renal failure respectively.³⁵ In the first case nephrotic syndrome partially improved with corticosteroid therapy combined with cessation of sulfasalazine. An additional case of severe UC, dural sinus thrombosis and lupus anticoagulant could be probably added in this list.⁴¹ The patient was successfully treated with osmotic agents, prophylactic anticonvulsant, and antiplatelet therapy, combined with i.v. steroids.

In some of the SLE cases endoscopic features were different from those of ulcerative colitis. Multiple “punched out” ulcers with pale mucosa were not seen in UC but in ischemic colitis and in the colonic involvement of vasculitis and SLE. In other cases endoscopic findings were compatible with those of ulcerative colitis.

6 5-ASA compound-induced lupus in IBD

Sulphasalazine-induced lupus syndrome has been reported several times in UC⁴²–⁴⁵ including children⁴⁶ as well as in CD patients.⁴⁷

Although 5-ASA preparations used to treat inflammatory bowel disease are reported to have fewer side effects than sulphasalazine, increased clinical use of these compounds including mesalazine has resulted in some reports of significant side effects including those fulfilling the criteria of a drug-induced lupus-like syndrome.⁴⁸–⁵²

The clinical pattern can be presented with SLE or SLE-like syndrome and may manifest with antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (anti-dsDNA), anti-histone antibodies (anti-histones) and a variety of symptoms including serositis, pulmonary parenchymal, joint symptoms and skin rush. Severe clinical manifestations are those of general vasculitis affecting the central and peripheral nervous system and lungs and may have a fatal evolution. Diagnosis may be typical but in some atypical cases the connection with medication can be ascertained by re-exposition.

Features which may discriminate between sulphasalazine-induced lupus and the association of IBD with idiopathic SLE are the presence of low complement levels (as drug-induced lupus is only rarely associated with low complement levels), presence of different types of autoantibodies which occur in idiopathic SLE [antibodies to C1q, anticardiolipin antibodies (which occur in 10–30% of SLE patients), anti-Ro and anti-La antibodies] and HLA status as HLA DR3 is associated with idiopathic disease, whereas DR4 occurs in drug-induced lupus.⁵³

Therapy includes sulphasalazine/5-ASA discontinuation and administration of corticosteroids. In severe cases cyclophosphamide can be used. Leukopenia, anemia, and high titres of antinuclear and DNA antibodies return to normal after withdrawal of the drug; resolution of symptoms, usually occurs over a period of four to six months.

According to a study⁵³ investigating predisposing factors in sulphasalazine-induced systemic lupus erythematosus slow acetylator genotype (enzyme N-acetyltransferase 2) and HLA haplotypes seem to predict disease induction. In addition, persistent SLE and development of nephritis were noted in patients with long duration of treatment and high cumulative dose of sulphasalazine (> 1000 g).

Sulphasalazine-induced lupus syndrome in ulcerative colitis has been reported in seven⁴²,⁴⁴–⁴⁶ patients including one child⁴⁶ among them.

In one of these patients⁴² with salazosulfapyridine-induced lupus syndrome the connection with medication was ascertained by re-exposition.

In another patient⁴⁴ pneumonitis, bilateral pleural effusions, echocardiographic evidence of cardiac tamponade, and positive autoantibodies were developed in the absence of joint symptoms. After cessation of the sulfasalazine and completion of a six-week course of corticosteroids, these problems resolved over a period of four to six months.

Sulphasalazine-induced lupus syndrome in CD has been reported in four²⁰,⁴⁷–⁴⁹ patients. In one of them sulfasalazine/mesalazine-induced lupus syndrome resulted in a fatal evolution despite methylprednisolone and cyclophosphamide use.⁴⁸

7 Anti-TNFα therapies and lupus in IBD

Induction of autoimmunity in the form of antinuclear antibodies and/or anti-dsDNA antibodies has been often seen in IBD patients treated with TNFalpha inhibitors.

On the other hand, the role TNFalpha plays in SLE is controversial and data on the likely effects of blocking TNFalpha on anti-DNA autoantibody production is always of interest.⁵⁴

In CD patients autoantibody formation like ANA and anti-dsDNA may occur in up to 53% of cases. According to the same study autoantibody formation may occur in up to 42% of patients during short-term infliximab treatment for Crohn's disease. Of interest 8% of these patients were positive before infliximab treatment.⁵⁵

Despite the significant prevalence of such autoantibodies (ANA and anti-dsDNA in 53% and 35% of infliximab-treated patients with CD, respectively), those antibodies are not generally associated with clinical signs of autoimmunity⁵⁶ and there is no indication for monitoring in patients who have no symptoms.⁵⁷

There is no clear explanation for this high prevalence of those autoantibodies. We may hypothesize that the apoptosis induced by anti-TNFs, infliximab and adalimumab, is effectively a DNA immunization, hence leading to at times high titers of ANA without illness associated with them.

Patients on anti-TNFα therapies may rarely present lupus-like syndrome⁵⁸–⁶⁰ or cutaneous lupus.⁶¹ True cases of SLE in IBD patients treated either with infliximab⁶²,⁶³ or adalimumab⁶⁴,⁶⁵ have been rarely reported.

In a prospective study investigating the occurrence of antinuclear antibodies in 125 consecutive CD patients treated with infliximab the cumulative incidence of ANA was 56.8% after 24 months. Antinuclear antibodies persisted up to 1 year after the last infusion, and only a few patients became seronegative. Two patients developed drug-induced lupus erythematosus. Antinuclear antibodies were associated with the female sex and skin manifestations.⁶² According to Mayo clinic experience in 500 patients treated with infliximab and followed-up for 17 months only three patients developed drug-induced lupus.⁶³ The safety profile of adalimumab in patients with CD was similar to that of other TNF antagonists in CD populations.⁶⁴

Cases were reversible and manageable upon discontinuation of treatment and ANA monitoring should not be routinely performed in anti-TNFα-treated patients with no clinically relevant symptoms.⁶⁶–⁶⁸

Adalimumab safety in CD clinical trials including induction trials (CLASSIC-I, GAIN), open-label period of CHARM, double blind maintenance (CLASSIC-II, CHARM) and all CD clinical trials including open-label extension, demonstrated only 3 lupus-like cases. Of note is the fact that none of the patients met the strict diagnostic criteria for DILE and patients experience a clinical improvement 6–12 weeks afterwards.⁶⁹–⁷²

The relative rarity of cases with systemic DILE due to adalimumab compared to those receiving infliximab or etanercept is still debatable.⁶⁴,⁷³

According to recent experience from a Spanish IBD group DILE seems more prevalent in adalimumab-treated patients compared to the infliximab-treated ones.⁷³ By contrast, in the CLASSIC-II trial no cases of DILE were noted.⁶⁴

Of interest, until 2007 none such DILE case had been reported to the Netherlands Pharmacovigilance Centre. In the same study, it has been hypothesized that adalimumab may boost the infliximab-induced mechanisms for anti-dsDNA development. In fact, increased cytokine and anti-dsDNA levels accompany SLE development upon infliximab–adalimumab conversion.⁷⁴

The question whether the development of drug-related lupus is a contraindication for switching from one TNFα inhibitor to another still remains unanswered.⁷⁵

Finally, certolizumab is not supposed to induce apoptosis, but there has been a report of a recurrent DILE following 3 months of therapy with certolizumab as a second anti-TNF agent after infliximab failure.⁷⁶ In a study of 180 IBD patients treated with anti-TNF antibodies (infliximab or adalimumab, or infliximab and adalimumab consecutively) factors predicting the development of lupus-like syndrome were analyzed. IBD patients of higher age treated with anti-TNF-α antibodies are at increased risk for development of ANA and lupus-like syndrome, while concomitant immunosuppressive therapy showed a protective effect.⁷⁷

A logical clinically relevant approach is that in cases of ANA positive patients who are switched from one anti-TNFα agent to another no specific caution or follow up is necessary except in those rare cases in which the patient was previously diagnosed with DILE or ‘lupus-like’ syndrome while receiving the initial anti-TNFα therapy.⁷⁸

Future studies and larger experience are of great importance in order to define the best diagnostic and treatment strategies in these complicated cases of complex autoimmunity (Fig. 1).

8 Conclusions

• IBD and SLE are multisystemic autoimmune related diseases. IBD predominantly affects gastrointestinal tract, while SLE may also present gastrointestinal involvement such as: vasculitis, pancreatitis and protein-losing enteropathy.

• Concomitant diagnosis of IBD and SLE is rare.

• Drug-induced lupus in IBD has been recognized. Sulphasalazine or 5-ASA may present a lupus-like syndrome with serositis, joint involvement, skin rashes and ANAs, anti-dsDNA and anti-histones positivity. Treatment includes discontinuation of the offending drug and administration of corticosteroids.

• Induction of autoimmunity in the form of ANAs and/or anti-dsDNA antibodies has been often seen in IBD patients treated with TNFα inhibitors although the occurrence of true lupus or lupus-like syndrome is rare.

• Coexistence of IBD and SLE is a clinical and therapeutic challenge for the clinicians.

Conflict of interest

None.

Figures

Fig. 1

Algorithm to confirm either systemic lupus erythematosus (SLE) or drug-induced lupus (DILE) and their respective managements in patients with inflammatory bowel disease and lupus symptoms.

Tables

Table 1

Overview of patients with concomitant diagnosis of inflammatory bowel disease (UC and CD) and lupus erythematosus.

Author	Year	Type of study	IBD diagnosis	Lupus diagnosis	Remarks
Fujimori et al.12	1987	Case	CD	SLE	Co-existing Sjögren's syndrome
Su et al.13	2008	Case	CD	SLE	Manifested with massive intestinal bleeding
Johnson et al.14	1985	Case	CD	SLE
Sanchez-Burson et al.15	2004	Case	CD	SLE
Toulemonde P et al.16	2001	Case	CD	SLE	CD followed SLE diagnosis
Mornet et al.17	1973	Case	CD	SLE
Principi et al.18	2004	Case	CD	SLE	Concomitant lupus nephritis
Sugimoto et al.19	1989	Case	CD	SLE	Lupus nephritis responded to infliximab
Nishida Y et al.20	1998	Case	CD	SLE	Family with 3 members diagnosed with CD
Ashworth et al.21	1992	Case	CD	Cutaneous lupus
Shafer et al.22	1970	Case	CD	SLE?
Dubrow et al.23	1966	Case	CD	SLE?
Shimizu et al.24	1999	Case	CD?	SLE	Differential diagnosis with lupus enteritis
Buchman et al.25	1995	Case	CD?	SLE	Differential diagnosis with lupus enteritis
Tsuchiya et al.8	1975	Retrospective	UC	SLE	Clinical overview of 35 cases of UC/SLE
Sultan et al.4	1999	Retrospective	UC	SLE	UC in 0.4% of all SLE patients
Font et al.32	1988	Case	UC	SLE
Medeiros et al.33	2009	Case	UC	SLE
Bourikas et al.34	2008	Case	UC	SLE	Concomitant non-Hodgkin lymphoma
Nieradko-Iwanicka et al.35	2006	Case	UC	SLE	Lupus nephritis
Sugiyama et al.36	1996	Case	UC	SLE	Lupus nephritis
Garcia-Porrua et al.37	1998	Case	UC	SLE
Koutroubakis et al.38	1998	Case	UC	SLE
Ishikawa et al.39	1995	Case	UC	SLE
Stevens et al.40	1994	Case	UC	SLE	Concommitant primary sclerosing cholangitis
Papi et al.41	1995	Case	UC	SLE?	Dural sinus thrombosis