Lupus-like syndrome caused by 5-aminosalicylic acid in patients...

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Lupus-like syndrome caused by 5-aminosalicylic acid in patients with inflammatory bowel disease Andrew W Kirkpatrick , Arthur A Bookman , Flavio Habal AW Kirkpatrick, AA Bookman, F Habal. Lupus-like syndrome caused by 5-aminosalicylic acid in patients with inflammatory bowel disease. Can J Gastroenterol 1999;13(2):159-162. BACKGROUND: Although 5-aminosalicylic acid (5-ASA) preparations used to treat inflammatory bowel disease are reported to have fewer side effects than sulphasalazine, increased clinical use of these compounds has resulted in increased reports of signifi- cant side effects. OBJECTIVE: To report four patients with antinuclear anti- body-positive migratory arthralgias and acute inflammation unrelated to the underlying inflammatory bowel disease, fulfilling the criteria of a drug-induced lupus-like syndrome. SETTING: A university-affiliated teaching hospital. INTERVENTION: Cessation of treatment with 5-ASA com- pounds. RESULTS: The cases described constitute a drug-induced lupus-like syndrome. All patients improved rapidly after discon- tinuation of 5-ASA compounds. CONCLUSIONS: Reversible lupus-like syndrome appears to be a rare but significant side effect of 5-ASA compounds. Patients treated with 5-ASA compounds who experience acute inflamma- tory symptoms or clinical deterioration not related to their gastroin- testinal disease should be screened to rule out a lupus-like reaction. Key Words: Aminosalicylic acids, Drug toxicity, Inflammatory bowel disease, Lupus-like syndrome Syndrome de pseudo-lupus provoqué par l’acide 5-aminosalicylique chez des patients atteints de maladie inflammatoire de l’intestin Trauma Services, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia; Department of Internal Medicine and Rheumatology, The Toronto Hospital, Western Division; Department of Gastroenterology, Division of Internal Medicine, The Toronto Hospital, Toronto, Ontario Correspondence and reprints: Dr FM Habal, The Toronto Hospital, Toronto, Ontario M5G 2C4. Telephone 416-340-5023, fax 416-595-5251, e-mail [email protected] Received for publication June 8, 1998. Accepted September 11, 1998 BRIEF COMMUNICATION

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Lupus-like syndrome caused by5-aminosalicylic acid

in patients withinflammatory bowel diseaseAndrew W Kirkpatrick ��

�, Arthur A Bookman �� ������, Flavio Habal �� �����

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AW Kirkpatrick, AA Bookman, F Habal. Lupus-like syndromecaused by 5-aminosalicylic acid in patients with inflammatorybowel disease. Can J Gastroenterol 1999;13(2):159-162.

BACKGROUND: Although 5-aminosalicylic acid (5-ASA)preparations used to treat inflammatory bowel disease are reportedto have fewer side effects than sulphasalazine, increased clinicaluse of these compounds has resulted in increased reports of signifi-cant side effects.OBJECTIVE: To report four patients with antinuclear anti-body-positive migratory arthralgias and acute inflammationunrelated to the underlying inflammatory bowel disease, fulfillingthe criteria of a drug-induced lupus-like syndrome.SETTING: A university-affiliated teaching hospital.INTERVENTION: Cessation of treatment with 5-ASA com-pounds.RESULTS: The cases described constitute a drug-inducedlupus-like syndrome. All patients improved rapidly after discon-tinuation of 5-ASA compounds.CONCLUSIONS: Reversible lupus-like syndrome appears to bea rare but significant side effect of 5-ASA compounds. Patientstreated with 5-ASA compounds who experience acute inflamma-tory symptoms or clinical deterioration not related to their gastroin-testinal disease should be screened to rule out a lupus-like reaction.

Key Words: Aminosalicylic acids, Drug toxicity, Inflammatory bowel

disease, Lupus-like syndrome

Syndrome de pseudo-lupus provoqué parl’acide 5-aminosalicylique chez des patientsatteints de maladie inflammatoire de l’intestin

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�Trauma Services, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia; �Department of Internal Medicine andRheumatology, The Toronto Hospital, Western Division; �Department of Gastroenterology, Division of Internal Medicine, The Toronto Hospital,Toronto, Ontario

Correspondence and reprints: Dr FM Habal, The Toronto Hospital, Toronto, Ontario M5G 2C4. Telephone 416-340-5023,fax 416-595-5251, e-mail [email protected]

Received for publication June 8, 1998. Accepted September 11, 1998

BRIEF COMMUNICATION

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Sulphasalazine is a proven effective treatment for ulcera-tive colitis (1-3). This drug, composed of a sulphapyri-

dine and a 5-aminosalicylic acid (5-ASA) moiety, is not,however, without side effects. It has been appreciated formany years that sulphasalazine is capable of causing a sys-temic lupus erythematosus (SLE)-like disorder in patientssuffering from inflammatory bowel disease (4-6). These ad-verse effects have been attributed to the sulphapyridine moi-ety, and thus the use of compounds containing only 5-ASAin patients demonstrating sulphasalazine-induced SLE hasbeen recommended (7).

Adverse reactions to 5-ASA therapy include watery diar-rhea, hypersensitivity reactions, perimyocarditis, pancreati-tis and renal toxicity (8). Recently, other serious drug sensi-tivity reactions, previously believed to be related to thesulphapyridine moiety, have been reported with increasingfrequency after treatment with 5-ASA, supporting the suspi-cion that 5-ASA compounds may not be free of lupus-like ef-fects. Lim and Hine (9) reported a patient who developed fe-ver, a vasculitic rash, arthritis, pericarditis and pericardialeffusion after treatment with mesalazine. Welte and col-leagues (10) reported 5-ASA-induced alveolitis associatedwith a generalized erythematous rash, and Hautekeete andcolleagues (11) found evidence of hypersensitivity and hepa-totoxicity after 5-ASA use. While these inflammatory reac-tions are clinically similar to the end-organ effects of drug-induced SLE, only two cases of 5-ASA-induced lupus-likesyndrome have been reported. In 1992, Dent et al (12) re-ported a case occurring after mesalazine use (12), and in1997, Gunnarson et al (13) reported a case occurring afterthe use of olsalazine. We report four cases of lupus-like syn-drome occurring after the use of 5-ASA compounds.

CASE PRESENTATIONSCase 1: A 26-year-old woman diagnosed with Crohn’s dis-ease at the age of 19 years had no previous rheumatic com-plaints. She was treated with 5-ASA (Asacol, Proctor & Gam-ble; 4 g daily) and prednisone (40 mg daily with a taperingdose). Colonoscopy revealed typical features of Crohn’s coli-tis. When her disease improved after medical treatment andshe was weaned from prednisone, she suffered repeated re-lapses requiring the reintroduction of prednisone. She hadbeen started on maintenance oral 5-ASA at age 21 years. Shenoticed the onset of morning stiffness and arthralgias of theankles, wrists and fingers, which improved promptly whenshe began taking prednisone (40 mg/day). Over the next twoyears, she continued to suffer recurrent episodes of arthralgiathat remitted with increased steroid doses and worsened asthe dose of steroids was tapered.

By November 1992, the patient developed elevated trans-aminase levels suggestive of a hepatitic process – peak aspar-tate aminotransferase (AST) level 770 U/L and alanineaminotransferase (ALT) level 453 U/L; total and indirectbilirubin 24 and 13 mol/L, respectively; alkaline phosphatase(ALP) 156 U/L; gamma-glutamyltransferase 81 U/L (normal5 to 25 U/L); 5�nucleotidase 24 U/L (normal 2 to 10 U/L);and erythrocyte sedimentation rate (ESR) 35 mm/h. Other

hematological and serological markers of hepatitis werenegative. The results of immunological studies were antinu-clear antibody (ANA)-positive at 1:320 and anti-DNA(Crithidia species)-positive. Results of tests for anti-Sm,anti-RNP, anti-Ro and anti-La autoantibodies were nega-tive (Table 1).

Diagnoses of drug-induced arthropathy and hepatitiswere considered, and the 5-ASA was discontinued in De-cember 1992. The arthritis resolved, and liver enzyme levelsreturned to normal. After all drugs were discontinued, in-cluding the steroids, her bowel habits remained normal. Bio-chemical tests indicated that her AST, ALT and ALP levelswere normal by November 1993. Repeat ESR was 5 mm/h,and the anti-DNA (Farr) level was 2 U/L (normal less than7 U/L). Her serology and transaminase levels were normal ather three-year follow-up examination.Case 2: A 68-year-old man who presented with typical histo-logical features of ulcerative colitis previously diagnosed withproctosigmoiditis was started on 5-ASA enemas (Salofalk,Axcan Pharma) and oral 5-ASA (Asacol; 4 g/day) in Janu-ary 1992. After beginning the treatment, the patient beganto complain of symptoms of polyarthralgias characterized bymorning stiffness and pain in the shoulders, elbows andknees. His symptoms continued to progress throughout 1993.He had an ESR of 38 mm/h. Nonsteroidal anti-inflammatorydrugs (NSAIDs) provided no relief, and prednisone andchloroquine only partially controlled his symptoms. An auto-antibody screen revealed a positive ANA (1:320), a positiveanti-DNA (Crithidia species) and an anti-DNA (Farr) of12 U/L (normal less than 7 U/L), as well as a negative anti-Sm, anti-RNP, anti-Ro and anti-La (Table 1). His bowel dis-ease remained in remission throughout the year, althoughthe arthropathy continued to progress. After two years oftherapy, the 5-ASA was discontinued; the rheumatic symp-toms resolved completely within three weeks, with no exac-erbation of the gastrointestinal disease. The patient’s ANAlevels and anti-DNA serology had reverted to normal at thefollow-up examination eight months after 5-ASA discon-tinuation and remained normal at the two-year follow-upexamination.

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TABLE 1Serological findings in 5-aminosalicylic acid-treated patients

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Case 3: A 23-year-old woman with a three-year history ofleft-sided ulcerative colitis was receiving 5-ASA (Salofalk)orally (2 g/day) and rectally (2 g nightly) when she began toexperience multiple joint pains. The pains began with swol-len index fingers, followed by pain in all proximal interpha-langeal joints, and developed into a migratory nocturnal paininvolving the knees, neck, back, shoulders and elbows. Re-sults of the physical examination of the musculoskeletal sys-tem were unremarkable, and no effusions were noted; hergastrointestinal disease remained stable. The pain in herjoints fully resolved with administration of prednisone(20 mg/day) for one week but recurred with gradual weaningof steroids.

Serological examination revealed a positive ANA of1:640. Anti-DNA (Crithidia species) was positive at 9 U/L(normal less than 7 U/L); anti-DNA (Farr) level was 9 U/L(normal less than 7 U/L); and anti-Ro, anti-La, and anti-Smautoantibody tests were all negative (Table 1). The eosi-nophil count was markedly elevated at 2.8x103/L (normal0.04x103/L to 0.4x103/L in a total leukocyte count of9.5x103/L). The patient’s symptoms resolved completelywhen the 5-ASA preparations were discontinued. Her ANAand anti-DNA antibody levels reverted to normal; she had anormal leukocyte profile at the one-year follow-up examina-tion.Case 4: A 47-year-old woman with previously negative auto-immune serology and a history of fibromyalgia was diagnosedwith ileal Crohn’s disease in 1994. She was initially suc-cessfully treated with 5-ASA 4 g (Pentasa, Hoechst MarionRoussel). Although her diarrhea cleared, she developed arash on her forearms, upper arms and trunk, and arthralgia ofher knees, ankles and wrists. Investigation revealed an ele-vated sedimentation rate, a positive ANA of 1:320, a posi-tive lupus erythematosus cell preparation and a positive anti-cardiolipin antibody count of 51.5 U (Table 1). After sixmonths on 5-ASA, the drug was discontinued. Her symp-toms cleared within six weeks of cessation of therapy. Sheremained well one year later; the only abnormality has been amildly elevated ANA level.

DISCUSSIONDrug-induced lupus was first associated with sulphadiazine(6,14,15). Since then, more than 50 other drugs have beenimplicated (14); procainamide and hydralazine are the mostcommon agents (6,16,17). Various medications may induceseroreactivity by both dose-dependent and dose-indepen-dent mechanisms (14,18). Drug-induced lupus caused by sul-phasalazine has been well described (17,18), and the follow-ing diagnostic criteria have been proposed (15,19).

� Absence of a history suggestive of idiopathic SLE beforedrug ingestion;

� Development of ANA and at least one clinical featureof lupus (eg, joint involvement, serositis, skin rashes)during sustained drug therapy; and

� Rapid improvement of clinical features afterdiscontinuation of the drug.

This spectrum of 5-ASA-induced side effects, which in-cludes arthropathy, biochemical evidence of hepatotoxi-cants and ANA positivity, constitutes a lupus-like reactionthat appears to be associated with 5-ASA and is reversibleon discontinuation of the drug. Arthritis, the most commonlydescribed extraintestinal manifestation of inflammatorybowel disease, occurs in up to 20% of patients with Crohn’sdisease (20,21) and ulcerative colitis (21,22). This seronega-tive arthritis usually consists of a migrating oligoarthritis in-volving fewer than four joints (20) that persists for weeks tomonths (22). In adults, arthritic attacks tend to coincidewith flare-ups of bowel disease (20,21). The characteristicarthritis of drug-induced lupus is a nondeforming symmetri-cal polyarthritis that affects the small joints of the hands,then the wrists, elbows, shoulders, knees and ankles (6,15).Our patients exhibited ANA-positive arthropathies thatworsened when the intestinal disease remitted and appearedto be partially responsive to steroid therapy. Musculoskeletalcomplaints caused by drug-induced lupus are usually con-trolled with NSAIDs or short courses of steroids (15). How-ever in these cases the patients did not respond to NSAIDs.

Only a minority of patients with a positive ANA developa clinical disease in response to medication (17). It is notnecessary to discontinue a medication solely on the basis ofan ANA seroconversion (6,14,15). However, when clinicalsymptoms or end-organ effects are noted, suspect medicationshould be withdrawn (6,14). Most symptoms of drug-inducedlupus are self-limiting when the offending drug is discontin-ued and conservative management instituted (6,15).

Patient 3 had marked eosinophilia. Mild increases in thenumber of circulating eosinophils, up to but not exceeding0.8x103/L, have been described in cases of ulcerative colitis(23,24). Anecdotal evidence of pronounced eosinophiliacoincident with clinical relapse has been reported in pa-tients with ulcerative colitis. Regardless, the rapid improve-ment that occurred when the 5-ASA treatment was discon-tinued supports our belief that the patients’ symptoms weresecondary to the 5-ASA.

The lupus-like syndrome induced by 5-ASA appears to bea rare, potentially serious, yet easily treatable complicationof 5-ASA treatment. The syndrome appears to be reversiblewhen the 5-ASA treatment is discontinued. We believe thatthe four cases presented are examples of a drug-inducedlupus-like reaction to 5-ASA compounds. Ethical considera-tions did not allow a rechallenge, which would have furtherconfirmed this relationship. Most arthropathies in patientswith inflammatory bowel disease are extraintestinal manifes-tations of the underlying disease. In cases in which patientsexhibit inflammatory symptoms such as arthropathies orhepatitis after 5-ASA therapy, the possibility of an adverseidiosyncratic reaction to 5-ASA compounds should be con-sidered. Serological studies to screen for abnormal ANA inthese settings may be warranted. A trial of discontinuation of

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the 5-ASA compound may result in cessation of the symp-toms and indicate an adverse reaction to 5-ASA.

ACKNOWLEDGEMENTS: We thank JC Marshall MD FRCSCFACS for reviewing the manuscript. This article was prepared withthe assistance of Editorial Services, The Hospital for Sick Children,Toronto, Ontario.

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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com