Pediatr Nephrol (2004) 19:438–441DOI 10.1007/s00467-003-1365-0

B R I E F R E P O R T

�zlem Erdogan · Ayse Oner · G�lay Demircin ·Mehmet B�lb�l · Leyla Memis · �igdem �ner ·Nural Kiper

A boy with consecutive development of SLEand Wegener granulomatosis

Received: 6 January 2003 / Revised: 6 October 2003 / Accepted: 8 October 2003 / Published online: 23 January 2004� IPNA 2004

Abstract An 11-year-old boy with consecutive develop-ment of systemic lupus erythematosus (SLE) and Wege-ner granulomatosis (WG) is presented. He was firstadmitted to the hospital with the findings of SLE,including crescentic glomerulonephritis, Coombs0 test-positive hemolytic anemia, hypocomplementemia, anti-nuclear antibody (ANA) positivity, and elevated levels ofanti-double-stranded (ds) DNA antibodies. He was treatedsuccessfully with steroids, cyclophosphamide, and peri-toneal dialysis. One month after his discharge he devel-oped an apparent viral infection. Three weeks afterwardshe was readmitted with the findings of lower respiratorytract involvement, maxillary sinusitis, nasal septumperforation, p- and c-antineutrophil cytoplasmic antibody(ANCA) positivity, but normal complement, ANA, andanti-ds DNA levels, suggesting the diagnosis of WG. Hedid not respond to anti-infectious and immunosuppressivetreatment, and he died of Pseudomonas sepsis.

Keywords Overlap syndrome · Systemic lupuserythematosus · Wegener granulomatosis

Introduction

Wegener granulomatosis (WG) is a systemic diseasemainly characterized by necrotizing, granulomatous vas-culitis of the upper and lower respiratory tract andglomerulonephritis [1]. The disease is uncommon inchildren, and its association with systemic lupus erythe-matosus (SLE) is extremely rare [2, 3]. We present here achild who initially presented with the clinical andlaboratory picture of SLE and developed WG afterresolution of many abnormalities of SLE.

Case report

An 11-year-old previously healthy boy was first admitted to thehospital with abdominal pain, nausea, vomiting, edema, andhematuria of 1 week duration. His parents were first-degreecousins but there was no family history of any significant disease,including autoimmune defects. Physical examination revealed awell-developed boy (weight and height were at the 25–50thpercentile). His heart and respiratory rates were 92 and 28/min,respectively, and his blood pressure was 100/60 mmHg. He hadperiorbital and pretibial edema. Laboratory examination showedhemoglobin 8.7 g/dl, white blood cell count 7,700/mm3, directCoombs0 test positive, reticulocyte count 2%, VDRL test positive,erythrocyte sedimentation rate 80 mm/h, blood urea nitrogen(BUN) 42 mg/dl, serum creatinine (SCr) 2.2 mg/dl, albumin 1.9g/dl, total protein 5.1 g/dl, and creatinine clearance 9.6 ml/min per1.73 m2. C3 was 40 mg/dl (normal 90–120 mg/dl), C4 7 mg/dl(normal 20–40 mg/dl), serum IgG 9.88 g/l (normal 5.7–15.7 g/l),IgM 2.22 g/l (normal 0.3–1.4 g/l), IgA 1.18 g/l (normal 0.86–5.4g/l), antinuclear antibody (ANA) positive in the homogenouspattern at a 1/320 titer, anti-double-stranded (ds) DNA 150 IU/ml(normal 0–7 IU/ml), anticardiolipin IgM 1.26 MPL (normal 0–5MPL) and IgG 9.96 GPL (normal 0–15 GPL). Urinalysis revealed4+ proteinuria and microscopic hematuria. His chest X-ray andechocardiography were normal. Renal biopsy demonstrated diffuseproliferative glomerulonephritis with 75% crescents (Fig. 1), andmesangial and capillary wall deposition of IgM and C3 in agranular pattern. With these clinical and laboratory findings, thepatient was diagnosed as having SLE with class IV lupus nephritis.

�. Erdogan · A. Oner · G. Demircin · M. B�lb�lDepartment of Pediatric Nephrology,Dr. Sami Ulus Children’s Hospital,Ankara, Turkey

L. MemisDepartment of Pathology,University Hospital of Gazi,Ankara, Turkey

�. �nerDepartment of Radiology,Dr. Sami Ulus Children’s Hospital,Ankara, Turkey

N. KiperDepartment of Pediatric Chest Disease,University Hospital of Hacettepe,Ankara, Turkey

A. Oner ())Bilkent 1, �amlık Sitesi, D7-Blok, no 21, 06530 Ankara, Turkeye-mail: ayseoner99@hotmail.comTel.: +90-312-4305455Fax: +90-312-4344151

He was given intravenous methylprednisolone pulse therapy(30 mg/kg per day, 3 consecutive days) followed by oralprednisolone, cyclophosphamide, and dipyridamole. Peritonealdialysis was performed because of oliguria and further deteriorationof renal function (BUN 130.7 mg/dl, SCr 4.2 mg/dl), and he was

discharged within 4 weeks after his clinical and laboratory findingsimproved.

One month after his discharge, he developed a possible viralinfection with fever, aphthous stomatitis, dermal vesicular lesions,and negative bacterial cultures. He recovered with acyclovirtherapy. Three weeks later, he was readmitted to the hospital withsevere dyspnea, cyanosis, cough, and fever. He had nephroticsyndrome with normal BUN, SCr, complement, and anti-ds DNAlevels, and negative ANA. On chest examination, bilateral finecrackles were detected. The sinus and chest radiographs showedmaxillary sinusitis and pulmonary interstitial infiltration. He wasgiven antiviral, antibacterial, and antifungal drugs, but did notimprove. All cultures and serological investigations for bacterial,viral, and fungal agents remained negative. After obtainingadditional blood tests, he was given intravenous methylpredniso-lone and cyclophosphamide (500 mg/m2) pulse therapy for adiagnosis of probable pulmonary vasculitis. These medicationswere continued at monthly intervals.

Despite pulse cyclophosphamide and methylprednisolone, hisrespiratory distress and pulmonary interstitial infiltration on chestX-ray did not improve. One month later, nasal septum perforationwas noted. Anti-glomerular basement membrane, anti-Ro, and anti-La antibodies (measured earlier) were found to be negative, whileboth p- and c-antineutrophil cytoplasmic antibodies (ANCA) were3+. Three consecutive thorax computerized tomograms performedwithin a period of 2 months showed a ground-glass appearance ofthe lungs, pulmonary nodules, and cavity formations, respectively(Fig. 2a–c). These findings led to the diagnosis of WG, andimmunosuppressive therapies were continued. Two months later hedeveloped pneumothorax, and was treated with underwater seal

Fig. 2 a Ground-glass appearance of the lungs on the first computerized tomogram of the thorax. b One month later: pulmonary nodules.c Two months later: cavity formations

Fig. 1 Renal biopsy showing extensive crescents and proliferativeglomerular tufts (hematoxylin and eosin, �200)

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tube drainage. However, he died because of Pseudomonas sepsisdespite combined anti-infectious therapy.

Discussion

This patient was first admitted with the clinical andlaboratory findings of SLE, including Coombs0 test-positive hemolytic anemia, class IV lupus nephritis,hypocomplementemia, positive ANA and VDRL test,and elevated anti-ds DNA level. A diagnosis of SLE wassupported by fulfillment of 4 of the 11 criteria of theAmerican College of Rheumatology (ACR) [4]. Initially,he did not show any findings suggesting WG. Withimmunosuppressive therapy, renal function, complement,and anti-ds DNA levels returned to normal, and ANApositivity converted to negative, showing improvement ofSLE. He developed respiratory distress with interstitialpulmonary infiltration on chest X-ray 3 weeks after apossible viral infection. During the course of the disease,persistence of pulmonary findings despite anti-infectioustherapy, development of pulmonary nodules and cavityformations, perforation of nasal septum, and p- and c-ANCA positivity led to the diagnosis of WG according tothe ACR criteria [5]. Histological confirmation was notsought because of his poor general condition.

WG is a systemic disease with multiple target organsand a variety of clinical manifestations [1]. Its diagnosiscan be obscured or delayed because of atypical and slowpresentation of clinical findings and a low incidence inchildhood [6]. Hall et al. [7] reported four children withWG whose initial clinical findings suggested Henoch-Sch�nlein purpura. Two had the diagnosis after end-stagerenal disease had developed. However, in our patient it islikely that SLE and WG developed consecutively, ratherthan one mimicking another, since both diseases showedtheir own characteristics. Moreover, the manifestations ofSLE, including ANA and anti-ds DNA positivity, hadsubsided before the findings of WG occurred. D’Cruz etal. [3] reported that the pattern of disease in five patientswho developed SLE in the 2nd or 3rd decade of lifechanged 11–35 years later into that of systemic vasculitis.This included WG in two patients, Churg-Strauss syn-drome in one, and polyarteritis nodosa in two. D’Cruz etal. [3] discussed whether the patients had both SLE andsystemic vasculitis from the beginning of their illness orwhether they first had SLE that evolved into systemicvasculitis. They favored the hypothesis that the clinicalpattern of a systemic autoimmune disease, SLE, pro-gressed to that of another connective tissue diseaseprobably under the influence of hormonal, environmental,or genetic factors. No similar case has been reported inchildhood of SLE and WG developing consecutively.

These two diseases have different immunologicalfindings besides their clinical presentations. In 90% ofpatients with active SLE, total hemolytic complementactivity (CH50) and early classic pathway complementcomponents, particularly C3 and C4, decrease and returnto normal during remission if there is no inherited

complement deficiency [8]. In WG, complement levelsand CH50 are usually normal or elevated [9]. Furthermore,ANA and anti-DNA are characteristically negative inWG, while ANA is present in the sera of almost allchildren with active SLE, and anti-DNA is pathogno-monic for SLE and is present at particularly high titers inchildren with active nephritis [8, 9]. Therefore, the firstclinical presentation of this patient was characteristic forSLE, but within 3 months typical clinical findings of WGdeveloped concordant with resolution of laboratorymarkers typical for lupus. Positive c-ANCA also support-ed the diagnosis of WG. Almost all patients with activeWG have ANCA positivity, with a higher frequency of c-ANCA than p-ANCA [10]. p-ANCA was also detected in31% of patients with SLE, while c-ANCA are extremelyrare in SLE [11, 12].

The exact pathogeneses of both SLE and WG areunknown. It is likely that a number of factors, includingimmune dysregulation, hormonal imbalance, and envi-ronmental factors such as infection, act together in thedevelopment of both diseases in genetically susceptiblehosts, and they share common HLA associations withHLA B8 and DR2 [8, 9]. Failure to appropriately down-regulate polyclonal B cell activation in SLE may result inproduction and deposition of various autoantibodies,some of which are pathogenic [8]. In WG, granulomatousreactions occur, possibly as the result of sensitized Tlymphocytes reacting with antigen and releasing variouscytokines that recruit macrophages to the site of injury.The activated macrophages release lysosomal enzymesand cause local tissue injury [9, 13]. The most commonlycited hypothesis for the role of ANCA in the pathogenesisof vascular injury is that an undetermined stimulus,perhaps an infection, elicits inflammatory cytokines thatinduce the expression of ANCA target antigens (protein-ase 3 and/or myeloperoxidase) on the neutrophil cellsurface. The binding of ANCA to these antigens maycause degranulation and respiratory burst of neutrophils,resulting in necrotizing vasculitis [14, 15].

The patient presented in this report may have had anincreased genetic predisposition to develop autoimmunediseases like SLE and WG, perhaps enhanced by parentalconsanguinity. After improvement of SLE due to immu-nosuppressive therapy, a viral infection might have beenthe triggering factor for the expression of ANCA targetantigens leading to the development of WG.

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3. D’Cruz D, Cervera R, Aydıntug AO, Ahmed T, Font J, HughesGRV (1993) Systemic lupus erythematosus evolving intosystemic vasculitis: a report of five cases. Br J Rheumatol32:154–157

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