ANCA-associated Goodpasture's syndrome in a patient with rheumatoid arthritis on penicillamine.

Although penicillamine has been used effectively in the management of a variety of diseases, several adverse reactions have been observed with prolonged administration of this agent. We report a case of Goodpasture's syndrome, as a result of induction of anti-myeloperoxidase antineutrophil cytoplasmic antibodies in a 51 year old man who was being treated with this drug for rheumatoid arthritis. This pulmonary-renal syndrome has been described on rare occasions in patients receiving penicillamine. Treatment with steroids and cyclophosphamide resulted in pulmonary and renal functional recovery.

Introduction

D-penicillamine is primarily used in the treatment of rheumatoid arthritis, systemic sclerosis, Wilson's disease, lead poisoning, and cystinuria. The treatment with this drug has been associated with untoward side effects, some of which are potentially hazardous, thus limiting its use. These include cytopenias, pemphigus, myasthenic syndrome, bronchiolitis, polymyositis, systemic lupus erythematosus (SLE) syndrome, and nephropathy.[1] Goodpasture's syndrome is a rare complication linked to the prescription of penicillamine.[2-7] We describe a patient with rheumatoid arthritis in whom Goodpasture's syndrome occurred during treatment with this drug. Immunosuppressive therapy was followed by pulmonary and renal functional recovery.

Case Report

A 51-year-old gentleman was referred to our unit with renal impairment, anemia, and hemoptysis. He was diagnosed with rheumatoid arthritis 9 years ago and was initially treated with methotrexate (7.5 mg twice a week). Due to hepatic toxicity, methotrexate was discontinued and the patient was started on penicillamine 250 mg/ day 7 years back. He was on regular follow-up with blood counts and routine urine examination. During this period, his symptoms were controlled with no extra-articular manifestations. He was a nondiabetic and had been diagnosed with hypertension 1 year ago. He was a reformed smoker, having quit smoking 12 years back.

Five months prior to presentation, the dose of penicillamine was increased to 500 mg/day (the patient weighed 64 kg). His present illness was characterized by a 3-month history of cough associated with blood-tinged expectoration (occasionally with clots). There was no pleuritic chest pain, dyspnea, orthopnea, or fever. He underwent a sputum examination, which was negative for acid-fast bacilli and showed a growth of Pseudomonas spp. Antibiotic treatment with ciprofloxacin, as per the sensitivity pattern, was given but his symptoms were not relieved. Investigations revealed a drop in hemoglobin from 13.8 g/ dl to 10.3 g/dl, a normal platelet count (1.5 l/cc), mild impairment of renal function (creatinine 1.3 mg/dl), and microscopic hematuria with proteinuria. The chest X-ray revealed bilateral reticulonodular shadows in lower zones and HRCT of the chest showed subpleural cystic lesions with fibrosis and alveolitis in both lower zones. He underwent fiberoptic bronchoscopy, which revealed distal alveolar hemorrhages, and bronchoalveolar lavage (BAL) was positive for hemosiderin-laden macrophages. The patient continued to have deterioration of renal function (creatinine 3.56 mg/dl) and was thus referred to our unit.

On admission, the patient had pallor, was euvolemic, and his blood pressure was 130/80 mmHg. There were no joint deformities or evidence of systemic vasculitis. Examination of the chest revealed bibasal end-inspiratory crackles. Investigations confirmed anemia (hemoglobin 6.7 g/dl) and there was worsening of renal parameters (creatinine 4.2 mg/dl). The urine sediment contained protein, red cells and red cell casts, and 24-h proteinuria was 1.6 g. In view of pulmonary hemorrhage along with rapidly progressive glomerulonephritis (RPGN), a clinical diagnosis of Goodpasture syndrome was made. We performed a renal biopsy which revealed 16 glomeruli, all of which had large foci of fibrinoid necrosis in capillary tufts, with associated karryorhexis [Figure 1]. Two glomeruli showed epithelial crescents and one had fibrous crescent. There was mild mesangial hypercellularity and capillary basement membrane was not thickened. Mild interstitial fibrosis was seen. The immunofluorescence study was negative for IgG, IgA, IgM, C3, C1q, and fibrinogen.

Figure 1

Photomicrograph of the renal biopsy showing a glomerulus with cellular crescent, hypercellularity, and fibrinoid necrosis. H and E, ×40

His serum was negative for rheumatoid factor activity and serum complement (C3 and C4) levels were normal. The assay for anti-glomerular basement membrane (GBM) antibodies and antineutrophil cytoplasmic antibodies (ANCAs) by indirect immunofluorescence were negative. Antinuclear antibodies (ANA) were detected (3+) on Hep 2 cells with a homogenous nucleolar pattern and anti-ds DNA antibodies were positive by Crithidia lucilae assay. Further investigations revealed a positive anti-myeloperoxidase (MPO)–ANCA activity by ELISA in a titer of >100 IU/ml and the absence of anti-proteinase 3 (PR3)–ANCA and antihistone antibodies.

The patient was treated with pulse intravenous methylprednisolone (500 mg/day) for 3 days followed by oral prednisolone (1 mg/kg) and pulse intravenous cyclophosphamide (500 mg). There was a steady improvement in renal parameters and no further evidence of fresh pulmonary hemorrhage. The serum creatinine 2 months later was 1.3 mg/dl.

Discussion

D-penicillamine is an effective therapy for rheumatoid arthritis but its exact mechanism of action is not yet clear. The most common renal complication involves proteinuria or the nephrotic syndrome with a benign urine sediment and normal renal function. Membranous changes are the predominant lesions found in these individuals with occasional mild mesangial or endothelial cell proliferation without crescents.[8] The withdrawal of the drug usually constitutes definitive therapy in these patients. The occurrence of necrotizing and crescentic glomerulonephritis, due to induction of ANCA, is another renal lesion reported on rare occasions in patients receiving penicillamine.[910]

The clinical presentation of our patient is that of Goodpasture's syndrome, which is classically associated with anti-GBM antibodies in Goodpasture's disease but is more commonly associated with ANCA, although a minority of patients have both auto-antibodies. The possibilities entertained at presentation were that of drug-induced vasculitis, anti-GBM disease, rheumatoid vasculitis, and drug-induced/idiopathic lupus.

The reported cases of penicillamine-associated Goodpasture's syndrome are few.[2-7] The clinical features of these patients were usually more typical of vasculitis than of anti-GBM disease where they lacked linear immunoglobulin deposits in GBM, crescentic change rarely involved all glomeruli, and renal recovery was possible despite severe renal impairment at presentation. It is interesting to note that in our patient, anti-MPO antibodies were detected by ELISA in the absence of staining of ethanol-fixed neutrophils by indirect immunofluorescence. These differences may be explained by methodology as our patient also had ANA. Hence the perinuclear staining may appear similar to the nuclear staining typical of ANA when ANCA are detected by using ethanol-fixed neutrophils alone. This artefactual staining pattern is abolished by the use of formalin-fixed neutrophils.[11]

MPO is localized to azurophilic granules of neutrophilic granulocytes and lysosomes of monocytes. Penicillamine interacts with neutrophil MPO,[12] a property that it shares with propylthiouracil and hydralazine. This interaction seems to be a key feature in drug-induced anti-MPO–associated vasculitis. However, it is not very clear how penicillamine induces autoimmunity. It is postulated that penicillamine may react with thiol groups on membrane proteins or intracytoplasmic or intranuclear components and affect protein trafficking and processing in different cell lineages, including immunocompetent cells.[13] The interaction of penicillamine with MPO could also alter MPO antigenic properties and promote a breach into self-antigen tolerance. Although the exact pathogenic mechanisms involved remain to be elucidated, both cell-mediated and humoral immunity appear to have important roles.

The possibility of anti-GBM disease in our patient was ruled out by the absence of linear deposits on immunofluorescence along with the absence of anti-GBM antibodies in serum.

The occurrence of rheumatoid vasculitis has long been recognized as a complication of RA in about 6% of patients. These patients usually have erosive lesions and strong seropositivity for the rheumatoid factor, and frequently have hypocomplementemia and circulating immune complexes. Renal involvement is unusual but individual cases have been well documented. Hence the Goodpasture's syndrome in our patient seems unlikely to be related to rheumatoid vasculitis, as he did not have any of the above-mentioned evidence of active disease. Also, the ANCA that have been detected in RA bind to neutrophil components other than PR3 and MPO.[14]

A drug-induced LE syndrome has also been reported in approximately 2% of patients treated with penicillamine.[15] Features of this syndrome include arthritis–arthralgia, occasional cytopenia, neurologic disturbances, Coomb's antibodies, and ANA, while antibodies against ds-DNA are rare. The possibility that the RPGN in our patient may have been a manifestation of penicillamine-induced lupus nephritis seems unlikely for several reasons: First, there was paucity of immune deposits on immunofluorescence along with normal serum complement levels; second, the kidneys are usually spared in drug-induced lupus; and finally, the absence of antibodies against histones along with the presence of anti-ds-DNA antibodies. Idiopathic lupus nephritis was also unlikely despite the presence of ANA and anti-ds-DNA antibodies since the patient did not exhibit other features of SLE along with the absence of hypocomplementemia and paucity of immune deposits on immunofluorescence.[16]

The antihypertensive agent hydralazine apart from causing a lupus-like syndrome has been shown to cause a systemic vasculitis with a pauci-immune RPGN, associated with ANCA with specificities for both MPO and lactoferrin. In addition, antibodies against nuclear components including ds-DNA and renal involvement appear to be more common in these patients. Thus, our patient's serologic profile bears resemblance to the group of patients described in a study by Short et al.,[17] who developed MPO–ANCA positive vasculitis following treatment with hydralazine.

Hence we conclude that the Goodpasture's syndrome in our patient was possibly due to the induction of anti-MPO ANCA-associated vasculitis related to D-penicillamine therapy.