Adalimumab-Induced Lupus Nephritis: Case Report and Review of the Literature

Introduction

Three anti-tumor necrosis factor (anti-TNF) therapies are approved for the treatment of Crohn's disease in adults in the United States: infliximab, adalimumab, and certolizumab pegol. Combination therapy of TNF-alpha inhibitors and a disease-modifying antirheumatic drug has been used in moderate to severe Crohn's disease in order to prevent immunogenicity. Drug-induced lupus (DIL) is a clinical syndrome with features similar to systemic lupus erythematosus (SLE). Diagnosis is often delayed because of chronicity and variability of symptomatology.1 Hydralazine was the first implicated culprit.2 Since then, hundreds of agents have been identified as triggers, including antiarrhythmics, antihypertensives, antibiotics, anticonvulsants, and TNF inhibitors.1-3 The expression of autoantibodies and the development of lupus are dependent on the dose and duration of exposure.4 This autoantibody expansion can be reversible with the discontinuation of the offending agents.

Case Presentation

A 36-year-old woman with a history of Crohn's disease (on long-term monotherapy with adalimumab), with 1 year of Raynaud's phenomenon, was found to have hematuria and proteinuria at her primary care physician's office. She was diagnosed with Crohn's disease on colonoscopy and biopsy in her late adolescence after presenting with bloody diarrhea as well as episodic morning stiffness in small and large joints. She was initially treated with steroids and mesalamine and subsequently with infliximab for a period of 2 years. Due to the recurrence of Crohn's symptoms, infliximab was transitioned to adalimumab, on which she was continued for 10 years.

At 36 years, routine urinalysis was notable for hematuria and proteinuria (962 mg). Creatinine was at baseline (0.8-0.9). Further investigations were significant for a positive ANA, anti-dsDNA, elevated anti-MPO, positive anti-histone antibody, and normal complement levels (C3 and C4). Her urine cytology and SPEP were normal. Renal ultrasound showed an 8.8 cm right kidney and an 11 cm left kidney with no other significant findings. Renal biopsy demonstrated lupus nephritis ISN/RPS class II (Figure 1).

Figure 1. A-C.

(A) 400× PAS stain showing a glomerulus with mild but diffuse mesangial matrix expansion with segmental increase in mesangial cellularity (arrow). (B) Direct immunofluorescence shows diffuse solid positive staining in the mesangium and rarely in some capillary walls for IgG 3+, IgA 3-4+, C3 2+, C1q 1+ kappa 3-4+, lambda 2+, fibrinogen 3+, with trace staining for IgM. (C) EM with extensive electron-dense mesangial deposits (arrow).

Her renal pathology was deemed related to the use of adalimumab, given new serology suggestive of DIL. Adalimumab was discontinued and she started on hydroxychloroquine and losartan. After three months of discontinuation, repeat labs were notable for a negative anti-dsDNA and MPO as well as improving proteinuria (<500mg).

Discussion

Tumor necrosis factor-alpha blockade has been associated with DIL, with higher risk with etanercept, adalimumab, and infliximab, and lower risk with other agents (golimumab and certolizumab).5-9 Tumor necrosis factor -alpha inhibitors have been associated with the development anti-dsDNA antibodies (5-77%). Anti-nuclear antibodies and anti-histone antibodies are nonspecific and can be positive in SLE as well as in DIL, making it difficult to distinguish both syndromes. Antiphospholipid antibodies are variably present.5-7

Drug-induced lupus secondary to anti-TNF agents manifests with a wide range of findings, such as skin rash, fever, arthralgia, serositis, thrombocytopenia, leukopenia, and with rare hypocomplementemia, hemolytic anemia, or neurologic involvement. The kidneys have rarely been implicated in DIL.9

Here, we present a case of adalimumab-induced lupus nephritis in a patient with Crohn's disease. Our patient presented with late-onset Raynaud's phenomenon and laboratory signs of renal injury after the use of adalimumab. We have found 1 case in the literature by Stokes et al10 that described a 52-year-old woman with rheumatoid arthritis who developed a positive ANA (titer 1:160) and anti-dsDNA (1:25) with gross hematuria after 3 doses of adalimumab, with histological evidence of class III lupus nephritis.10 In a review of 21 documented cases of adalimumab-induced autoimmunity, 15 cases of adalimumab-induced lupus were described, with no cases of nephritis.9 Two French studies found 9 cases of adalimumab DIL, with no renal involvement.3,11

In our case, diagnosis was especially difficult by the development of symptoms 10 years after the initiation of adalimumab, whereas in the case described by Stokes et al. symptoms developed more acutely after exposure. Biopsy confirmation of lupus nephritis and resolution of symptoms and serology following withdrawal of adalimumab highly suggests DIL nephritis in our patient. This case highlights the need for increased awareness and screening for DIL nephritis in patients on adalimumab who present with markers of renal injury.

Conclusion

This case report greatly supports the possibility that adalimumab can induce SLE and lupus nephritis, with a possible duration-dependent effect. Physicians should be mindful of this possibility in any patient on adalimumab who presents with signs or laboratory markers of renal injury.