Complete remission of myeloperoxidase–anti-neutrophil cytoplasmic antibody-associated crescentic glomerulonephritis complicated with rheumatoid arthritis using a humanized anti-interleukin 6 receptor antibody (original) (raw)

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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1Nephrology Center and 2Department of Pathology, Toranomon Hospital, Tokyo, Japan.

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Keiichi Sumida, Yoshifumi Ubara, Tatsuya Suwabe, Noriko Hayami, Rikako Hiramatsu, Eiko Hasegawa, Masayuki Yamanouchi, Junichi Hoshino, Naoki Sawa, Fumi Takemoto, Kenmei Takaichi, Kenichi Ohashi, Complete remission of myeloperoxidase–anti-neutrophil cytoplasmic antibody-associated crescentic glomerulonephritis complicated with rheumatoid arthritis using a humanized anti-interleukin 6 receptor antibody, Rheumatology, Volume 50, Issue 10, October 2011, Pages 1928–1930, https://doi.org/10.1093/rheumatology/ker222
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Sir, ANCA-associated necrotizing and/or crescentic GN (CrGN) has been reported to be complicated with RA [1–3]. Recently, some reports have demonstrated the efficacy of anti-TNF agents in the treatment of ANCA-associated CrGN complicated with RA [4, 5]. However, no reports have demonstrated the efficacy of tocilizumab, a humanized anti-IL-6 receptor antibody for ANCA-associated CrGN complicated with RA.

In November 2001, a 74-year-old Japanese woman was admitted to our hospital with persistent proteinuria and haematuria, and elevated MPO–ANCA titre. She had been diagnosed with RA in 1995, and treated with 5 mg of oral prednisolone (PSL) and 4 mg of MTX per week. On admission, the physical examination was normal, except for swollen and tender joints of both hands. Urinalysis showed 0.70 g proteinuria/24 h and several dysmorphic red cells and red cell casts. Haematological results indicated a white blood count of 9.9 × 109/l, haemoglobin 14.1 g/dl, platelet count 402 × 109/l. Serum creatinine was 0.7 mg/dl, CRP 1.7 mg/dl, ESR 52 mm/h, RF 17 U/ml (normal 0–10 U/ml), ACPA 54.3 U/ml (normal <4.5 U/ml), ANA 1 : 80, MPO–ANCA 56 EU (normal <20 EU). Serum immunoglobulin (Ig) G, IgA, IgM, CH50 and components of complement were normal. Investigations for cryoglobulinaemia and antibodies to ENA, dsDNA, GBM and proteinase 3 were negative. Chest X-ray and CT were normal.

A renal biopsy was performed. On light microscopy, 11 glomeruli were observed, of which 2 were sclerotic. Of the nine non-sclerotic glomeruli, four showed fibro-cellular crescentic formation and two showed cellular crescent with extensive necrosis and disruption of Bowman’s capsule (Fig. 1). IF microscopy showed negative staining in the glomeruli. Electron microscopy showed partial thickening of the basement membrane and partial subendothelial oedema of the glomerulus with no immune deposits. These results indicated MPO–ANCA-associated pauci-immune GN with necrotizing and crescentic formation complicated with RA.

Fig. 1

Light microscopy of renal biopsy shows cellular crescent with extensive necrosis and disruption of the Bowman’s capsule, indicating necrotizing and CrGN (periodic acid-Schiff stain; original magnification ×400).

Intravenous CYC (IVCY; 500 mg), followed by oral PSL at 30 mg/day was initiated. Within 1 month after the administration of IVCY and PSL, her disease activity improved, except for the persistent haematuria. However, her disease activity worsened gradually with tapering of the PSL to 7.5 mg/day during the 6 years of follow-up. The administration of tacrolimus (3 mg/day) failed to suppress her disease activity with exacerbation of the arthritis, elevated CRP level and MPO–ANCA titre, and increased haematuria. At this time, the CRP and MPO–ANCA titre were 2.5 mg/dl and 120 EU, respectively, and haematuria was >30 erythrocytes per high-power field. Then, in September 2008, the tacrolimus was ceased, and intravenous administration of tocilizumab was started at 8 mg/kg/month. After 3 weeks, her symptom of arthritis and CRP level, as well as the severe persistent haematuria, improved dramatically. We were also able to taper off the PSL within 6 months. At present, after 2 years, the RA remains in remission without any haematuria or proteinuria, and the patient is still being treated with tocilizumab at 8 mg/kg/month without any adverse effects. Interestingly, although the activity of MPO–ANCA-associated GN as indicated by the CRP level and haematuria has improved completely; only the serum MPO–ANCA titre still remains high.

RA is a chronic, systemic autoimmune disease characterized by inflammatory changes in joints, and sometimes involves extra-articular features, including vasculitis. Although rheumatoid vasculitis with usually severe systemic manifestations may occur in the course of RA, kidney involvement including crescentic necrotizing GN has rarely been reported [6]. Messiaen et al. [2] reported two patients with RA who developed necrotizing CrGN with high titres of anti-MPO antibodies in the absence of overt extra-renal vasculitis, and suggested it to be a RA-related complication. Some reports have indicated that serum TNF-α and serum IL-6 were also increased in patients with MPO–ANCA-associated CrGN, in the active stage, and correlated well with anti-MPO antibody titre [7]. Anti-MPO antibodies have been demonstrated to activate endothelial cells and stimulate the production of IL-6 by endothelial cells in vitro [8]. In the pathogenesis of MPO–ANCA-associated CrGN with RA, we speculate that anti-MPO antibodies induced by RA activate neutrophils and endothelial cells, stimulate the production of IL-6 and precipitate endothelial injury and activation, resulting in necrotizing and CrGN in patients with RA.

The therapeutic options for MPO–ANCA-associated CrGN complicated with RA include the administration of CSs, MTX and CYC [1], and plasmapheresis [3]. There have been some reports of the efficacy of anti-TNF agents in treating MPO–ANCA-associated CrGN with RA [4, 5]. Recently, tocilizumab has proved effective for the treatment of not only RA but also systemic rheumatoid vasculitis [9]. In the present case, the administration of tocilizumab, which directly inhibits IL-6, could suppress both the articular inflammation and endothelial injury of the glomerular capillaries, and consequently, improve the symptoms of both RA and CrGN, i.e. haematuria. The persistently high MPO–ANCA titre despite improvement of the CrGN may support the possible association between MPO–ANCA and the induction of IL-6, which is the downstream cytokine that is induced by MPO–ANCA in B lymphocytes. Our observations strongly suggest that tocilizumab is a safe and effective treatment in MPO–ANCA-associated CrGN complicated with RA and may be a new therapeutic option not only for MPO–ANCA-associated CrGN complicated with RA, but also for MPO–ANCA-associated CrGN.

Acknowledgements

Funding: This study was partially funded by the Okinaka Memorial Institute for Medical Research.

Disclosure statement: The authors have declared no conflicts of interest.

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