Proliferative Diffuse Glomerulonephritis in Rheumatoid Arthritis

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To the Editor:
Presently, it is considered that patients with rheumatoid arthritis (RA) do not present with well-defined, characteristic renal lesions. The renal lesions observed in them tend to be due to either the medication (non-steroidal anti-inflammatory drugs, gold salts, or D-penicillamine) or amyloidosis.1
In February 2009, a 34-year-old woman with a 9-year history of seropositive RA presented to the hospital with 3+ pretibial pitting edema, metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint synovitis in both hands, and normal blood pressure (120/80 mm Hg). Complete blood counts, and hepatic and renal function, were unremarkable. Serum electrophoresis showed polyclonal hypergammaglobulinemia. Urinalysis revealed 4+ protein, blood cells, and hyaline casts. The 24-hour proteinuria was 5 g/day. Immunology tests evidenced positive anti-cyclic citrullinated antibodies (anti-CCP) at levels of 39 U/mL (normal, ≤5 U/mL), C3 at levels of 92 mg/dL (normal, 90–180), and C4 at levels of 17 mg/dL (normal, 10–40). Test results for antinuclear antibodies (ANA) HEp-2, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, cryoglobulins and ANCA were negative. Serology for hepatitis B and C virus, and HIV were negative. At that time, the patient was being treated with methotrexate (MTX 15 mg/week), folic acid (5 mg/week), prednisone (5 mg/day), and ibuprofen (400 mg/day). Previously, she had received hydroxychloroquine which was changed to MTX as a result of persistent disease activity.
Renal ultrasonography and biopsy of the abdominal fat were normal.
Renal biopsy revealed diffuse proliferative glomerulonephritis without histological evidence of interstitial nephritis or amyloidosis (lightly eosinophilic extracellular amorphous material on hematoxylin–eosin and or periodic acid-Schiff stainings). Immunofluorescence showed diffuse granular deposits of IgM (+++), IgG (+), C1Q (++), and IgA (dispersed deposits of slight intensity) in the mesangium and glomerular basement membrane (Fig. 1A, B).
The patient was treated with methylprednisolone (1 g/day) for three consecutive days, followed by prednisone (40 mg/day) and cyclophosphamide (1 g/m2/month) for 6 months, while MTX was discontinued. After six pulses of cyclophosphamide, the 24-hour proteinuria was negative and treatment was switched to azathioprine (100 mg/day).
Two years later, the patient returned with a polyarticular flare, accompanied by morning stiffness for 2 hours. Thus, treatment with MTX (15 mg/week) and folic acid (5 mg/week) was restarted.
In August 2016, 5 years after the last flare-up, the patient was stable with low activity of RA (DAS 28:3.18), and was receiving treatment (MTX 20 mg/week and leflunomide 20 mg/day). Laboratory test results were remarkable for anti-CCP antibodies 54 U/mL (normal values ≤ 5); and negative for ANA (HEp-2), anti-dsDNA, and ENA. Serology for hepatitis B and C viruses and for HIV was negative. The 24-hour proteinuria continued to be negative and renal function was normal.
Mesangial glomerulonephritis is usually the most common histological form in patients with RA who have renal dysfunction and/or urinary alterations (proteinuria and/or hematuria).2,3
However, necropsy studies have shown that the most common renal lesion is nephrosclerosis.4 On the other hand, amyloidosis continues to be a frequent manifestation in these patients,5 which was ruled out in our patient because this alteration was not observed in the biopsy of abdominal fat or the renal biopsy.
In the few reported cases of diffuse proliferative glomerulonephritis in patients with RA, this was associated with vasculitis and the use of gold salts.4
However, our patient never received gold salts nor had signs or symptoms of vasculitis.
More recently, biological drugs such as TNF-alpha inhibitors, tocilizumab, and abatacept, have been associated with the development of renal manifestations6; medications that were not used in this case.
Some reports suggest that anti-CCP antibodies are associated with erosive arthritis in patients with SLE,7 in which diffuse proliferative glomerulonephritis is a frequent renal manifestation; however, our patient did not have clinical or autoantibodies compatible with SLE.

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