Rheumatoid arthritis and PLA2R-associated mebranous nephropathy. Cause or coincidence?

Abstract

Key clinical message: The coexistence of rheumatoid arthritis (RA) and PLA2R-associated membranous nephropathy (MN) is uncommon. It is difficult to demonstrate whether the mechanisms of renal pathology are triggered by RA, but it has been observed that the pro-inflammatory molecules present in RA increase the expression of PLA2R. Rituximab could be effective in both conditions.

Abstract: RA affects 0.5% of adults in our country. It is an inflammatory disease that predominantly affects the joints causing destruction of the articular cartilage. Approximately 50% of patients present extra-articular manifestations. Renal involvement is relatively frequent and clinically significant because it worsens the course and mortality of the primary disease. The histological renal damage observed in these patients includes a wide variety of entities and histological patterns with both glomerular and tubulointerstitial involvement, with secondary MN being one of the most frequent. Coexistence with primary MN is rare. We present the case of a 46-year-old male recently diagnosed with RA who was referred to the nephrology department for renal function deterioration and subnephrotic proteinuria. The autoimmune study showed positive anti-PLA2R. Due to the unusual association between both entities, it was decided to perform a renal biopsy which showed abundant spikes. The immunofluorescence study showed contiguous parietal IgG positivity (3+). Immunohistochemistry showed positive granular IgG4, confirming the diagnosis of PLA2R-associated MN. MN is one of the most common causes of nephrotic syndrome in adults. The determination of anti-PLA2R has been a great advance in the rapid differential diagnosis of MN. In recent years, new target antigens associated with certain underlying pathologies have been discovered. However, PLA2R is not associated with any disease or exposure and therefore remains the antigen responsible for 80% of primary NMs. Anti-PLA2R antibodies can be produced by loss of central or peripheral tolerance. Whether these mechanisms are triggered by RA itself is difficult to prove. The cytokine TNF-like weak inducer of apoptosis (TWEAK) has been associated with RA. This proinflammatory molecule increases the expression of PLA2R in podocytes, sensitizing them to the damaging action of anti-PLA2Rs, which could justify a causal relationship between the two pathologies. The anti-PLA2R positivity in a patient with membranous nephropathy should not be sufficient to refrain from searching for a secondary cause, as a kidney biopsy is mandatory when another underlying disease coexists. Treatment should be tailored to the individual risk profile for progression. Rituximab could be an optimal option for both entities.

Keywords: positive antiPLA2R; primary membranous nephropathy; rheumatoid arthritis; weak apoptosis‐inducing TNF‐like (TWEAK).