Diffuse mesangial IgA glomerulonephritis in a patient with rheumatoid arthritis: a possible extra-articular manifestation in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an inflammatory joint disease, in which, unlike systemic lupus erythematosus (SLE), renal involvement is uncommon. The major causes of renal disease in RA are usually linked to amyloid or secondary effects of drugs. Nevertheless the relation between IgA, IgA-rheumatoid factor (RF) and renal disease in patients with RA is not clear, but the affinity of IgA for mesangium, skin and synovium might explain clinical presentation of RA with mesangial IgA glomerulonephritis. The case of a 42-year-old Caucasian man with RA and diffuse mesangial IgA glomerulonephritis proven by renal biopsy is presented. The patient was treated with boluses of methylprednisolone 1000 mg and cyclophosphamide 1000 mg monthly for 13 months. Between boluses there was a supported therapy with methylprednisolone 8 mg/day. After a year of treatment full clinical and laboratory remission of RA and IgA glomerulonephritis was achieved. Pathogenic therapy will be stopped and the patient followed-up.

BACKGROUND

Usually renal complications in rheumatoid arthritis (RA) are due to the treatment with different antirheumatic drugs, preliminary non-steroidal anti-inflammatory drugs (NSAIDs) as well as to amyloidosis as a result to long-lasting disease. There may be affinity of IgA and IgM-rheumatoid factor (RF) for mesangium, which might explain clinical presentation of RA with mesangial IgA or IgM glomerulonephritis.

CASE PRESENTATION

A 42-year-old man was admitted to the rheumatology clinic with very active and aggressive RA of the hands, elbows, knees and shoulders, with morning stiffness lasting several hours. RA was proven according to American College of Rheumatology (ACR) criteria. The patient had deteriorating renal function with creatinine levels rising from 86 to 159 μmol/litre within a couple of weeks and urine protein loss of 1 g/24 h. He had arterial hypertension up to 140/100 mm Hg. Vasculitis complicating RA was diagnosed based upon the clinical picture and laboratory data. Based on that, treatment with pulse methylprednisolone and cyclophosphamide (as in the protocol for systemic lupus erythematosus (SLE)) was started, with methylprednisolone at 8 mg/day inbetween.

A renal biopsy was performed. It showed 15 glomeruli, 8 of which were sclerotic. In the mesangium there was increased matrix substance, with mesangial cell proliferation in some places that was more prominent in some segments. Some of the glomeruli had segmental sclerosis and hyalinosis of capillary loops. The basal membranes of the glomeruli outside the sclerotic segments did not show any changes. The majority of the interstitium was fibrotic with mononuclear cell infiltration. In the tubular system there were groups of atrophic ducts. Some arterial vessels had thickened walls (fig 1). Immunofluorescence revealed 4+ mesangial deposits of IgA and 4+ deposits of C3 in the glomeruli and arterial walls (fig 2). The intensity of mesangial IgA deposits correlated with the severity of disease, but not with the serum IgA-RF.

Figure 1.

Increased matrix substance in the mesangium, with mesangial cell proliferation.

Figure 2.

Mesangial deposits of IgA and C3 in the glomeruli and arterial walls.

The above-mentioned treatment was continued for 13 months, based on a clinical picture of aggressive RA complicated by deteriorating renal function as a result of diffuse mesangial IgA nephritis. After the treatment, at follow-up the patient had no proteinuria and the creatinine level was 73 μmol/litre; arthritis is in remission and the corticosteroid used between pulses was tapered to 4 mg/day, with a trend to stopping it on the basis of use of steroid-sparing drugs.

INVESTIGATIONS

Laboratory data revealed elevated an erythrocyte sedimentation rate (ESR) of 100 mm/h, anaemia (haemoglobin (Hb)=99 g/litre), creatinine 86 μmol/litre increasing to 159 μmol/litre (73 μmol/litre at follow-up after treatment), proteinuria 1 g/24 h, 30–40 erythrocytes, granular casts. There was no elevation of serum rheumatoid factors (IgM, IgA, IgG).

DIFFERENTIAL DIAGNOSIS

Idiopathic IgA glomerulonephritis, amyloidosis in RA, glomerulonephritis in SLE.

TREATMENT

Boluses of methylprednisolone 1000 mg and cyclophosphamide 1000 mg were administered monthly for 13 months. Between boluses there was a supported therapy with methylprednisolone 8 mg/day.

OUTCOME AND FOLLOW-UP

After a year of treatment the patient achieved full clinical and laboratory remission. There are no symptoms and signs of RA and IgA glomerulonephritis in the patient at present. The pathogenic therapy was stopped and the patient was followed-up (creatinine 73 μmol/litre, no proteinuria, erythrocytes and granular casts in the urine sediment at follow-up). The aggressive therapy was stopped, the maintaining daily corticosteroid was tapered to 4 mg/day, with a trend to stopping it with the use of steroid-sparing drugs. We believe that the aggressive pathogenic treatment is suitable for such complicated cases and does not allow dilating progression of both diseases, especially of renal failure. We have ensured an illness free period for our patient.

DISCUSSION

RA is an autoimmune inflammatory joint disease, in which, unlike SLE, renal involvement is uncommon. The major causes of renal disease in RA are usually linked to amyloid or secondary effects of drugs. A total of 26% of all biopsied glomerulonephritides in the Bulgarian population have IgA nephritis.¹ We have no data about the frequency of nephritides, including IgA nephritis among patients in the Bulgarian population who are rheumatic.

Nevertheless, the study of Korpela et al shows that mesangial glomerulonephritis (MesGN) has been a frequent renal finding in patients with RA presenting with haematuria and/or proteinuria.²

The relation between IgA, IgA-RF and renal disease in patients with RA is not clear, but the affinity of IgA for mesangium, skin and synovium might explain the clinical presentation of RA with mesangial IgA glomerulonephritis.^3–5 A similar association was also noted in a patient with Henoch–Schonlein purpura and ankylosing spondylitis with IgA nephropathy. Pollet et al⁶ described a striking association of IgM-RF with MesGN. They suggested that a functional response by the renal mesangium to remove IgM-RF–IgG complexes could lead to these mesangial lesions. The results from clinical follow-up studies^7,8 and the clinicopathological correlations in the renal biopsy material of 110 and 158 patients with RA^9,10 suggest that MesGN is probably related to RA itself. Clinicopathological correlations and association with RF imply that MesGN represents an extra-articular manifestation of the basic rheumatoid disease. Patients with RA presenting with haematuria and/or proteinuria have to undergo renal biopsy. Early aggressive RA itself requires methotrexate at a dose of 10–15 mg/weekly (if there is no other organ involvement; kidneys, liver, lungs etc) together with corticosteroids 6–8 mg/day as a bridge therapy. If there is no response to methotrexate, biological treatment (anti-tumour necrosis factor (TNF)α or rituximab) is added. In our patient RA was aggressive and with deteriorating renal function as a result of IgA nephritis from the very beginning. In this case it is contraindicated to use methotrexate or any other disease-modifying antirheumatic drug (DMARD), or any biological treatment. For that reason the treatment of choice was pulse methylprednisolone combined with pulse cyclophosphamide.

There are no guidelines, but a multitude of tested therapeutic schemes for the treatment of IgA nephritis. It is accepted to use more aggressive pathogenic therapeutic schemes, including cyclophosphamide, with deteriorating renal function.^11–13 For the past 20 years we have used pulse therapy with cyclophosphamide without serious side effects. The treatment is according to the generally accepted schemes in the world, following the safety regulations (enough water/solution supplies) and strict clinical and laboratory control.¹³ The great success in our patient is not only the clinical and laboratory remission of both diseases, but in restoring the normal renal function, which has already been retained for 2 years.¹⁴

LEARNING POINTS

• Rheumatoid arthritis (RA) can affect the renal glomeruli as a mesangial IgA glomerulonephritis, because of the affinity of IgA-rheumatoid factor (RF) to mesangium.

• Patients with RA, proteinuria and haematuria must undergo renal biopsy, because of the suspicion of IgA or IgM glomerulonephritis.

• IgA nephropathy itself principally does not necessitate aggressive cytotoxic treatment.

• More aggressive cytotoxic plus methylprednisolone therapy, including IgA, is aimed at RA when it is complicated by nephritis with deteriorating renal function.