Focal segmental glomerulosclerosis lagged behind the onset of rheumatoid arthritis by 7 years: A case report and literature review.

INTRODUCTION: The co-existence of focal segmental glomerulosclerosis (FSGS) and rheumatoid arthritis (RA), presenting either together or in succession, is very rare. A variety of histopathological features in the clinical renal disease may occur in RA. Only 8 studies have previously reported this poorly understood connection. CLINICAL FINDINGS/DIAGNOSES: A case of a 54-year-old male with RA lasting for more than 7 years developed cheirarthritis as the first signs. Symmetric polyarthralgia and multiple swollen joints throughout the body were followed, accompanied with morning stiffness. Gradually, he suffered from albuminuria, hypoalbuminemia, edema, and hyperlipidemia in 2014. The patient had the history of administering loxoprofen, celecoxib, leflunomide, and methotrexate. He was diagnosed as RA, nephrotic syndrome. Renal biopsy confirmed FSGS.
CONCLUSION: Our case and the review of the literature indicate that FSGS is one of the causes of nephrotic syndrome in RA. It strongly suggested that RA patients with the abnormal kidney functions should be routinely screened for FSGS to guide the therapy, achieve both RA and FSGS remission, determine a prognosis, and avoid end-stage renal lesion.

Introduction

A variety of histopathological features in the clinical renal disease may occur in rheumatoid arthritis (RA). Main histology patterns in RA are amyloidosis, papillary necrosis, chronic interstitial nephritis, vasculitis, and capillary proliferative glomerulonephritis.[ In addition, a few rare types are also found in RA, including focal segmental glomerulosclerosis (FSGS). These renal changes have been considered to be mediated by an immunological and inflammatory procedures and/or by nephrotoxic effects of numerous drugs usually used in RA treatment, such as non-steroidal anti-inflammatory drugs (NSAID) and disease-modifying anti-rheumatic drugs (DMARD).[

FSGS is a cause of nephrotic syndrome and can lead to global sclerosis. In FSGS, the scarring occurs only in some of the glomeruli. Only part of glomeruli is damaged which can lead to kidney failure. FSGS has been reported in the patients with RA. However, FSGS and RA occur infrequently in the same patient and the association between them remains obscure.[ The current study describes a confirmed case of RA in a patient diagnosed with FSGS on renal biopsy. A review of English literature has revealed and a correlation between RA and FSGS may be present, although pathogenic mechanisms are not fully elucidated.

Case report

A 54-year-old male presented to our department with arthritis, involving multiple joints. His symptoms started in 2007. When he first developed spontaneous arthritis of third proximal interphalangeal (PIP) joint, presented with painful swelling, accompanied by morning stiffness lasting for hours and relieved by warmth and activity. In July 2012, the above-mentioned symptoms were aggravated. Multiple arthralgia and swollen joints involved in bilateral PIP joints, wrists, elbows, knees, and ankles joints, along with a limited range of motion. He visited our hospital and was diagnosed as RA. The symptoms were relieved after starting on treatment with corticosteroids, NSAIDs (loxoprofen, celecoxib), and immunosuppressive agents (methotrexate, leflunomide). Having outpatient review and treatment regularly in our hospital, his condition was stable. At the beginning of 2015, he suffered from nontender subcutaneous nodules on the left forearm. The nodule could disappear with injection of corticosteroids. The symptoms appeared repeatedly but he paid no attention to it. Since then, he followed up with his rheumatologist intermittently. He is currently on medication with prednisone (5 mg/d), NSAID, and methotrexate (15 mg /w). During the course of disease, there was no xerostomia, xerophthalmia, rampant tooth, recurrent oral or genital ulcers, hair loss, photosensitivity, rashes, Raynaud's phenomenon, lower back pain, or talalgia. Particularly, proteinuria was present. He did not have any nocturia, oliguria, pollakisuria, urgent urination, odynuria, or gross hematuria. Defecation was normal. His body weight did not change obviously.

In mid-November 2015, the patient presented to our department of rheumatology with the complaints of the swelling and pain of multiple joints and edema of bilateral lower limbs. There were no symptoms in the respiratory, cardiovascular, and gastrointestinal systems. On examination, nontender subcutaneous nodules measuring 2 × 1.5 cm (rheumatoid nodule confirmed) over the extensor surface on the left forearm with no limitation of range of motion. Tenderness and swelling of the second and third PIP joints of right hand, the third PIP joints of left hand, bilateral knees, wrists, shoulders, and ankles were present. Pitting edema was present in the lower limbs, and bilateral palpebral edema was also present. The laboratory examination showed as follows: erythrocyte sedimentation rate 88.00 mm/h, C-reactive protein 18.8 mg/L, purified protein derivative test, tuberculosis antibody or T-cell spot test were negative, 24 hours urine protein 12.56 g/24 h, albumin 18.30 g/L (normal>40 g/L), serum total cholesterol 12 mmol/L (normal<5.7 mmol/L), triglyceride 2.37 mmol/L (normal<1.7 mmol/L), creatinine 82 μmmol/L, rheumatoid factor 1280 Iu/mL, antiperinuclear factor 1:80, antikeratin antibody 1:80, anticyclic cirullinated peptide antibodies 826.2 RU/mL, human leucocyte elastase +, anti-SSA, anti-SSB, anti-SM, anti-RNP, anti-Jo1, anti-Scl70, anti-double-stranded deoxyribonucleic acid, cytoplasmic antineutrophil cytoplasmic antibody (ANCA), perinuclear ANCA, protease-3, myeloperoxidase, anti-mitochondrial antibody, and human leukocyte antigen-B27 were normal or negative.

Renal biopsy revealed glomeruli with segmental sclerosing lesions. The electrolyte microscope showed no electron-dense deposits and only visceral epithelial cell foot process effacement (Fig. 1). To stop the progressing of disease, we used methyprednisolone160 mg/4 days, human albumin 20 mg/5 days, prednisone acetate15 mg /QD, celecoxib200 mg/BID, leflunomide10 mg/QD, and other symptomatic treatment. After intensive treatment proteinuria level dropped to 7.2 g/24 h, serum albumin levels were increased to 24.9 g/L, renal function gradually returned to normal, and the patient was discharged in a stable condition.

Figure 1

Renal biopsy shows the pathological alteration of FSGS (indicated by arrows) Light microscope: glomeruli with segmental sclerosing lesions ((a) hematoxylin–eosin stain; (b) masson stain; (c) periodic acid-Schiff stain; (d) periodic acid-silver methenamine stain, ×200 magnification). Immunofluorescent staining shows no immune-type deposits. Electrolyte microscope (e, f): no electron-dense deposits and only visceral epithelial cell foot process effacement. FSGS = focal segmental glomerulosclerosis.

This case report has been approved by the Ethics Committee of the Second Hospital of Shanxi Medical University and got the written consent of the patient.

Discussion

RA is a systemic disease involving multiple arthritis and synovitis, but also vasculitis may be present and cause extra-articular manifestations. In our patient, the presence of nephritic syndrome could be either due to previous medication with NSAIDs or associated with RA. There were no clinical or laboratory findings of vasculitis in our patient, and this could easily rule out the possibility of vasculitis involvement of kidneys. Dutta and Khan[ described a patient with RA, in whom renal biopsy revealed FSGS. She denied the history of taking drugs usually responsible for glomerulonephritis and her FSGS was concluded to be a direct manifestation of RA. However, another patient with RA who developed FSGS had been received regular treatment with NSAID, prednisolone, and D-penicillamine with improvement of the RA.[ Just the same to our patient sharing a common history of risk factors associated with FSGS. They did not exclude the possibility that the FSGS was due to NSAID, prednisolone, or D-penicillamine. NSAID,[ penicillamine,[ or gold[ therapy has been reported to be complicated by FSGS. FSGS as a manifestation of RA patients has rarely been reported which summarized in Table 1. These results indicate a deleterious role of FSGS model with RA and suggest a possible cross-talk between them in the progression of disease.[

Table 1

Major characteristics of FSGS patients with RA in published studies.

Moreover, the review literature did not mention any correlation between RA disease activity and the manifestation of FSGS. In our case, our patient was in remission with DAS 28 decreasing from 5.62 to 3.49, proteinuria from 12.56 g/24 h to 7.272 g/24 h, and albumin increasing from 18.3 g/L to 24.9 g/L. The above-information might suggest that RA disease activity had positive relation to the manifestation of FSGS. May be the correlation is most likely due to similar pathological mechanisms that FSGS is a predominantly T-cell mediated disease, which is also true in RA.

Our patient had a confirmed diagnosis of FSGS after the onset of RA with the history of administering loxoprofen, celecoxib, methotremate, and leflunomide. However, there are no evidences that indicate above drugs are associated with the development of FSGS. On the other hand, some other studies have reported that FSGS was detected in RA patients, suggesting that pathologic changes in RA may relate to the development of FSGS. FSGS and RA can share common pathogenic mechanisms. Primary FSGS is predominantly a T-cell-mediated disease, a small body of data points to the role of B-cell dysregulation in the pathogenesis of the disease. RA is characterized by immunologic derangement of T-cells and B-cells, with the production of autoantibodies and cytokines. Circulating permeability factors produced by T- and B-cells, such as glomerular IgM, deposited complement proteins, and that complement fragments co-localize in the glomeruli of patients with FSGS, are in their activated form.[ Thus, FSGS causes nephrotic syndromes in adults and is constantly linked to immunomediated mechanisms.[

Conclusion

Although we cannot entirely rule out the possibility that the FSGS in our patient may be due to the use of NSAIDs or other approaches prior to the patient coming under our care, the role of RA as a causal factor of the renal lesion should also be strongly considered. FSGS is one of the causes of nephrotic syndrome in RA.

Acknowledgment

The authors thank Dr Chong GAO for reviewing the manuscript.