Female with rash, acute kidney failure and rheumatoid arthritisM Atlani1, P Gandhi2, H Gulwani3, S Kaur3
1 Department of Nephrology, Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India
2 Research in Medical Biotechnology, Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India
3 Department of Pathology, Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.101642
Source of Support: None, Conflict of Interest: None
This case describes a 42-year-old female with longstanding history of rheumatoid arthritis (RA) and Felty syndrome (FS). She presented with acute renal kidney failure, skin rash and hemoptysis. A clinical suspicion of small vessel vasculitis (SVV) was thought, serology was also positive for various markers of SVV. However, these serology markers could be false-positive in a patient of rheumatoid arthritis. A renal biopsy was performed that led to the final diagnosis of cryoglobulinemic vasculitis. Patient was managed according to the standard guidelines for therapy (plasmafiltration and immunosuppression). It is challenging to manage a patient of RA, in the presence of Felty syndrome-related granulocytopenia and thrombocytopenia. Patient initially showed signs of improvement, but finally succumbed to complications of therapy. The case provides insight into the diagnosis and management of such cases.
Keywords: Felty syndrome, cryoglobulinemia, small vessel vasculitis
Renal diseases in rheumatoid arthritis (RA) are not common. More often it develop as a complications of therapy. The most common forms of primary renal disease in RA are membranous glomerulonephropathy and a pure mesangial proliferative glomerulonephritis.  The case describes the diagnosis and management of a rather uncommon cause of renal disease in a patient of RA.
A 42-year-old female, a known case of rheumatoid arthritis (RA) for ten years was admitted with a history of passing reduced quantity of cola-colored urine for three days and anuria for one day, along with cough, shortness of breath and blood-mixed sputum. She had received various regimens of methotrexate, hydroxychloroquine and steroids for seven years, which she had stopped for the last two and a half years and was taking tramadol hydrochloride and paracetamol as and when required. There was no history of fever or drug intake in the recent past. She exhibited swan neck deformities of hands, pallor, and palpable purpuric rash over both lower limbs, bilaterally scattered crepts in the chest and splenomegaly.
On lab investigation she was found to have pancytopenia, deranged renal functions and 2+ proteinuria and active sediments in urine. Anti-neutrophilic cytoplasmic antibody-perinuclear (P-ANCA) and cryoglobulins in serum were found positive. Immunofixation showed cryoglobulins to be of mixed variety of Immunoglobulin M and G (IgM and IgG) with no prominent "M" band found on electrophoresis. Antibody against Hepatitis -C virus and its RNA (Anti-HCV and HCV RNA) were negative in serum. Rheumatoid factor (RA factor) and Antinuclear antibody (ANA) was positive; but ds-DNA (Double stranded DNA) was negative. She had hypo-complementemia also. Anti-glomerular basement membrane (Anti-GBM) antibody was negative. Prothrombin time and Partial thromboplstin time (PT and PTT)(Later also remained normal) were normal. Bone marrow biopsy did not reveal evidence of hematological malignancy. Upper gastrointestinal endoscopy did not show evidence of varices. Serial X-rays of chest revealed frequently changing fluffy shadows, suggestive of pulmonary hemorrhage. Her detailed clinical investigations are presented in [Table 1].
Provisional clinical diagnosis made was small-vessel vasculitis (SVV) mediated by either anti-neutrophilic cytoplasmic antibody or cryoglobulinemia or secondary to rheumatoid vasculitis itself, in presence of rheumatoid arthritis and Felty syndrome.
Empiric treatment was started and a diagnostic procedure was performed when the patient stabilized.
She was given one session of heparin-free hemodialysis and plasma filtration was initiated. Daily two liters of plasma was replaced with 5% albumin, normal saline (0.9%) and fresh frozen plasma in total, for seven days. Pulse of methylprednisolone was given (750 mg) for three days. It was followed by oral prednisolone (50 mg once daily with plan of weekly tapering of 10 mg/week). Cyclophosphamide could not be started in view of pancytopenia. With this treatment pulmonary hemorrhage resolved, rash and urine output improved and she became symptomatically better but she relapsed within three days of stopping plasma filtration.
Five more sessions of plasma filtration were given. Injection granulocyte colony stimulating factor (G-CSF) was administered, which resulted in surge of Total leucocyte count (TLC) to 54,000/mm 3 within a day and marginal increase in platelets. A pulse of cyclophosphamide (750 mg) was given simultaneously. TLC dropped to pretreatment levels within a week and injection G-CSF was repeated. After one month of treatment, patient's skin, pulmonary and renal manifestations remained in remission but platelet count dropped to 27,000/ mm 3 . She died of massive upper gastrointestinal (GI) bleed, possibly due to steroid-induced ulcer.
Renal disorders in RA occur either as a complication of therapy used in the treatment of RA, Non steroidal antiinflammatory drugs (NSAID), penicillamine, cyclosporine, analgesics, and gold); or are caused by the disease itself (glomerular lesions i.e. Mesangio proliferative Glomerulonephritis (GN)amyloidosis, vascular lesions and tubulointerstitial lesions.  Renal involvement in RA due to above causes occurs without systemic involvement. Penicillamine and gold causes nephrotic syndrome (membranous nephropathy) which usually recovers after withdrawal of these drugs. NSAIDS can cause nephrotic syndrome of minimal change variety along with interstitial nephritis, if in use for quite some time. However, the patient was not receiving any of these drugs. Among other renal lesions amyloidosis (AA) causes heavy proteinuria with bland urinary sediments and renal failure. Clinical presentation is one of longstanding RA, developing bilateral pitting edema and chronic kidney disease gradually. Other glomerular lesions can cause mild proteinuria and varying amounts of hematuria and pyuria.
This patient had rapidly progressively renal failure along with other systemic involvement. Renal involvement in RA along with systemic involvement could be a part of vasculitis. Vasculitis may be antineutrophil antibody-mediated or cryoglobulinemic or rheumatoid itself. ANCA could be false positive in patients with RA. Cytoplasmic antineutrophil (c-ANCA) antibodies have been suggested to occur in RA, especially in patients with longstanding disease, and p-ANCA in RA indicates severe disease with increased inflammatory activity.  Cases of ANCA-negative crescentic glomerulonephritis with systemic involvement have also been reported.  Therefore the mere presence of ANCA antibodies may not be the key factor in the pathogenesis of disease.
There was presence of Type-III polyclonal cryoglobulins (IgG and IgM mixed type) in the patient sera. Cryoglobulins are the single or mixed immunoglobulins that undergo reversible precipitation at low temperatures. This is an in vitro phenomenon, the actual mechanism(s) of cryoprecipitation remains obscure, it could be secondary to intrinsic characteristics of both mono- and polyclonal immunoglobulin (Ig) components; it can be caused as well by the interaction among single components of the cryoprecipitate. Cryoglobulinemia is usually classified into three subgroups according to Ig composition: Type I cryoglobulinemia is composed of only one isotype or subclass of immunoglobulin. Both Type II and Type III mixed cryoglobulins are immune complexes composed of polyclonal IgGs, the autoantigens, and mono- or polyclonal IgMs, respectively; the IgMs are the corresponding autoantibodies with rheumatoid factor (RF) activity.  Renal involvement due to cryoglobulins, in itself is very rare in patients with RA. It occurs when cryoglobulins form circulating immune complexes.  In a retrospective analysis across eight French centers, non-HCV-associated Type II Mixed cryoglobulinemia (MC) was found only in two cases of RA.  In another series where MC without evidence of hepatitis C virus infection was assessed, from 1980-2006, no case related to RA was found.  Clinically, isolated proteinuria and hematuria are more common than nephrotic syndrome, nephritic syndrome, or acute renal failure. Renal involvement is one of the most serious complications of cryoglobulinemia and typically manifests early in the course of the disease (within three to five years of diagnosis). Failure to treat may result in renal failure. 
Rheumatoid vasculitis, a severe necrotizing polyangiitis may sometimes complicate the course of longstanding RA but renal involvement (diffuse necrotizing glomerulonephritis) is less common in this form of vasculitis. Penicillamine is also known to cause systemic vasculitis in patients of RA, but our patient did not ever receive this drug. 
Patient had simultaneous presence of Felty syndrome-the triad of seropositive (Rheumatoid factor (RF)-positive) rheumatoid arthritis (RA), splenomegaly, and granulocytopenia.  Bone marrow examination had ruled out any possibility of malignancy.
Skin or renal biopsy may be helpful in confirming the cause. Renal biopsy has the advantage of suggesting renal prognosis and treatment aggressiveness, however, it is more invasive. Since the rash subsided with treatment and no fresh rash was available for biopsy, renal biopsy was done.
The recommended treatment for vasculitis with severe symptoms i.e. rapidly progressive renal failure and pulmonary symptoms is pulse methylprednisolone for three days followed by oral prednisolone with slow tapering over two to three months, along with cyclophosphamide and plasmapheresis.  In particular, both traditional plasma exchange and double-filtration plasma exchange are able to markedly reduce the levels of circulating immune-complex, especially the cryoglobulins. , Oral cyclophosphamide (50-100 mg/day for two to six weeks) during the tapering of aphaeretic sessions can reinforce the beneficial effect of plasma exchange; moreover, it can prevent the rebound phenomenon that may be observed after the discontinuation of aphaeresis.  Plasma exchange is particularly useful in severe MC complications such as active membranoproliferative glomerulonephritis. Rituximab, an anti-CD20+ B-cell monoclonal antibody therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients,  but reports related to its use in secondary cryoglobulinemia, other than HCV are not available.
The treatment for FS is not well established, only a small series of case reports suggest use of immunosuppressants like methotrexate, cyclophosphamide or rituximab. Repeated doses of G-CSF (Given above in text) at regular intervals have also been suggested to keep leukocyte counts at minimum desired level to avoid infections and prolong patient survival. , Anti-G-CSF autoantibodies are common in neutropenia due to FS. In individual patients, these autoantibodies have a neutralizing capacity. In patients without neutralizing antibodies, hyposensitivity of the myeloid cells to G-CSF appears to be central to the pathogenesis of neutropenia in FS.  G-CSF administration causes the maturation of immature WBC precursors in the bone marrow and rapid rise in TLC.
This patient relapsed within three days of stopping initial plasmapheresis of seven days, as cyclophosphamide was avoided due to granulocytopenia. More sessions of plasmapheresis and pulse of cyclophosphamide were administered under cover of G-CSF, to correct granulocytopenia secondary to Felty syndrome. All manifestations except thrombocytopenia remained under remission but she died of upper GI bleed.
Kidney biopsy [Figure 1] revealed 20 glomeruli. Most of these glomeruli were hypercellular [Figure 1]a and revealed increased mesangial cellularity with lobular accentuation. The mesangium and capillary spaces were infiltrated by polymorphonuclear cells and monocytes. There was reduplication of the capillary walls on silver-stained sections. Few of the glomeruli showed intracapillary cryoglobulinemic thrombi that were eosinophilic on hematoxylin-eosin stain [Figure 1]b and were also positive with Periodic acid-Schiff (PAS) [Figure 1]c and Congo red negative. Several hyaline thrombi were also noted in the glomerular capillary vessels that stained red on Masson's trichrome stain [Figure 1]d. Three glomeruli showed fibrocellular crescents and one of the glomeruli was sclerosed. The tubules were mostly unremarkable except for hyaline casts. Interstitum revealed chronic lymphomononuclear inflammatory cell infiltrate, no nodular infiltrate or granuloma was found. No significant vasculitis was noted among larger blood vessels. Immunofluorescence revealed subendothelial and intracapillary glomerular deposits of IgG, IgM and C3, and kappa light chains.
This patient had multisystem involvement secondary to small-vessel vasculitis. Chronic rheumatoid arthritis poses special difficulty with respect to diagnosis of the cause of small-vessel vasculitis, as several serum markers can turn out to be false positive (ANA, ANCA) because of increased inflammatory activity of the disease itself (RA). Kidney biopsy was suggestive of Membrano-proliferative glomerulonephritis (MPGN) Type 1 (double contours of glomerular basement membrane-"Tram tracks" on silver stains) which is almost always the renal lesion in mixed cryoglobulinemia.  It also showed intracapillary cryoglobulinemic thrombi, suggestive of cryoprecipitates. These cryoprecipitates appear as highly organized microtubular or finely fibrillar structure on electron microscopy, but because of non-availability of facility at the center it was not performed. Pathogenesis and microscopic features of cryoglobulinemic glomerulonephritis have been discussed in detail by D'Amico G and Fornasieri A.  No evidence of segmental or global glomerular necrotizing lesions was found, which is characteristic of renal lesion of ANCA-mediated small-vessel vasculitis. Immune deposits visible on immunofluorescence also ruled out paucimmune glomerulonephritis as a cause of renal lesion. Rheumatoid vasculitis, a severe necrotizing polyangiitis may sometimes complicate the course of longstanding rheumatoid arthritis, but renal involvement (diffuse necrotizing glomerulonephritis) is less common in this form of vasculitis and no evidence of the same was found.  Skin biopsy may also be helpful in diagnosis, but renal biopsy has the advantage of guiding treatment aggressiveness and assessing prognosis of renal disease also.
We conclude that kidney biopsy is very useful to confirm the cause of renal failure and small-vessel vasculitis (ANCA/Cryoglobulinemic/Rheumatoid) involving major organ systems in patients with rheumatoid arthritis. Use of cyclophosphamide may not be safe in the presence of Felty syndrome despite simultaneous use of G-CSF.