|Year : 2016 | Volume
| Issue : 3 | Page : 167-170
Uncommon clinical presentation of cryoglobulinemia vasculitis successfully treated with rituximab and mycophenolate mofetil
María Ahijón Lana1, Carmen De La Cruz Tapiador1, Lucio González Sanz2, Aurelio Hernández Laín3, Alejandro Jesús González Gutierrez1, Bárbara Gutierrez Ruano4, José Ramón Rodríguez Franco1
1 Department of Rheumatology, Central Defense University Hospital Gómez Ulla, Madrid, Spain
2 Department of Neurophysiology, Central Defense University Hospital Gómez Ulla, Madrid, Spain
3 Department of Pathology, University Hospital 12 de Octubre, Madrid, Spain
4 Department of Neurology, Central Defense University Hospital Gómez Ulla, Madrid, Spain
|Date of Web Publication||11-Aug-2016|
Dr. María Ahijón Lana
Glorieta del Ejercito, 1. 28047, Madrid
Source of Support: None, Conflict of Interest: None
We report the case of a 80-year-old woman with a severe mononeuritis multiplex over bilateral lower limb, with no other clinical signs or symptoms of vasculitis. Laboratory test showed elevated erythrocyte sedimentation rate and C reactive protein, low C4 levels, positive rheumatoid factor and polyclonal IgG and IgA cryoglobulins at a high cryocrit. Malignancies disorders and infectious diseases screening was negative. Nerve biopsy revealed signs of vasculitis with inflammatory infiltrate of epineural vessels, axonal degeneration and moderate loss of myelinated fibres. The diagnosis of essential mixed cryoglobulinemia vasculitis was established. She received treatment with plasmapheresis and high doses of steroids with progression of the symptoms to the upper limbs and persistence of positive cryoglobulins, low C4 levels and high acute phase reactants. She required treatment with rituximab and mycophenolate mofetil to control the disease. In conclusion we report an uncommon clinical presentation of a cryoglobulinemia vasculitis successfully treated with two B- cell depleting therapies.
Keywords: Cryoglobulinemia, mononeuritis multiplex, mycophenolate mofetil, rituximab
|How to cite this article:|
Lana MA, Tapiador CD, Sanz LG, Laín AH, González Gutierrez AJ, Ruano BG, Rodríguez Franco JR. Uncommon clinical presentation of cryoglobulinemia vasculitis successfully treated with rituximab and mycophenolate mofetil. Indian J Rheumatol 2016;11:167-70
|How to cite this URL:|
Lana MA, Tapiador CD, Sanz LG, Laín AH, González Gutierrez AJ, Ruano BG, Rodríguez Franco JR. Uncommon clinical presentation of cryoglobulinemia vasculitis successfully treated with rituximab and mycophenolate mofetil. Indian J Rheumatol [serial online] 2016 [cited 2018 Jan 22];11:167-70. Available from: http://www.indianjrheumatol.com/text.asp?2016/11/3/167/187416
| Introduction|| |
Cryoglobulins are circulating immunoglobulins that precipitate "in vitro0" at cold temperatures. Type I cryoglobulins are single monoclonal immunoglobulins, Types II and III are comprised different immunoglobulins, with a monoclonal and a polyclonal component in Type II, and only polyclonal immunoglobulins in Type III. Type II and III are often referred to as mixed cryoglobulinemia.
Cryoglobulins have been observed in a wide variety of diseases; Type I cryoglobulins are always linked to a B-cell lymphoproliferative disorder meanwhile mixed cryoglobulins are associated with connective tissue disease, malignant hematologic disorder, or infectious process. Hepatitis C virus infection represents the main cause of mixed cryoglobulinemia. In the absence of a demonstrable underlying disease, the condition is called essential cryoglobulinemia. ,
Cryoglobulinemia can cause a small vessel vasculitis involving the skin, the joints, the peripheral nerve system, and the kidneys. The most frequently reported neurologic manifestation is a distal sensory or sensory-motor polyneuropathy. ,,
We report a patient who presented a mononeuritis multiplex as the first and unique manifestation of a cryoglobulinemia vasculitis (CV) and who received treatment with rituximab (RTX) and mycophenolate mofetil (MMF) with good response.
| Case Report|| |
An 80-year-old woman was admitted at the emergency department with a distal lower limb weakness in form of bilateral foot drop. The symptoms started 6 days back when she had a fall related to weakness in her left ankle. She had a history of iron-deficiency anemia, hyporexia, and weight loss in the previous 4 months with normal endoscopy study, and osteoporotic vertebral fractures in treatment with denosumab and oral supplementation with calcium and Vitamin D.
She had no previous history of fever, Raynaud's phenomenon, skin lesions, chest or abdominal pain, oliguria, joint pain, or arthritis.
Neurological examination revealed a strength weakness in tibialis anterior graded two and extensor hallucis longus graded three on the Medical Research Council scale bilaterally, paresthesias and hypoesthesia with stocking-distribution and the absence of tendon reflexes over both ankles.
Cerebrospinal fluid examination (including bacterial culture and cytology) was normal. Laboratory studies were performed including complete blood count, erythrocyte sedimentation rate (ESR), concentrations of electrolytes, C-reactive protein (CRP), thyroid-stimulating hormone, antithyroid antibodies, serum Vitamin B12 and folate, hepatic enzymes, creatinine, urinalysis, protein electrophoresis and immunofixation in serum and urine, rheumatoid factor (RF), antinuclear antibodies (ANA), antiextractible nuclear antigens, anti-DNA antibodies, antineutrophil cytoplasmic antibodies, Cryoglobulins, C3 and C4 levels, and malignancies disorders screening. Results revealed microcytic and hypochromic anemia (hemoglobin 11.3 g/dL), elevated ESR (71 mm/h) and CRP (5.17 mg/dL, normal value < 0.5 mg/dL), low C4 levels (1.93 mg/dL) with normal C3 levels, and positive RF (347 U/mL) and positive cryoglobulins comprised polyclonal IgG and IgA (cryocrit 20%). Serologic test for hepatitis B virus and HCV, HIV, and syphilis were negative. Mantoux and booster were negative. Total body CT showed a mild splenomegaly with no evidence of malignancy.
Electrodiagnostic studies were consistent with a severe sensory-motor peripheral polyneuropathy of the lower limb. Peroneal nerve motor and sensory amplitudes were absent bilaterally; motor amplitudes were also reduced on bilateral posterior tibial nerve. Electromyography (EMG) showed denervation in L5 myotome muscles bilaterally.
Sural nerve biopsy was performed demonstrating signs of vasculitis with transmural inflammatory infiltrate of epineurial vessels consisting mainly of CD45+ lymphocytes [Figure 1], with signs of acute-subacute axonal degeneration with endoneurial macrophage infiltration and moderate to severe loss of myelinated fibers [Figure 2]. Epineurial vessels showed fibrous thickening and signs of recanalization [Figure 3].
|Figure 1: Sural nerve biopsy. Transmural inflammatory infiltrate of epineurial vessels (blue arrow) (H and E, ×10)|
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|Figure 2: Sural nerve biopsy. Transverse semi-thin plastic sections (×40). The blue arrows point the few remaining myelinated fibers|
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|Figure 3: Sural nerve biopsy. Epineurial vessels showed fibrous thickening (blue arrow) and signs of recanalization (red arrow) (Gomori trichrome, ×40)|
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The diagnosis of essential mixed cryoglubulinemic vasculitis was established. The patient was treated with five sessions of plasmapheresis, five intravenous pulses of methylprednisolone, and oral prednisone at doses of 1 mg/kg with persisting hypocomplementemia, high ESR and CRP and progression of the symptoms to the upper limbs with distal weakness, paresthesias, and hypoesthesia with glove-distribution. Muscle power was grade 5/5 in biceps, triceps, and deltoids, 4/5 in fingers and wrist flexors, 2/5 in the interosseous of the right hand, and 4/5 in the interosseous of the left hand.
Nerve conduction study was repeated showing diminished change in the muscle electrical response amplitude on right sided ulnar and median nerve, and absent motor amplitudes of posterior tibial never in the left side [Figure 4]. Sural nerve sensory and peroneal nerve sensory-motor amplitudes were absent bilaterally. EMG showed denervation of the interosseous muscles [Figure 4].
|Figure 4: Second electrophysiological examination: a absent motor amplitudes of posterior tibial nerve in the left side and b acute denervation of right sided first interosseous muscle with fibrillations potentials and positive sharp waves|
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Accordingly, with the findings of this second electrodiagnostic study, the clinical scenario was considered to be severe sensory-motor mononeuritis multiplex.
She received treatment with RTX (4 weekly doses of 375 mg/m 2 ) and after oral MMF (2 g/day). Six months after the treatment, there is no progression of the symptoms, and laboratory test shows negative cryoglobulins and normal values of acute phase reactants and complement. EMG was repeated showing a slight improvement with an increase of the motor amplitudes on right-sided median nerve and signs of reinnervation on the lower limbs.
| Discussion|| |
Elevated cryoglobulin levels can remain asymptomatic or cause an immune-complex mediated systemic vasculitis mainly affecting the small vessels. Different studies have found a prevalence of vasculitic symptoms in 30-50% of patients, mainly women, which have been related to the presence of high cryocrit levels (>5%), association with a systemic autoimmune disease, hypocomplementemia, positive RF, and ANA.  At onset, cutaneous involvement occurs in 70-90% of patients, arthralgias in 40-60%, renal involvement in 20-35%, and peripheral neuropathy in 60-70%. Other clinical manifestations as central nervous system involvement, mesenteric vasculitis, pulmonary or cardiac involvement are rare (<5%). Peripheral neuropathy is more common in patients with mixed cryoglobulinemia and the clinical manifestations range from distal sensory or sensory-motor polyneuropathy to mononeuritis multiplex. ,, Some studies have found a correlation between the immunological markers and pattern and severity of clinical features. The presence of high RF reactivity and low C4 levels has been associated with peripheral neuropathy, and the presence of high cryocrit levels (>5%) has been associated with mononeuritis multiplex. ,
Our patient presented with a mononeuritis multiplex in the context of an essential mixed cryoglobulinemia, interestingly other vasculitic symptoms were absent. Gemignani et al. found positive cryoglobulins in 11 patients out of 100 patients with uncharacterized peripheral neuropathy. Skin manifestations were absent in four patient. The most frequent manifestation was a sensory polyneuropathy, none of them had a mononeuritis multiplex. 
There are paucity data available regarding the treatment of patients with cryoglobulinemic vasculitis. The results from the French Autoimmunity and RTX Registry reported a dramatic efficacy and steroid-sparing effect of RTX in 23 patients with nonviral CV, but an increased rate of severe infections was revealed in the safety analysis.  These results were confirmed in 2012 when data from 242 patients with nonviral mixed cryoglobulinemia were published.  A randomized controlled trial was conducted in 2012 comparing RTX to conventional treatment (glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) in 59 patients with severe mixed viral and nonviral CV. In this study, monotherapy with RTX showed to be superior therapy for severe CV. 
Due to the increased risk of infections in this patient because of her age and the use of high doses of steroids, we decided to avoid RTX as maintenance therapy. MMF is another B-cell depleting therapy and has shown satisfactory effects on CV related to hepatitis C infection. 
In conclusion, we present a case of CV with an unusual clinical presentation, which required aggressive treatment to control the disease and finally responded to the combination of two B-cell depleting therapies.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]