Cutaneous ulcers with type I cryoglobulinemia treated with plasmapheresis

ARTICLE

Auteur(s) : A.T. VILA, M.A. BARNADAS, J. BALLARÍN***, R. GARCÍA***, C. JUAREZ**, P. MADOZ*, E. RAMILA*, A. ALOMAR

Departments of Dermatology, Hemotherapy*, and Immunology**. Hospital de la Santa Creu i Sant Pau. 
Department of Nephrology***. Fundació Puigvert. Sant Antoni M^a Claret, 167, 08025 Barcelona. Spain

Article accepted 16/12/2003

Plasmapheresis has been successfully used to treat several dermatological diseases such as pemphigus vulgaris [1], bullous and cicatricial pemphigoid [1], scleromyxedema [2] and cryoglobulinemia [3-10].
We present a case of recalcitrant cutaneous ulcers associated with renal failure in cryoglobulinemia type I that improved with plasmapheresis associated to immunosuppressive agents.

Case report

In April 1999 a 72-year-old male was referred to the Department of Dermatology because of a flare of purpuric lesions. Past medical history included non-insulin-dependent diabetes mellitus, hypercholesterolemia and bronchiectasis.
Physical examination revealed a generalised eruption mainly located on the acral areas: ears (Fig. 1), elbows, hands, buttocks, knees and feet. The lesions consisted of livedoid purpuric papules and plaques, some of which were necrotic.
Histopathologic examination of two cutaneous lesions showed hemorrhage. In one biopsy fibrin deposits in the vessel walls were accompanied by a scarce neutrophilic infiltrate with leukocytoclasia (Fig. 2a). In the other biopsy intravascular thrombi were observed (Fig. 2b). A direct immunofluorescence (DIF) test of lesional skin showed intense deposits of IgG (Fig. 3a), C3 and fibrinogen, and weak deposits of IgA, IgM and C1q on the superficial and deep dermal vessels. DIF with anti-kappa (Fig. 3b) was also very intense at the same level whereas with anti-lambda it was very weak.
Results of laboratory tests showed the following abnormal values: hemoglobin 112 g L^-1 (normal 135-170), white blood cells 3.24 × 10⁹ L^-1 (normal 3.8-11), lymphocytes 0.68 × 10⁹ L^-1 (normal 1-4), glucose 7.9 mmol L^-1 (normal 4.7-6), total serum protein 50.7g L^-1 (normal 69-74), albumin 25.8g L^-1 (normal 41-49), IgG levels 608 mg 100 ml^-1 (normal 723-1685), VSG 110 mm 1 h (normal 1-10). Cryoglobulins were present at a concentration of 306 mg 100 ml^-1 (normal < 8) with a homogeneous component IgG-kappa. The precipitation of this Ig G-kappa occurred at a very high rate at 22°C. Urinalysis revealed proteinuria 2.45 g 24 h^-1 (normal < 0.1) without hematuria. Liver and renal function tests, complement (CH50, C3 and C4), Ig A and Ig M levels, anti-smooth muscle, anti-gastric mucosa, antinuclear, antimitochondria, anti-U1RNP, anti-SM, anti-SSB/La, anti-SSA/RO antibodies and serologic tests for syphilis and hepatitis were normal or negative.
Due to proteinuria, a kidney biopsy was carried out and a membranous proliferative glomerulonephritis was diagnosed. DIF of kidney showed granular deposits of IgG, C3 and C1q in mesangium.
Therapy with oral prednisone was initiated (75 mg/day at a tapering dose). However, control of cutaneous vasculitis was incomplete. Flares of generalized livedoid purpuric lesions appeared on acral areas and extremely painful necrotic ulcers from 0.5 to 3 cm. developed over them. Worsening of urinary analysis required admission to the Department of Nephrology on three occasions.
Multiple myeloma was diagnosed following a bone marrow aspiration and a lythic bone lesion in March 2001. Fifteen days later the patient was admitted to the Nephrology Department due to a flare of cutaneous lesions (Fig. 4a) associated to renal failure (creatinine 180 umol L^-1 (normal 70-130) and proteinuria 0.8 g 24 h^-1) with an increase of cryoglobulins (110 mg 100 ml^-1). In view of no response to prednisone (80 mg/d) and cyclophosphamide (150 mg/d) in April 2001 therapy with cycles of plasmapheresis was initiated (for three consecutive days in April and four in May). Seven cycles of plasmapheresis were carried out over one month. Plasma exchange was performed with discontinuous flow separator (Cobe Spectra). At each session the equivalent of 1.3-1.4 patient’s theoretical plasma volume was exchanged with a similar amount of 5% human albumin. After the third cycle skin lesions started to improve (Fig. 4b) with almost complete resolution of necrotic lesions after the seventh cycle; cryoglobulin levels decreased and renal function returned to normal. Intravenous antibiotics were required because of P. aeruginosa, Corynebacterium and S. epidermidis infection. Cyclophosphamide was stopped because of severe leukopenia and prednisone was continued at a tapering dose (20-30 mg/d).
In August 2001 cutaneous lesions worsened with progressive renal failure (creatinine 144 umol L^-1, proteinuria 4 g 24 h^-1 and hematuria) and a further increase in cryoglobulins (criocrit 30% (normal < 2%)) was observed. Although prednisone was increased to 80 mg/d, and cyclophosphamide was reinitiated, no improvement was seen in either cutaneous lesions or kidney function. Consequently, ten cycles of plasmapheresis were reintroduced over 3 weeks with subsequent clinical and analytical recovery (Table 1). The patient continued ambulatory treatment with oral prednisone (20 mg/d) plus cyclophosphamide (50 mg/d) without complete control of cutaneous lesions or cryoglobulins.

In the following months the patient presented several episodes of respiratory and urinary tract infections requiring hospitalization. The patient died due to acute repiratory failure in May 2002.

Discussion

A 72-year-old male presented cutaneous lesions induced by type I cryoglobulinemia (paraprotein IgG-kappa) associated with membranous proliferative glomerulonephritis and later developed multiple myeloma.
Cryoglobulins are serum immunoglobulins that precipitate when serum is cooled to below 37°C [11]. They are classified into three groups: type I are formed by an isolated monoclonal immunoglobulin, type II are mixed cryoglobulins with a monoclonal component possessing antibody activity towards polyclonal IgG, and type III are mixed polyclonal cryoglobulins [4]. The diagnosis of cryoglobulinemia depends on the demonstration of a protein that precipitates on cooling of serum [5].
Type I cryoglobulinemia is usually formed by monoclonal IgM and less frequently by monoclonal IgG [4]. Precipitation of these cryoglobulins in blood vessels produces cold-induced symptoms or symptoms due to hyperviscosity [5]. There is a high frequency of related lymphoproliferative disorders such as multiple myeloma, Waldenström’s macroglobulinemia, lymphoma and chronic lymphocytic leukemia [4, 11].
The most frequent manifestations related to type I cryoglobulins are cutaneous symptoms followed by Raynaud’s phenomenon, renal manifestations, hemorrhage, neurologic symptoms, acrocyanosis, articular manifestations and arterial thrombosis [4]. In Cohen et al. [11] series, cutaneous lesions in patients with type I cryoglobulinemia were mainly located in the lower extremities and consisted of inflammatory macules and papules (92%), ulcers and hemorrhagic crusts (58%), scarring (50%), infarction (42%), pigmentary changes (33%), livedo reticularis and petechiae (17%), leg edema and telangiectases (8%).
Treatment of cryoglobulinemia should be directed to the underlying cause if known, but otherwise involves control of cryoglobulin levels and clinical features [5]. In the presence of cutaneous ulcers, pharmacological therapy should be initiated. Prednisone, hydroxychloroquine, azathioprine, chlorambucil, cyclophosphamide, intravenous gammaglobulin and colchicine have been used [6]. A combination of immunosuppressive therapy and plasmapheresis may be considered in ulcers that do not heal with the aforementioned drugs.
Plasmapheresis is a technique that removes pathogenic cryoglobulins, immune complexes and autoantibodies from the circulation [6, 7], thereby improving symptomatology [3-8]. It has been reported to be useful in disorders such as pemphigus vulgaris [1], bullous and cicatricial pemphigoid [1], scleromyxedema [2], cryoglobulinemia [3-10], thrombotic thrombocytopenic purpura [8-10] systemic lupus erythematosus [8], myasthenia gravis [7, 8, 10] and Goodpasture’s syndrome [7-10].
In cryoglobulinemia, besides a specific treatment if the etiology is known, plasmapheresis can be used as effective adjunt therapy to minimize rapidly progressive or severe cutaneous, renal and/or neurologic involvement.
Periodical plasmapheresis may control the levels of cryoglobulins, thereby preventing renal deterioration and allowing a decrease in the dose of immunosuppressor drugs and their side effects [10]. The number and periodicity of procedures are not well established and depend upon the rate of cryoglobulin synthesis in each case.
Common mild side effects include chills, hypoglycemia, hypocalcemia, bronchospasm, urticaria, paresthesias, transient fever, nausea, vomiting, transient fever, mild cytopenia and hypotension. Rare potentially severe side events include arrhythmias and anaphylaxis [3, 6, 9]. The risk-benefit rate of plasmapheresis should be evaluated in each case before prescribing this therapy.
We would like to emphasize that in our patient, plasmapheresis was effective in decreasing cryoglobulin levels and improved cutaneous lesions and kidney function. It is important to take into consideration that concomitant therapy with prednisone or other immunosuppressive agents is required to prevent a rapid cryoglobulin rebound as the improvement in clinical and laboratory alterations obtained by plasmapheresis is usually transient [6, 10].
In conclusion, plasmapheresis is a useful therapy for the acute phase of cryoglobulinemia although the effect is transient and it should therefore be administered in association with other immunosuppressive agents. n

References

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