Cryoglobulin-Associated Retinal Vasculitis: Retrospective Case Series

Abstract

Purpose: To highlight clinical and imaging features of 5 patients diagnosed with retinal vasculitis and cryoglobulins. Methods: This retrospective case series describes clinical and angiographic features of retinal vasculitis and serum cryoglobulins and is the most extensive series to our knowledge. Results: Five female patients were diagnosed with retinal vasculitis and serum cryoglobulins. The average age at time of cryoglobulin identification was 46 years (range, 28-72 years), although retinal vasculitis had been present for various durations. Fluorescein angiograms demonstrated large-vessel and small-vessel segmental leakage in 3 patients, only large-vessel segmental leakage in 1 patient, and only small-vessel segmental leakage in 1 patient. Treatment included topical steroids, intraocular steroid injections, oral corticosteroids, oral antimetabolites, and biologic therapy. At the time of this report, 4 of 5 patients had persistent angiographic leakage; however, none had retinal vascular occlusions. Conclusions: Various treatments were efficacious, although resolution was difficult. No patient experienced retinal vascular occlusions or other types of end-organ compromise.

Introduction

Cryoglobulinemia is a rare condition defined by the laboratory detection of serum cryoglobulin proteins that can form intravascular precipitates and lead to vasculitis and end-organ compromise. The condition is associated with lymphoproliferative disorders, hepatitis C virus, and HIV.^1–3 Cryoglobulinemic vasculitis typically presents with arthralgia, neuropathy, skin ulcers, and purpura ⁴ and is usually treated with systemic steroids and immune modulatory therapy. It is unknown whether treatment of cryoglobulin-associated retinal vasculitis would be as effective as that in the context of Behçet disease, sarcoidosis, or multiple sclerosis.^5,6 The purpose of this retrospective review was to highlight the clinical and imaging features of 5 patients diagnosed with cryoglobulin-associated retinal vasculitis.

Methods

The Institutional Review Board at the University of Minnesota approved this retrospective case series. The research adhered to the tenets of the Declaration of Helsinki and was conducted in an ethically responsible manner. Informed written consent for participation in research was obtained from patients at the University of Minnesota. Patients with retinal vasculitis who were seen by a single provider (J.Y.) at the uveitis clinic at the University of Minnesota were included if serum cryoglobulins were detected by rheumatologists at the Division of Rheumatic and Autoimmune Disease, University of Minnesota Department of Medicine (L.M., S.L.-E.).

Results

Five patients were diagnosed with cryoglobulins and retinal vasculitis. The average age at the time of cryoglobulin identification was 46 years (range, 28-72 years), and all 5 patients were women. The mean time from the known onset of uveitis to the detection of cryoglobulins was 9 years, although 3 patients had cryoglobulins detected 3 to 24 months after uveitis/retinal vasculitis was diagnosed. Treatment included topical steroids, intraocular steroid injections, oral corticosteroids, oral antimetabolites, and biologic therapy (Table 1).

Table 1.

Clinical and Angiographic Features of 5 Patients With Cryoglobulin-Associated Retinal Vasculitis.

Case	Sex	Age at Diagnosis of Uveitis (Y)	Age at Initial Identification of Serum Cryoglobulins (Y)	Interval From Onset of Uveitis and Identification of Cryoglobulins (Y)	FA Leakage Pattern	Treatment
1	F	28	28	0.25	LVL	Prednisone Methotrexate Azathioprine
2	F	71	72	1	SVL, LVL	Steroid drops Prednisone
3	F	44	46	2	SVL, LVL	Prednisone Mycophenolate anti-TNF alpha agents Intravitreal dexamethasone implant
4	F	18	28	10	SVL	Steroid drops Prednisone Azathioprine
5	F	25	53	32	SVL, LVL	Steroid drops Intraocular steroid injections Methotrexate a

Abbreviations: FA, fluorescein angiography; LVL, large-vessel leakage; SVL, small-vessel leakage; TNF, tumor necrosis factor.

^aUsed decades prior with intolerance and lack of efficacy.

Fluorescein angiograms (FAs) were obtained at various times in relation to the detection of cryoglobulins, and the most recent angiograms were included along with laboratory results closest to cryoglobulin seropositivity. All patients had similar-appearing angiograms for both eyes; thus, only 1 image was included for each patient before and after treatment. Four of the 5 patients had persistent angiographic leakage; however, none developed retinal vascular occlusions or retinal neovascularization during the study period. Table 1 lists the clinical and angiographic characteristics of the group, and each patient’s treatment course is summarized herein.

Case 1

A 28-year-old woman without significant medical history presented with sudden onset of flashing in the temporal visual field of her right eye. A fundus examination showed retinal vascular sheathing, and retinal angiography identified numerous areas of large-vessel segmental leakage without occlusions or peripheral nonperfusion in both eyes (Figure 1A). Laboratory investigation was negative for infectious and inflammatory causes of retinal vasculitis, and vessel inflammation improved with a tapering course of oral prednisone. Given the persistent symptoms and incomplete resolution of vascular inflammation, the patient was referred to the rheumatology department.

Figure 1.

Before treatment, initial fluorescein angiograms (FAs) showed (A) large-vessel segmental leakage prior to detection of cryoglobulins in Case 1, (B) peripheral large-vessel and small-end-vessel leakage prior to initiation of therapy in Case 2, (C) large-segmental and small-vessel leakage in Case 3, and (D) subtle, peripheral small-vessel leakage in Case 4. (E) In Case 5, early FA showed mixed large-segmental and small-vessel leakage.

An extensive laboratory evaluation included negative findings or normal levels of C-reactive protein, erythrocyte sedimentation rate, complement component 3 (C3), complement component 4 (C4), serum protein electrophoresis, urine protein electrophoresis, immune complex panel, urinalysis, urine protein, urine protein-to-creatinine ratio, hepatitis B and C, and HIV. Cryoglobulin immunoglobulin M (IgM) and Raji immune complexes were identified, and the patient was referred to the hematology department. A bone marrow biopsy was negative for lymphoproliferative disorders.

Oral methotrexate 15 mg weekly was initiated. After clinical improvement and 1 year of quiescence (Figure 2A) along with resolution of serologic cryoglobulins, the methotrexate was discontinued due to plans for conception. Four months after discontinuing methotrexate, the patient developed photopsia and aching in the left eye with recurrence of retinal vasculitis and associated optic disc edema. Oral prednisone was restarted and, given that there were trace amounts of monoclonal cryoglobulin IgM, azathioprine was started because methotrexate could not be used due to the patient’s pregnancy plans. Clinical stability was achieved on azathioprine monotherapy.

Figure 2.

After treatment, follow-up fluorescein angiography (FA) was performed. (A) Case 1 had significant improvement in large-vessel segmental leakage after 17 months on methotrexate. (B) In Case 2, therapy was stopped for more than 12 months and FA showed persistent large-vessel and small-vessel peripheral leakage. (C) After mycophenolate and anti-tumor necrosis factor therapy there was improved but persistent large-vessel and small-vessel leakage in both eyes of Case 3. (D) Case 4 showed nearly resolved small-vessel leakage. (E) Case 5 showed persistent large-vessel and small-vessel leakage.

Case 2

A 71-year-old woman presented with photopsia in the left eye and metamorphopsia in both eyes. A mild degree of vitreous haze was present, and FA identified a macular hyperfluorescent spot without leakage in the left eye as well as peripheral large-vessel and small-vessel hyperfluorescence in both eyes (Figure 1B). Results from a laboratory evaluation, which included tests for complete blood count (CBC), comprehensive metabolic panel (CMP), angiotensin-converting enzyme (ACE), Lyme ELISA, hepatitis B and C, HIV, and QuantiFERON, were normal or negative. Topical steroid and nonsteroidal drops were started along with oral prednisone; however, elevated intraocular pressure (IOP) necessitated a rapid taper of corticosteroids and the addition of IOP-lowering drops.

A rheumatology evaluation was negative for Raynaud phenomenon, Sjögren syndrome, or other clinical syndromes; however, laboratory testing identified cryoglobulin monoclonal IgM. A hematology evaluation identified monoclonal gammopathy of unknown significance (MGUS), which did not require treatment. Given the absence of sight-threatening macular edema or retinal vascular occlusions, the vitreous opacities and persistent small-vessel and large-vessel leakage (Figure 2B) were only observed without additional therapy.

Case 3

A 44-year-old woman with a history of laser-assisted in situ keratomileusis surgery in the left eye and polycystic ovarian syndrome (PCOS) presented with subacute blurry vision in her right eye and splotchy vision in her left eye. The clinical examination was significant for retinal vascular sheathing and perivascular hyperpigmentation in both eyes. FA showed nonocclusive, segmental vascular staining of large vessels as well as peripheral small-vessel leakage in both eyes (Figure 1C). Diagnostic testing for infectious and inflammatory causes of retinal vasculitis were all negative and included CBC, CMP, ACE, antineutrophil cytoplasmic antibodies, rheumatoid factor, C3, C4, cardiolipin antibodies, lupus anticoagulant, Bartonella quintana, Bartonella henselae, Lyme, QuantiFERON, and syphilis antibodies. Test findings for hepatitis B and C and HIV were also negative. Magnetic resonance imaging of the brain did not identify evidence of demyelinating disease, and ocular genetic testing did not identify any known mutations.

Oral corticosteroids were initiated; then, the patient was transitioned to 1000 mg, twice-daily oral mycophenolate mofetil. The patient was referred to the rheumatology department, which did not identify any systemic inflammatory condition; however, adalimumab injections were added every 14 days for ongoing retinal vasculitis. Given the persistent elevation of her white blood cell count, erythrocyte sedimentation rate, and C-reactive protein, the patient was referred to the hematology department, which ruled out lymphoproliferative disorders. The rheumatology department subsequently identified cryoglobulins and switched biologic therapy from adalimumab injections to infliximab infusions. Systemic inflammatory markers normalized, and the retinal vascular leakage improved. After an infusion reaction to infliximab necessitated discontinuing its use, persistent angiographic leakage (Figure 2C) prompted an intravitreal dexamethasone implant to be administered in the left eye and alternative systemic therapies to be considered.

Case 4

A 27-year-old woman with a history of type II diabetes mellitus and PCOS had been treated with corticosteroid drops for uveitis every few months in the preceding 9 years. During evaluation at the University of Minnesota, a dilated examination identified vitreous cells in both eyes and FA identified subtle peripheral small-vessel leakage in both eyes (Figure 1D). The patient was treated with oral prednisone and prednisolone drops for 2 months and was referred to the rheumatology department. An extensive evaluation was negative for underlying systemic infectious and inflammatory diseases, including hepatitis B and C and HIV, but was positive for serum cryoglobulins. Intermittent courses of prednisolone drops and oral prednisone were used to treat iritis and retinal vasculitis without the patient developing macular edema or retinal vascular occlusions. The patient was started on azathioprine due to plans for pregnancy, and the retinal vessel leakage improved (Figure 2D).

Case 5

A 53-year-old woman with a long history of retinal vessel vasculitis and cystoid macular edema (CME) (Figure 1E) was treated with methotrexate decades prior with intolerance and lack of efficacy. She was subsequently treated with steroid and nonsteroidal drops as well as occasional regional steroid eye injections primarily for CME. A rheumatology evaluation for systemic, infectious, and inflammatory disease included the following normal/negative laboratory studies: CBC, CMP, antinuclear antibody, rheumatoid factor, cyclic citrullinated peptide, Lyme, QuantiFERON, Treponema, hepatitis B and C, and HIV. A slightly reduced C4 and trace cryoglobulin IgM proteins were identified. FA showed persistent small-vessel and large-vessel hyperfluorescence as well as disc and foveal leakage (Figure 2E). Antimetabolites were recommended for active retinal vessel inflammation and CME as well as joint pain and stiffness.

Conclusions

Cryoglobulinemia-associated retinal vasculitis was first discussed in a case series of 13 patients that included 1 patient with an unusual presentation of retinal vasculitis. ⁷ We know of only 3 case reports of retinal vasculitis secondary to cryoglobulinemia, including a case of a 72-year-old man with retinal and systemic vasculitis associated with multiple myeloma ⁸ and another of a 64-year-old man with scleritis and retinal vasculitis associated with mixed cryoglobulinemia. ⁹

A previous study of 443 patients with cryoglobulinemia found a female-to-male ratio of 3:2. ¹⁰ All patients in the present series were women, and the average age at time of identification of cryoglobulins in this cohort was 46 years (range, 28-72 years). All patients had large and/or small retinal vessel leakage typically in the periphery, although some also had leakage in the posterior pole. Three of the 5 patients had angiographic macular edema, although only 1 had CME detected by optical coherence tomography during the study period. None of the patients developed retinal vascular occlusions or retinal neovascularization during the study period, although 1 patient had prior peripheral retinal laser treatment that may have protected against retinal ischemia.

Cryoglobulin-associated immune complex vasculitis is an uncommon cause of retinal vasculitis and is typically seen in patients with leukemia, lymphoma, or hepatitis C.^7–9 All patients in the present series had cryoglobulin IgM antibodies without underlying associated infections or inflammatory disorders, and only 1 patient (Case 2) was monitored for MGUS, which did not require treatment. All 5 patients were treated with typical therapies for retinal vasculitis^11–15 including topical and/or oral corticosteroids (5 of 5), antimetabolites (3 of 5), and 2 tumor necrosis factor alpha inhibitor biologic agents (1 of 5). Rituximab has been used to reduce antibody production and associated immune complex deposition in patients with cryoglobulin-associated retinal vasculitis.^16,17 None of the patients in this series was treated with rituximab, although it had been considered as an alternative treatment, particularly for the patient in Case 3.

As cryoglobulins were identified at various points in the clinical course, consideration could be given to other causes of retinal vasculitis in these patients. Given that evaluations for associated infectious or inflammatory conditions were unrevealing, we categorized these patients as having cryoglobulin-associated retinal vasculitis. Two of the 5 likely had systemic symptoms associated with cryoglobulins, which improved with antimetabolite treatment.

Retinal vasculitis secondary to cryoglobulinemia is a rare condition; however, it can be managed in a stepwise fashion with oral prednisone transitioned to oral antimetabolites, adding biologic agents if necessary. No patients in this series developed retinal vascular occlusions.