Cold agglutinin disease: A case report with atypical clinical findings

Abstract

A female in her 60s presented to the allergy and immunology clinic for further investigation of ongoing dermatitis. She presented with chronic acrocyanosis, mainly in her left lower extremity, extending distally from her mid thigh with concurrent ulcerations in her foot resulting in immobility secondary to pain. She experienced these symptoms for years without a definitive diagnosis. The lack of diagnosis was due, in part, to her atypical symptoms and laboratory findings that required a high level of clinical suspicion to diagnose. Extensive autoimmune workup was largely unrevealing with the exception of a cold agglutinin titer of 1:250 and a positive anticomplement C3b direct antiglobulin test. A diagnosis of cold agglutinin disease was made and treatment with rituximab monotherapy was initiated.

Introduction

Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia in which immunoglobulin M (IgM) antibodies are formed against red blood cells (RBCs) in cooler temperatures. Symptoms can include anemia, livedo reticularis, acrocyanosis, Raynaud’s syndrome, and fatigue. Epidemiological data are limited; however, an observational study looking at Norway and Italy reported in Norway a prevalence of 20.5 cases per 1,000,000 people and an incidence of 1.9 cases per 1,000,000 people per year. In Italy, they report a prevalence of 5 cases per 1,000,000 people and an incidence of 0.48 cases per 1,000,000 people per year. ¹ As this data were isolated to Norway and Italy it is suggestive of the worldwide prevalence and incidence but does indicate the difference in average yearly temperature which would naturally play a role in overall data. We report a case of CAD with debilitating symptoms that presented as a diagnostic challenge over decades.

Case presentation

A female patient in her 60s presented to the allergy and immunology clinic for further investigation of ongoing dermatitis. She has a complex medical history of chronic diastolic heart failure, irritable bowel syndrome, nonseasonal allergic rhinitis, complex regional pain syndrome of the left lower extremity, depression, eczematous dermatitis, hypertension, fibromyalgia, gastroesophageal reflux, gastroparesis, anxiety, hypothyroidism, insomnia, anemia, migraine headache, cardiovascular disease, osteoporosis, Raynaud’s syndrome, restless leg, rosacea, senile purpura, vitamin D deficiency, and urticarial vasculitis. The clinic sent her to the emergency room for symptoms of acutely worsening discoloration, lack of a palpable pulse, and a concern for acute vasculitis in her left lower extremity.

She was admitted to the hospital and a physical examination revealed blood pressure of 119/68 mmHg, temperature of 99.2 F (37.3°C), respiratory rate 13, pulse of 74 beats per minute, oxygen saturation of 93% on room air, marked erythema of the left lower extremity with blue discoloration along bilateral toes, erythema of bilateral hands, cold-to-touch extremities, diminished radial pulses bilaterally, and absent pedal pulses bilaterally. Review of systems was positive for fatigue, weakness, myalgias, chronic headache, and dizziness.

The patient had been dealing with chronic symptoms for well over a decade and had extensive workups prior to this presentation. Previous investigations included scans and biopsies of multiple normal arterial-brachial indexes and decreased toe–brachial indexes, an MRI of her left foot with only a focal soft tissue wound/ulcer at the tip of the third digit, and multiple skin biopsies which showed superficial perivascular and mixed-cell dermatitis most suggestive of a dermal hypersensitivity reaction. Her previous laboratory findings evidenced normal hemoglobin, normal total bilirubin, persistently elevated mean corpuscular volume (MCV) ranging 101–103 fL, normal vitamin B12 and folate, and a persistently decreased complement C4 at <8.0 mg/dL.

Laboratory tests were obtained upon the patient’s admission to the hospital. These demonstrated hemoglobin, total bilirubin, ESR, lactic acid, vitamin B6, serum protein electrophoresis, dsDNA, anti-smith, ribonucleoprotein, anti-SSA/SSB, rheumatoid factor, myeloperoxidase, PR3, anti-CCP, Jo1, SCL70, beta-2-glycoprotein, anti-centromere, RNA poly III, cardiolipin, C3, hepatitis panel, T-spot, aldolase, cryoglobulin, and urine heavy metal screen were all normal. Notable findings on this presentation included a weakly positive antinuclear antibody of 1:80 with a speckled pattern and a C4 of <8 mg/dL as had previously been documented in this patient. A peripheral smear taken during a prior hospitalization revealed normochromic and normocytic RBCs with red blood cell agglutination. A bone marrow aspirate and biopsy revealed no evidence of amyloid, myelodysplastic syndrome, lymphoplasmacytic lymphoma, or plasma cell dyscrasia, and did not reveal a MYD88 mutation.

A bilateral arterial doppler was obtained which revealed widely patent vasculature demonstrating no evidence of vascular compromise. The patient underwent a left lower extremity electromyography that showed severe, predominantly sensory, sensorimotor, and axonal peripheral neuropathy. She then underwent a right sural nerve and right vastus muscle biopsy. Her sural nerve revealed no pathologic abnormalities. Her muscle biopsy showed neurogenic atrophy without evidence of myopathy or myositis.

At outpatient follow-up, following her discharge, the patient’s laboratory findings of C3 and C4 were low at 87 mg/dL and <8 mg/dL, respectively. Ganglioside GD1a antibody immunoglobulin G returned negative, hemoglobin was 13 g/dL, lactate dehydrogenase was elevated at 350 U/L, haptoglobin was <30 mg/dL, and absolute reticulocyte count was 120 K/UL. The patient’s cold agglutinin titers were positive at 1:256 and confirmed with thermal amplitude testing as well as a positive anticomplement C3b direct antiglobulin test. A diagnosis of CAD was made and therapy with rituximab was initiated.

Discussion

Through various advancements in the study of hematologic disorders the classification of primary CAD has more recently been refined in conjunction with the International Consensus Classification and the 5th edition of the World Health Organization classification. ³ Primary CAD is now recognized as an autoimmune hemolytic anemia mediated from the proliferation of clonal B cells producing monoclonal cold agglutinins separate from an underlying lymphoproliferative lymphoma or monoclonal gammopathy. ³ While secondary cold agglutinin syndrome is seen in infections with Epstein–Barr virus, Mycoplasma pneumoniae, in lymphoproliferative disorders, or autoimmune disorders.^2,3 The autoantibodies primarily form in a temperature of 3°C–4°C, however, they can form at higher temperatures. Hemolysis in CAD has previously been identified as being driven primarily by complement-mediated factors. ² This is reinforced by hypocomplementemia being a common finding in CAD.^1,4 This patient presented over decades with nonclassical symptoms and laboratory findings which required a high level of clinical suspicion. As discussed above, she presented with low-normal hemoglobin and normal total bilirubin. Further investigation revealed decreased haptoglobin, elevated lactate dehydrogenase, decreased complement C4, intermittently decreased complement C3, spuriously elevated MCV, agglutination on peripheral smear, positive DAT anticomplement, and positive cold agglutinin titers. This is reiterated when comparing to a multinational observational study of 232 patients by Berentsen et al, these uncommon findings our patient presented with include a normal hemoglobin exhibited in only 10% of patients in this study, normal total bilirubin exhibited in only 14% of patients, as well as no clonal paraprotein identified on serum electrophoresis which was present in only 20% of patients. Symptomatically, Berentsen reported 70% of their patients presented with only acrocyanosis. In contrast, our patient presented with acrocyanosis, Raynaud’s phenomenon, and ulcerations, which was only reported in 9.5% of their patient population. ¹ Together, the uncommon laboratory findings and severe clinical context underscore the chronic nature of the disease process and unusual presentation in our patient.

In terms of therapy, options exist to target B-cell pathologies and more recently direct complement-mediated hemolysis therapy. ⁴ Currently, there are no guidelines to steer treatment but the most commonly used therapy in patients who require treatment is rituximab in combination or as monotherapy as a large portion of cold agglutinin syndrome is in relation to a lymphoproliferative disease.^5,6 Berentsen et al reported that 44% of their patients underwent rituximab monotherapy, with 59% reporting some objective response in improved symptoms but without complete resolution. This rate of improvement is not uncommon and was seen in earlier prospective, nonrandomized studies looking at rituximab monotherapy with results ranging from 45% to 54% of overall response.^7,8 The alkylating antineoplastic agent bendamustine has been studied for potential benefit with higher yields in overall response.^1,6 In Berentsen’s report, rituximab plus bendamustine combined therapy proved to be 78% responsive, and of this group, 53% reported complete resolution. In other prospective, nonrandomized studies of bendamustine and rituximab combination therapy showed overall response rates ranging from 71% to 78%.^1,9 More recent therapy has been directed at complement-mediated hemolysis through the complement C1 inhibitor sutimlimab. Previous studies have analyzed treatment with the complement C5 inhibitor, eculizumab. However, only modest benefits were seen as complement-mediated hemolysis is known to be C3b mediated, and therefore C5 inhibition would not recover upstream degradation.^6,10 Sutimlimab, however, would be expected to be more fruitful as it could reduce downstream degradation at C3b and has been shown to prevent deposition of C3 fragments on RBCs.^4,6 The CARDINAL study and CADENZA trial were early studies investigating the use of sutimlimab in CAD. The CARDINAL trial revealed stable improvement in hemoglobin levels at 1 year in 83% of patients, normalization of bilirubin levels in 71% of patients, and a clinically meaningful reduction in fatigue by the first week.^4,11 The CADENZA trial demonstrated similar findings with 73% of patients achieving an increase in hemoglobin as well as normalization of bilirubin levels within a single week as compared to 10% in the placebo arm.^4,12 For patients without an identifiable underlying lymphoproliferative disease, with unclear hemolysis, or who have a less than desirable result from rituximab monotherapy, combination therapy should be pursued or alternative therapy options explored.

Our patient underwent treatment with rituximab monotherapy and had improvement in objective laboratory findings including normalized haptoglobin, improved complement levels, improved lactate dehydrogenase, and normalization of MCV suggesting a lack of active agglutination. However, similar to findings in other retrospective studies, she still experiences persistent symptoms without complete resolution. She is currently undergoing consideration for a second line treatment of bendamustine along with other potential alternative treatments.

Conclusion

We present a unique case of CAD with atypical lab findings and difficult clinical presentation. This case adds important context to the difficulty in diagnosis of this disease. CAD should be considered in a patient with hypocomplementemia and unexplained circulatory symptoms including Raynaud’s phenomenon and ulcerations. Treatment should be tailored to the underlying cause if identified. More studies are needed to identify a clear treatment regimen for CAD.