Retinopathy in a Patient With IgM MGUS: Causal Association οr an Epiphenomenon?

Abstract

Background/Aim

The presence of a monoclonal gammopathy of undetermined significance (MGUS) even in small amounts may trigger tissue damage through immunological or other mechanisms, irrespective of the potential for malignant transformation. The aim of the study was to present a case of monoclonal gammopathy of clinical significance with ocular manifestations and discuss relevant literature.

Case Report

In our case, a patient presented with vision disturbances that was eventually attributed to the underlying IgM MGUS after extensive workup to exclude other potential etiologies. The patient showed a clinical response with the fixed-duration DRC (dexamethasone, rituximab, cyclophosphamide) regimen that persisted for at least 1.5 years. Herein, we present, in detail, the patient management and discuss the underlying pathophysiology of this rare entity with few available published data in this field.

Conclusion

A high level of clinical suspicion is necessary in order to detect the association between MGUS and a clinical sign or symptom that cannot be attributed elsewhere.

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by an abnormal proliferation of monoclonal plasma cells that does not satisfy the diagnostic criteria for multiple myeloma (MM) or Waldenström’s macroglobulinemia (WM) due to low disease burden, while there is no evidence of related organ dysfunction. However, this small B-cell or plasma cell clone may cause complications associated with the secreted monoclonal immunoglobulin, due to its physicochemical or immunological properties, or other paraneoplastic mechanisms. In such cases, the monoclonal gammopathy acquires clinical significance and the term monoclonal gammopathy of clinical significance (MGCS) has been proposed. The aim of this study is to describe the management of a case of MGCS with ocular manifestations and discuss relevant literature in this field.

Case Report

Clinical presentation and medical history. A 72-year-old man presented with progressive worsening blurred vision since few months. He complained about reduced visual acuity mainly in high-light conditions. From his past medical history, he was diagnosed with IgM MGUS 22 years ago. The most recent IgM level was 1,450 mg/dl, compared to 400 mg/dl at diagnosis before 22 years (Figure 1). The current bone marrow biopsy revealed 8-10% infiltration of monoclonal plasma cells. The evaluation for MYD88 gene mutational status showed MYD88 wild type. The patient also had a history of hypertension, dyslipidemia, thyroid disease, gastritis, bilateral cataract surgery, and a transient ischemic attack 15 years ago. He was a current smoker (40 pack-years) and he did not drink alcohol. His medications included levothyroxine, acetylsalicylic acid, atorvastatin and olmesartan with amlodipine and hydrochlorothiazide. He had reported no other personal or familial history of ocular disease.

Figure 1. Sequential evaluation of IgM kinetics during and after treatment with DRC. BM: Bone marrow; PCs: plasma cells; IgM: immunoglobulin M. DRC: Dexamethasone, rituximab, cyclophosphamide.

Ocular findings. The ophthalmological examination revealed reduced vision in high light conditions and in bright environment. The best corrected visual acuity was 6/10 in the right eye and 6.5/10 in the left eye. The optical fields examination revealed an arc-shaped scintillating scotoma. The ophthalmoscopy (fundoscopy) and color photographing of the fundus showed no particular alterations on the retina. The optical coherence tomography and the fluorescent angiography showed no abnormal findings. However, the classic electroretinography (light and dark) demonstrated an electronegative electroretinogram, which was compatible with inner retinal dysfunction at the retinal layer of bipolar cells.

Imaging findings. The brain and eye magnetic resonance imaging (MRI) did not detect any abnormal findings in the optic nerves, the optic chiasm and the optic tracts. There were minimal small vessels lesions in the subcentral loci of the right frontal lobe.

Differential diagnosis and further workup. In this context, the patient underwent further examination to rule out occult malignancy and cancer-associated retinopathy, as well as autoimmune-related retinopathy. The clinical examination did not reveal any clinical manifestation of autoimmune disease, whereas serum markers were negative for auto-antibodies suggestive of autoimmunity, except for the previously known thyroid disease. The upper and lower endoscopy of the gastrointestinal tract showed grade 1 gastritis and the colonoscopy showed a colon polyp which was removed completely and the biopsy showed no signs of malignancy. The dermatological examination demonstrated no lesions suspicious for melanoma or other skin cancer and positron emission tomography/computed tomography (PET/CT) was negative for hypermetabolic lesions suggestive of malignancy. The cerebrospinal fluid analysis was negative for the presence of B-cells or plasma cells, whereas there was a T-cell population consisted of CD3+/CD4+ (60%) and CD3+/CD8+ (40%) T-lymphocytes, which is non-disease specific. The glucose levels were normal, total protein level increased at 83 mg/dl (normal range 15-45 mg/dl), and no red blood cells or other cells were present.

Taking into consideration the above, an association between the patient’s retinopathy and the IgM MGUS emerged as a potential diagnosis and an ocular immunology panel for cancer-associated retinopathy and autoimmune retinopathy was evaluated. The investigation included testing for antibodies against carbonic anhydrase II, heat shock protein 27, heat shock protein 60, aldolase, enolase, arrestin, tubulin, pyruvate kinase M2, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), recoverin, Rab6 and TULP1. The patient was positive for antibodies against carbonic anhydrase II and arrestin, whereas immunohistochemistry on human retina using patient’s serum was positive with moderate staining of the outer and inner segment of photoreceptor cells.

Treatment and patient outcomes. Based on the above results, ophthalmologic examination, clinical presentation, and history we set the diagnosis of IgM-related retinopathy and the patient started treatment with dexamethasone 20 mg on day 1, rituximab 375 mg/m2 on day 1 and cyclophosphamide 100 mg/m2 on days 1 to 5 (DRC regimen) administered every 3 weeks for 6 cycles. The patient tolerated treatment well except for gastrointestinal toxicity, but dose modifications or treatment delay were not necessary. The IgM level was gradually reduced, and the patient had a minor hematological response (>25% IgM reduction) at one month post treatment completion and a partial hematological response (>50% IgM reduction) at three months post treatment completion (Figure 1). The bone marrow biopsy following treatment revealed a reduced percentage of 3% clonal plasma cells. The patient reported a gradual improvement of ocular symptoms. The electroretinography showed an improvement by 50% for the cones and by 75% for the rods along with a reversal of the previously electronegative phenotype. There was also an improvement in best corrected visual acuity to 7/10 in both eyes. At one-and-a-half-year post treatment completion, the patient’s condition remains stable. However, regarding the ocular immunology profile, the patient remained positive for carbonic anhydrase II and arrestin, whereas he was also positive for enolase post treatment. The patient gave his written informed consent for the publication of this Case Report.

Discussion

A wide range of ocular manifestations has been described in patients with plasma cell dyscrasias. A case-control study has shown that ocular surface disease as determined by the Ocular Surface Disease Index (OSDI) and cataract are more frequently encountered in patients with monoclonal gammopathies, who have also worse best-corrected visual acuity (BCVA) scores compared to healthy, age-matched individuals (1). Although hyperviscosity has been well described as the underlying cause of ocular symptoms and finding in patients with high immunoglobulin levels, especially IgM in WM, a further examination of the available data has shown that diseases of the cornea, the retina, the retinal artery/vein, the uvea, the optic nerve, the conjunctiva and the extraocular muscles may also be present even in patients with low levels of clonal immunoglobulins (2). Paraproteinemic keratopathy (PK) is probably the most well-described ocular finding in patients with monoclonal gammopathy of ocular significance (MGOS) and is characterized by the deposition of monoclonal immunoglobulins that accumulate and crystalize in the cornea (3,4). Interestingly, the burden of the monoclonal gammopathy has not been correlated with the morphology or the severity of the ocular abnormalities (3).

However, in our patient the ocular complications were associated with retinopathy and fulfilled all the essential diagnostic criteria for autoimmune retinopathy (5). To the best of our knowledge, only one case of autoimmune retinopathy associated with IgGλ MGUS has been previously reported (6). In our case, the abnormality in visual function could not be directly attributed to any apparent ocular or systematic disease, there was no sign of fundus lesions or retinal degeneration or dystrophy or overt intraocular inflammation, the electroretinogram was abnormal, and serum anti-retinal antibodies were detected. The presence of anti-retinal antibodies should be interpreted in the context of other findings, due to lack of specificity and a universally accepted detection technique across laboratories. Indeed, it has been reported that anti-retinal antibodies may be found in up to one third of healthy individuals (7). In cases of cancer-associated retinopathy, antibodies against tumor-related antigens present cross-reactivity with retinal antigens, and these auto-antibodies target retinal cells and induce apoptosis (7). In turn, damaged photoreceptor cells may release arrestin-enolase complexes which are processed by resident antigen-presenting cells and induce the production of anti-arrestin and anti-enolase auto-antibodies. Anti-arrestin antibodies have been also reported in patients with melanoma, breast cancer, colon cancer and bladder cancer. Anti-enolase antibodies have been also detected in patients with gynecological cancer, skin cancer and hematologic malignancies. Carbonic anhydrase II is an essential metallo-enzyme for the regulation of acid-base balance and energy homeostasis in human cells. Antibodies against carbonic anhydrase II have been reported in both autoimmune- and cancer-associated retinopathy including hematological cancer (7). In our patient a direct activity of the monoclonal IgM against retina antigens was not tested. Whether there was a direct activity of the monoclonal IgM or whether polyclonal antibodies against the retina antigens were produced as a result of molecular mimicry to clonal antigens could not be differentiated. Given the rarity of autoimmune retinopathy in B-cell/plasma cell malignancies and the individual immunologic characteristics of the monoclonal immunoglobulins, a direct anti-retina effect of our patient’s IgM is the most probable mechanism. Thus, we treated the retinopathy as related to the underlying IgM MGUS. The DRC regimen includes a steroid (dexamethasone), an anti-CD20 monoclonal antibody (rituximab) and an antimetabolite with immunosuppressive activity (cyclophosphamide). All these drugs may be used in autoimmune retinopathy, as well, and we cannot rule out that the observed improvement was also due to the immunomodulatory effect of these drugs (5). Rituximab has been also effective in a case of autoimmune retinopathy associated with IgGλ MGUS (6). The treatment result was satisfactory, although the symptoms were not resolved completely and the assessment of the response durability requires longer follow-up. Notably, the reduction of IgM levels was associated with stabilization and mild improvement of BCVA. Although there are no pertinent data in the literature, a more aggressive therapeutic approach aiming at the eradication of the IgM clone could be considered to further improve the outcomes, however, the risk of toxicity should be weighed against the potential benefits. Intra-ocular treatment might be considered as well for direct immunomodulation following discussion in a multidisciplinary tumor board.

Conclusion

The presence of a monoclonal gammopathy even in small amounts may trigger tissue damage through immunological or other mechanisms. A high level of clinical suspicion is necessary in order to detect the association between MGUS and a clinical sign or symptom that cannot be attributed elsewhere such as vision disturbances in our case. Referral to expert centers is important to establish the diagnosis and determine the risk/benefit ratio and optimal timing of treatment.

Conflicts of Interest

The Authors declare no relevant conflicts of interest.

Authors’ Contributions

INS, EK, MG, ET and MAD performed research. JT contributed analytical tools. INS and MG wrote the paper. All Authors reviewed, provided feedback and approval of the final version of the paper.