AQP4 antibody-seropositive neuromyelitis optica spectrum disorder in a patient with mixed connective tissue disease: a case report

Introduction

In 2015, the International Consensus of Neurology classified anti-AQP4-IgG or anti-MOG-IgG related longitudinally extensive transverse myelitis (LETM) and anti-AQP4-IgG or anti-MOG-IgG related neuromyelitis optica (NMO) within the group of diseases identified under the term “neuromyelitis optica spectrum disorder (NMOSD)” (1).

In the literature, some articles have pointed out that NMOSD may coexist with connective tissue diseases (CTDs), although, to date, no extensive epidemiologic data has exhaustively investigated the clinical aspects of this association.

A recent review reported that there were very few indexed publications in the scientific literature addressing this topic, but it is well-documented that positive anti-nuclear antibodies (ANA) are found in patients with NMOSD in a percentage that approximately ranged from 31% to 82.6% (2). Among these antibodies, anti-DNA, anti-SSA and anti-SSB are more frequently encountered in these patients (3). This coexistence probably reflects the predisposition of patients to multiple autoimmune diseases, both organ specific and non-organ specific (3), though further studies are needed to improve knowledge of the pathogenesis of these clinical associations. Several studies involving patients with overlap between CTD and NMOSD reported that systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) were more frequently found associated in comparison with other CTDs (2-5). Conversely, up to now, only a few anecdotal cases of NMOSD and mixed connective tissue disease (MCTD) have been described (6,7).

Moreover, a paucity of studies have looked into the role of ANA in the severity of NMOSD. To date, many clinical aspects of this association remain unknown. Recently, Fan et al. [2021] suggested that patients with CTD and anti-AQP4- or anti-MOG-related NMOSD may be exposed to an increased risk of further relapse episodes of myelitis and incremental disability (2). Herein, we report a rare case of a patient with AQP4-IgG related NMOSD associated with MCTD. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-23-48/rc).

Case presentation

A 58-year-old Caucasian man was admitted to the Emergency Department (ED) with low back pain and walking inability. The patient suffers from Type 1 diabetes mellitus, and he reported repeated episodes of the Raynaud’s phenomenon and arthralgia often associated with morning stiffness in his anamnesis. He had an unsteady gait, paraesthesia of the lower limbs, and pain in the left lumbar area of the spine. The neurological examination revealed pyramidal signs with asymmetric and progressive paraparesis associated with hypoesthesia and bladder dysfunction. A previous spine magnetic resonance imaging (MRI) showed central cord abnormalities and a subsequent nervous system MRI disclosed an extensive cervico-dorsal myelitis (C3–D12). Neither expansive formations in the extramedullary endocanal site nor primitive bone marrow lesions were found (Figure 1A). No traumatic bone lesions appeared on the lumbosacral spine X-ray. Among laboratory examinations at entrance a blood cell count showed leukopenia [white blood cell (WBC) 3.4×10³/µL] and serum protein electrophoresis showed slight polyclonal hypergammaglobulinemia.

Figure 1 Spinal cord on MRI. Long extensive centro-medullary abnormalities extending from C3 to D12 (A) and from C6 to D6 (B). MRI, magnetic resonance imaging.

The somato-sensory (SEPs) and motor evoked potentials (MEPs) confirmed dysfunctions of the cordonal and pyramidal tracts. A cerebrospinal fluid (CSF) examination revealed a leukocyte count of 10 cells/µL, total proteins of 66 mg/dL with 311 mg/L albumin, 139 mg/dL glucose and 98 mg/L total IgG, with the absence of atypical cells. Microbiological examinations came back all negative. The isoelectrofocusing results (Isofocusing kit for on the semi-automatic Hydrasys System, Sebia Italia Srl, Firenze, Italy) showed oligoclonal bands with a mirror pattern (type 4), suggesting an absence of intrathecal synthesis, compatible with a blood-brain barrier (BBB) dysfunction due to an inflammatory process in the central nervous system (CNS). An indirect immunofluorescence (IFI) analysis on serum for detecting ANA revealed a Coarse Speckled pattern with high titre of 1:1,280 and the ensuing serum immunometric determinations showed reactivity for the following autoantibodies: Ab anti-SSA-Ro (20 U/mL), anti-RNP (272.0 U/mL) and IgG anti-Beta2 glycoprotein (13 U/mL). Anti-SSB-La, anti-Sms, anti-Scl-70, anti-Jo-1, anti-MPO, anti-PR3, IgG and immunoglobulin M (IgM) anti-cardiolipin, anti-GAD and anti-IA2 came back all negative.

The further serological recombinant IFI examination (anti-neuronal autoantibodies kit, Euroimmun Italia Srl, Padova, Italy) revealed the presence of IgG antibodies against AQP4, leading to a diagnosis of NMOSD with MCTD. A steroid intravenous therapy with 1 g/day of methylprednisolone for 5 days was started and was followed by a steroid oral treatment with 50 mg per day of prednisone.

A few days later, in December 2020, a noncontrast spiral chest computed tomography (CT) showed in the lingula segment and in both lower lobes ground-glass opacity (GGO), thickening of interlobular septa and traction bronchiectasis. A subsequent spine MRI showed a reduction of the extensive myelitis (Figure 1B).

The visual evoked potentials (VEPs) were compatible with past bilateral retrobulbar optic neuropathy (RBON). The patient improved, and one month later he showed a reduction of lower limb weakness, good trunk control in a sitting position, and initial recovery of the standing position. He was discharged for rehabilitation, and subsequently, he started maintenance treatment with intravenous rituximab (1 g twice over a 2-week interval, and after 1 g every 6 months) with a good prognosis (4,8).

At his last control visit after 9 months, the patient was in treatment with rituximab, walked normally without pain and his last cervico-dorsal spine MRI showed negative results (Figure 2).

Figure 2 Sagittal T2-weighted MRI sequences of thoracic (A) and lumbar (B) regions of the spine approximately 9 months after the start of therapy. The figure shows the complete regression of the signal alteration extending from C6 to D6 documented in the previous examination. The spinal cord and the conus medullaris show normal morphology and signal intensity. MRI, magnetic resonance imaging.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Clinical symptoms associated with a high titre of serum anti-RNP antibodies (272 U/mL; IFI 1:1,280 coarse spoken) in our patient fall within the criteria for MCTD. Thus, herein we describe an unusual coexistence between MCTD and anti-AQP4-related NMOSD in a patient checked into our Emergency Department. The first case was published by Parperis in 2012 (6); two further cases involving two young females were described by Silva et al. in 2018 (7).

A pulmonary disease in our patients may be linked with high probability to rheumatologic disease. Therefore, GGO, interlobular septal thickening, and traction bronchiectasis are the most common features found in interstitial lung disease (ILD) on high-resolution computed tomography (HRCT) and are frequently found in the pulmonary disease of MCTD patients (9). Long-term follow-up studies have demonstrated that respiratory complications are observed in 20% to 80% of patients (10-12). Among these, the ILD is the most common pulmonary manifestation, with reported frequencies ranging from 21% to 50% (11).

Taking into account all the clinical evidence described above, we classified the rheumatologic disease of our patient as MCTD on the basis of Kasukawa’s criteria (13). These criteria (Table 1) classify rheumatology disease as MCTD when patients show at least one of the common symptoms plus positivity for anti-RNP Ab plus one or more signs/symptoms of the mixed symptoms in at least two of the three disease categories [SLE, systemic sclerosis (SSc), and polymyositis] (13). Hence, our patient met the following points of these criteria: Raynaud’s phenomenon as a common symptom; polyarthritis and leukopenia among five SLE-related symptoms; pulmonary disease among SSc-like findings; and positivity for anti-RNP antibodies as a serological criterion.

The association between RNP Abs and AQP4 is rarely described in the literature (14). Furthermore, as MCTD shows low prevalence in epidemiology studies and shares its clinical manifestations with other rheumatic diseases, its recognition represents a diagnostic challenge in clinical experience (15). Hence, over the years, many strategies have been adopted to try to standardize its diagnosis and specific criteria are proposed to this aim (16). Over the years, four methods (Sharp, Alarcón-Segovia, Kasukawa, and Kahn) have been introduced to recognize MCTD, but none of these classify this condition unequivocally, and none of these have sufficiently reached consensus for diagnosis (13). John et al. [2020] reported that the Kasukawa method showed the best sensitivity when compared with other criteria, demonstrating that it is more suitable to rule out disease in comparison with other criteria that may be more helpful to rule in MCTD (13). However, criteria may help to diagnose MCTD, but since they do not capture the same patients and there are no uniform guidelines for evaluating this clinical condition in a clinical setting (17), diagnosis may often be based on the judgment of the expert physician (13).

After our first evaluation, considering that our patient showed peripheral demyelination with the presence of serum anti-ANA antibodies, we hypothesized that he might be affected by an atypical CNS manifestation due to a systemic connective disease (18). CNS manifestations, such as aseptic meningitis, cerebrovascular disease, demyelinating syndrome, and myelitis have been described in association with systemic autoimmune diseases. In these pathologies, vasculitis, microangiopathic hypercoagulable state, and anti-phospholipid antibodies may damage the cells of the nervous system (19). Since it has been known that a lesion to the CNS may also be linked to an astrocytopathy mediated by anti-AQP4 or anti-MOG-IgG (4), our patient finally underwent testing for these serum autoantibodies.

Autoimmune neurological disorders, classified as NMOSD, are a group of clinical phenotypes that require for their diagnosis both clinical and laboratory investigations. Unlike multiple sclerosis (MS), which has been linked to a significant rate of recovery after an acute event even in the absence of treatment, damaged astrocytes in NMOSD have a reduced ability of regeneration and axon regrowth, frequently leading to a minimal recovery, particularly in untreated patients (4). Therefore, NMOSD may recur with more severe episodes and incomplete recovery, increasing the risk of permanent disability in patients (20). Moreover, the recurrences can occur in 2 to 3 years, with age, female gender, and evidence of systemic autoimmune disease as the most important risk predictors (21). Compared to other clinical manifestations of NMOSD, patients with LETM present a higher risk of developing disability, especially when symptoms first appear after age 50 years (22,23). In addition, although the main role of ANA antibodies in NMOSD has not been fully understood, a recent study published by Fan et al. [2021] found that the median time from disease onset to the Expanded Disability Status Scale (EDSS) of 4.0 was significantly longer in ANA-negative patients compared to ANA-positive (2). The overlap of the two autoimmune diseases would expose our patient to a higher risk of aggressive disease. Consequently, an early diagnosis with a prompt start of treatments is required to avoid the progression of the disabling symptoms.

The correct identification of cases with coexistence between CTD and NMOSD may have consequences for the establishment of appropriate therapy. The therapeutic strategy for neurological diseases in patients with MCTD is not well-defined due to the low incidence of cases (7); thus, it is still unclear which standard treatment should benefit patients with both NMOSD and CTD. Regarding the acute phase, all patients with a diagnosis of NMOSD should be treated with a combination of steroids and plasmapheresis as the first line of therapy, whereas resistant patients may benefit from second-line agents such as IV cyclophosphamide. Eculizumab, inebilizumab and satralizumab, currently approved second-line agents for NMOSD, were not utilized for CTD treatment in clinical experience (4). Results from a randomised controlled trial (RCT) suggested that rituximab has a favourable effect in patients with NMOSD (24), and consequently may be successfully used to control symptoms of both SLE and NMOSD in patients with overlapping diseases (25,26). As several case reports described that standard therapy with rituximab was used to successfully control symptoms of both CTD and NMOSD in patients with concomitant disease (4), our patient started rituximab for his maintenance therapy. However, to date, the clinical efficacy of rituximab in these patients has not yet been established conclusively (4).

Conclusions

The coexistence of NMOSD and MCTD has so far been poorly described, and many of its clinical aspects are not yet fully known. Missed diagnosis of rheumatologic or neurologic diseases may lead to treatment delay and, potentially, irreversible disability. Close collaboration between neurologists and rheumatologists is critical to improve clinical and therapeutic management of these patients. A multicentric study collecting patients with the coexistence of NMOSD and CTD may be required to improve knowledge of this clinical condition.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-23-48/rc

Peer Revie File: Available at https://acr.amegroups.com/article/view/10.21037/acr-23-48/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-23-48/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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