Rare overlap of cryoglobulinemic vasculitis and anti-mda5 dermatomyositis: a case report

¹Department of Internal Medicine, Hédi Chaker University Hospital, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia, ²Department of Radiology, Hédi Chaker University Hospital, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia, ³Department of Immunology, Habib Bourguiba University Hospital, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia

^&Corresponding author
Amal Haddad, Department of Internal Medicine, Hédi Chaker University Hospital, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia

Introduction    

Idiopathic inflammatory myopathies (IIMs) include polymyositis, dermatomyositis (DM), necrotizing myopathy, inclusion body myositis, and overlap syndromes with myositis. Among these, DM is subclassified based on myositis-specific autoantibodies, including anti-melanoma differentiation-associated protein 5 (anti-MDA5), which is strongly associated with rapidly progressive interstitial lung disease (RPILD) [1]. Although neuromuscular involvement is a hallmark of DM, peripheral neuropathy is rarely reported and poorly understood. Whether neuropathy represents a direct inflammatory process or an indirect consequence of associated conditions such as vasculitis is often debated, making its clinical management highly challenging. Cryoglobulinemic vasculitis, a small-vessel vasculitis mediated by cryoglobulin deposition, is frequently associated with infections, lymphoproliferative disorders, and autoimmune diseases. It is important to distinguish asymptomatic cryoglobulinemia from true cryoglobulinemic vasculitis, which involves active inflammatory damage to blood vessels [2]. Although its occurrence in patients with DM is extremely rare, it is strongly associated with peripheral neuropathy. Herein, we report a unique case of anti-MDA5 DM associated with type II cryoglobulinemia complicated by severe phrenic nerve neuropathy. Although obtaining direct mechanistic evidence, such as a nerve biopsy, is often clinically unfeasible in critically ill patients, this case provides crucial insights into the empirical and successful use of targeted immunotherapy for life-threatening overlapping manifestations.

Patient and observation     

Patient information: a 46-year-old woman with a history of hypothyroidism and adrenal insufficiency presented with acute respiratory distress, diffuse myalgia, and dysphagia in the context of general deterioration.

Clinical findings: on admission, the patient had stage IV dyspnea with an oxygen saturation of 54% on room air. Dermatological examination revealed ulceronecrotic skin lesions with tissue loss, associated with areas of hyperpigmentation and hypopigmentation (Figure 1). Pharyngeal muscle involvement resulted in dysphagia and nasal regurgitation of liquids. Osteoarticular examination revealed synovitis of the wrists and metacarpophalangeal and proximal interphalangeal joints, as well as flexion contractures of the elbows. Neurological examination revealed tetraparesis with proximal muscle weakness but no sensory deficit. The patient was unable to stand or walk without assistance due to severe kyphosis.

Diagnostic assessment: the biological workup revealed lymphopenia (730/mm³), aregenerative anemia with a hemoglobin level of 9.8 g/dL, elevated ferritin levels (1085 ng/mL), an erythrocyte sedimentation rate of 95 mm/h, and a C-reactive protein level of 93 mg/L. Creatine phosphokinase levels were elevated. Protein electrophoresis showed an inflammatory profile with polyclonal hypergammaglobulinemia (24.1 g/L) without any monoclonal component. Thoracoabdominopelvic computed tomography (CT) revealed lesions consistent with organizing pneumonia. Echocardiography findings were normal. Electromyography demonstrated bilateral axonal damage to the phrenic nerves and asymmetric axonal motor involvement in the four limbs. Brain and spinal MRI findings were normal. Muscle MRI confirmed bilateral quadriceps myositis, and the muscle biopsy findings were consistent with dermatomyositis (Figure 2).

MRI of the hand showed features of destructive erosive arthropathy involving the 2^nd and 3^rd metacarpophalangeal joints of the right hand and the proximal interphalangeal joint of the 3rd finger of the left hand. Bilateral distal radioulnar synovitis was observed, which was associated with left intercarpal and radiocarpal synovitis. The overall pattern was suggestive of rheumatoid arthritis. The infectious workup, including serologies for hepatitis B and C, HIV, and toxoplasmosis, was negative. Immunological testing revealed positive antinuclear antibodies at a titer of 1/640, associated with type II cryoglobulinemia. The myositis antibody panel identified the presence of anti-MDA5 antibodies. The diagnosis of anti-MDA5 dermatomyositis associated with symptomatic cryoglobulinemic vasculitis was established.

Therapeutic intervention: given the severe pharyngeal and respiratory involvement, the patient was treated with three boluses of methylprednisolone, followed by high-dose oral corticosteroids at 1 mg/kg/day for two months, with a gradual taper. She also received 20 mg/week methotrexate and oxygen therapy. The initial evolution was unfavorable, with persistence of cutaneous, respiratory, and muscular symptoms. Several attempts to withdraw oxygen therapy were unsuccessful due to desaturation. Given the absence of clinical improvement, a second-line treatment was initiated, consisting of intravenous immunoglobulin at 2 g/kg and rituximab at a dose of 1 g on days 1 and 15.

Follow-up and outcomes: following this combined therapy, the patient showed progressive improvement in muscle strength and respiratory symptoms, allowing for the successful withdrawal of oxygen therapy. The skin lesions gradually healed, and muscle strength reached 4/5. Before discharge, the patient was able to stand and walk independently without assistance. The cutaneous lesions were completely resolved.

Informed consent: written informed consent was obtained from the patient for publication of this case report.

Discussion     

Our findings describe a rare and life-threatening overlap of anti-MDA5 DM and type II cryoglobulinemia, highlighted by severe diaphragmatic paralysis due to phrenic nerve neuropathy. This case adds to the pertinent knowledge by illustrating that acute respiratory distress in anti-MDA5 DM is not strictly limited to RPILD or direct muscle weakness, but can also be driven by severe, underlying neurogenic damage potentially mediated by associated cryoglobulinemic vasculitis.

Although the presence of cryoglobulins in the serum has been reported in patients with dermatomyositis or polymyositis, the association between these two entities remains rare and poorly documented, and its mechanism is still not well understood [2-5]. Among the few reported cases, Voll et al. described a 73-year-old patient with polymyositis who presented with purpura in the lower limbs and cryoglobulinemia without other clinical signs of vasculitis [4]. Another case involved a 31-year-old woman with inflammatory myopathy associated with sensory-motor axonal neuropathy and cryoglobulinemia, who responded well to corticosteroid treatment and cyclophosphamide, suggesting that cryoglobulinemia could be considered a differential diagnosis for unexplained inflammatory myopathy [2].

In our case, the diagnosis of anti-MDA5 DM was established due to proximal muscle weakness without sensory involvement, bilateral quadriceps myositis confirmed by MRI, a muscle biopsy showing suggestive features, and positive anti-MDA5 antibodies. The associated cryoglobulinemia was deemed secondary to the DM, as extensive workups excluded lymphoproliferative disorders, viral infections (including hepatitis B and C), and other connective tissue diseases. The ulceronecrotic skin involvement could be attributed to either pathology.

Another major feature of our patient was severe respiratory distress upon admission. Pulmonary involvement in anti-MDA5 dermatomyositis is usually associated with rapidly progressive interstitial pneumonia or respiratory muscle involvement, particularly the diaphragm. However, in our patient, respiratory distress was secondary to diaphragmatic paralysis due to axonal neuropathy of the phrenic nerves, as demonstrated by electromyography [6]. Neurogenic involvement is uncommon in patients with isolated dermatomyositis. In our institutional experience of 130 patients with IIM, this is the third case of diaphragmatic paralysis and the first case of IIM associated with cryoglobulinemia. Peripheral neuropathy associated with dermatomyositis and polymyositis is complex and poorly understood. Neuromyositis, defined as the association between dermatomyositis or polymyositis and neuropathy, is a controversial concept. Some studies suggest that neuropathy could be a secondary manifestation of muscle inflammation, while others believe that it might result from a common pathological process affecting both muscles and nerves [6-8].

However, in our patient, this peripheral neurogenic involvement could be attributed to cryoglobulinemic vasculitis, although the muscle biopsy did not show signs of vasculitis. The coexistence of these two entities poses a real diagnostic challenge owing to clinical overlap, especially between neuromuscular involvement and mixed-origin respiratory distress. Corticosteroid treatment remains the cornerstone of the management of dermatomyositis. In our case, IVIG administration was justified by severe, life-threatening involvement (respiratory distress and dysphagia). Methotrexate, at a dose of 15-20 mg/m²/week (not exceeding 20 mg/week), was initiated in combination with other drugs in accordance with recommendations because of its proven effectiveness in dermatomyositis [9].

The use of rituximab at a dose of 375 mg/m² x 4 or 1 g on two occasions, although not systematically used as first-line therapy in dermatomyositis, was decided because of the severity of cutaneous and neurological involvement, likely secondary to cryoglobulinemic vasculitis [10]. The evolution under treatment was marked by progressive improvement in muscle, respiratory, and cutaneous symptoms, confirming the importance of early and aggressive management to limit systemic complications of the disease. The critical takeaway from this case is that acute respiratory failure in anti-MDA5 DM should not automatically be attributed to interstitial lung disease or primary myopathy. Clinicians must actively screen for overlapping conditions, such as cryoglobulinemia, which can drive rapidly progressive, life-threatening phrenic neuropathy.

We acknowledge the inherent limitations of this report. Direct histological evidence of phrenic nerve vasculitis-the confirmatory mechanistic evidence-could not be obtained due to the anatomical unfeasibility and extreme clinical risk of performing such a biopsy in a severely dyspneic patient. Nevertheless, the underlying mechanism is strongly suspected to be ischemic. Cryoglobulinemic vasculitis classically induces inflammation and thrombosis of the vasa nervorum, leading to severe axonal degeneration. In the context of anti-MDA5 DM, where endothelial injury is already a prominent feature, the superimposition of cryoglobulin precipitates likely acted as a trigger for rapid neural ischemia, which was successfully reversed by targeted immunosuppression.

Conclusion     

This case highlights the heterogeneity of the clinical presentations of anti-MDA5 dermatomyositis and emphasizes the importance of investigating associated vascular and neuromuscular complications. The rare association with cryoglobulinemic vasculitis may reflect a pathophysiological overlap that requires further characterization to optimize diagnostic and therapeutic strategies.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Amal Haddad, Mariam Ghribi: methodology, resources analysis, writing. Sameh Marzouk, Mouna Guermazi, Zouhir Bahloul: investigation, review and editing. Sawsen Feki, Zeinab Mnif, Amina Kammoun, Hend Hachicha: investigation. All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship. All authors have read and agreed to the final version of this manuscript.

acknowledgements     

We acknowledge all the colleagues who assisted or collaborated on this study. The authors used an AI-assisted language editing tool to improve the grammar and clarity of the manuscript. The authors reviewed and edited all content and take full responsibility for its accuracy, originality, and integrity.

Figures     

Figure 1: clinical presentation showing ulceronecrotic skin lesions with tissue loss, associated with areas of hyperpigmentation and hypopigmentation

Figure 2: muscle biopsy findings consistent with dermatomyositis: A) variation in myofiber diameter, with the presence of atrophic round muscle fibers (H&E, ×100); B) Presence of sparse necrotic muscle fibers (H&E, x200); Cs) Septal and perivascular mononuclear inflammatory infiltrate (H&E, ×100); D) Gomori trichrome staining showing the absence of vacuoles in the muscle cell cytoplasm (Gomori trichrome, x200)

References