Trigeminal involvement in dermatomyositis with double positivity for anti-transcriptional intermediary factor 1 gamma and anti-Ku antibodies: A case report and literature review

Abstract

Anti-transcriptional intermediary factor 1 gamma antibody and anti-Ku antibody double-positive dermatomyositis and trigeminal neuropathy involvement are often regarded as clinically distinct diseases with differing pathogenesis. Herein, we present a rare case of dermatomyositis with dual positivity for anti-transcriptional intermediary factor 1 gamma and anti-Ku antibodies, accompanied by trigeminal neuropathy. Both conditions showed significant improvement following standard dermatomyositis treatment. A review of the literature revealed that cases of anti-transcriptional intermediary factor 1 gamma-positive dermatomyositis complicated by trigeminal involvement are very rare, and their pathogenesis and association remain unclear. To the best of our knowledge, this is the first reported case of dermatomyositis with dual positivity for anti-TIF1-γ and anti-Ku antibodies, accompanied by trigeminal neuropathy. This case highlights the need for clinicians to pay closer attention to this rare coexistence.

Introduction

Dermatomyositis, a subtype of idiopathic inflammatory myopathies, is characterized by a distinctive set of skin abnormalities and a wide range of systemic clinical features. ¹ In dermatomyositis, disease-specific autoantibodies are detectable in more than 70% of patients and are strongly associated with specific clinical phenotypes. In recent years, growing evidence has further elucidated the clinical significance of these autoantibodies. ² Trigeminal neuralgia is a neuropathic facial pain disorder marked by sudden, severe, and paroxysmal pain that significantly impairs quality of life. ³ Anti-transcriptional intermediary factor 1 gamma (TIF1-γ)-positive dermatomyositis and trigeminal neuropathy involvement are often regarded as clinically distinct conditions with differing pathogenesis. Herein, we report a rare case of dermatomyositis with dual positivity for anti-TIF1-γ and anti-Ku antibodies, accompanied by trigeminal neuropathy involvement, both of which showed marked improvement following standard dermatomyositis treatment.

Case presentation

A 74-year-old woman was referred to our institution (Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China) in August 2024 with a 6-month history of progressive facial neuropathy. Over the past month, she developed limb weakness, Gottron’s papules, and a violaceous erythematous rash. Her persistent facial dysesthesia was accompanied by left-sided trigeminal neuralgia and restricted mouth opening due to pain, which had previously been diagnosed as classical trigeminal neuralgia at other facilities.

The patient’s medical history included well-controlled hypertension and type 2 diabetes mellitus under pharmacologic management. She denied any history of tobacco use. Her personal, reproductive, and family histories were noncontributory, with no known exposure to environmental toxins or occupational hazards. The reporting of this study conforms to the Case Report (CARE) guidelines. ⁴

On physical examination, the patient presented with Gottron’s papules and violaceous erythematous rashes on the dorsal aspects of both hands and elbows. She exhibited mild muscular tenderness in the extremities, with bilateral thigh muscle strength graded as 5− and upper limb strength graded as 5 (Medical Research Council scale). Laboratory investigations revealed markedly elevated muscle-derived enzymes, including creatine kinase (CK, 3061 U/L) and lactate dehydrogenase (LDH, 629 IU/L), accompanied by transaminitis (aspartate transaminase (ALT), 145 U/L; alanine transaminase (AST), 134 U/L) (Table 1). Laboratory tests revealed a mild elevation of C-reactive protein (CRP; 0.7 mg/L). The antinuclear antibody (ANA) was positive at a titer of 1:1000 with a speckled pattern. Myositis-specific antibody testing performed using a line immunoassay (LIA; EUROLINE, Euroimmun) revealed strong positivity for anti-TIF1-γ (+++) and anti-Ku (+++) antibodies, whereas other autoantibodies were negative (detailed laboratory results are provided in Table 1).

Table 1.

Relevant laboratory findings at presentation.

Parameters	Results	Normal range values
Inflammation markers
Erythrocyte sedimentation rate (mm/h)	21	1–20
C-reactive protein (mg/L)	0.7	0–6
Ferritin (µg/L)	286.10	13–150
Muscle enzymes
Alanine aminotransferase (U/L)	145	7–40
Aspartate aminotransferase (U/L)	134	13–35
Creatine kinase (U/L)	3061	40–200
CK-MB isoenzyme activity (IU/L)	202	0–24
Immunological panel
Antinuclear antibodies	1:1000, speckled
Anti-neutrophil cytoplasmic antibodies	Negative
Anticardiolipin antibodies	Negative
Rheumatoid factor (IU/mL)	5.6	<14
Extractable nuclear antigen antibodies (anti-Jo1, anti-RNP,  anti-Sm, anti-SSA, anti-SSB, anti-Scl-70)	Negative
Inflammatory myopathies panel
Anti-TIF1-γ	+++
Anti-Ku	+++
Other antibodies: anti-Mi-2α, anti-Mi-β, anti-MDA5, anti-NXP2, anti-SAE1, anti-PM-Scl100, anti-PM-Scl75, anti-Jo1, anti-SRP, anti-PL7, anti-PL12, anti-EJ, anti-OJ, and anti-Ro52	Negative
Viral and parasitological screening
Epstein–Barr virus IgG and IgM	Negative
Cytomegalovirus IgG and IgM	Negative

anti-Jo1: anti-histidyl–tRNA synthetase antibody; anti-RNP: anti-ribonucleoprotein antibody; anti-Sm: anti-Smith antibody; anti-SSA: anti-Sjögren’s-syndrome-related antigen A antibody; anti-SSB: anti-Sjögren’s-syndrome-related antigen B antibody; anti-Scl-70: anti-topoisomerase I antibody; anti-TIF1-γ: anti-transcriptional intermediary factor 1 gamma; anti-MDA5: anti-melanoma differentiation-associated gene 5 antibody; anti-Mi-2α/anti-Mi-2β: anti-nucleosome-remodeling-deacetylase complex antibodies (Mi-2 α and β subunits); anti-NXP2: anti-nuclear matrix protein 2 antibody; anti-SAE1: anti-small ubiquitin-like modifier-activating enzyme 1 antibody; anti-PM-Scl75/anti-PM-Scl100: anti-exosome complex antibodies (PM-Scl 75 and 100 kDa subunits); anti-SRP: anti-signal recognition particle antibody; anti-PL7: anti-threonyl–tRNA synthetase antibody; anti-PL12: anti-alanyl–tRNA synthetase antibody; anti-OJ: anti-isoleucyl–tRNA synthetase antibody; anti-Ro52: anti-Ro52 kDa protein antibody; IgG: immunoglobulin G; IgM: immunoglobulin M; CK-MB: creatine kinase-MB.

Magnetic resonance imaging (MRI) revealed extensive, symmetrical intramuscular edema, particularly pronounced in the lower extremities (Figure 1). This finding was consistent with active inflammatory myopathy. Electromyography demonstrated sarcolemmal irritability, characterized by fibrillation potentials in the biceps brachii muscle and positive sharp waves in the right deltoid, right biceps brachii, right quadriceps femoris, and tibialis anterior muscles. Furthermore, the polyphasic motor units of the right quadriceps femoris and right gastrocnemius muscles showed increased activity, with a narrow mean duration and low amplitude. Whole-body positron emission tomography/computed tomography (PET/CT) revealed no evidence of malignancy or paraneoplastic involvement. The diagnosis of dermatomyositis was established based on the presence of Gottron’s papules with violaceous erythema over the dorsal hands and elbows, progressive symmetrical proximal muscle weakness (predominantly affecting the lower extremities), and strongly positive anti-TIF1-γ antibodies.

Figure 1.

Bilateral thigh MRI showing symmetrical hyperintensity of the thigh muscle on T2WI, indicating muscle edema. MRI: magnetic resonance imaging; T2WI: T2-weighted imaging.

To determine whether hypogeusia accompanied by difficulty in mouth opening was attributable to a neurological disorder or a neurological alteration associated with dermatomyositis, we performed a skull base MRI. The T2-weighted fat-suppressed signal of the left temporalis, masseter, and medial pterygoid muscles showed a slight increase and marginally greater enhancement (Figure 2). Magnetic resonance trigeminal imaging (MRTA) revealed that the left trigeminal nerve was in close proximity to the crossing small vessels. Concurrent otorhinolaryngology consultation, nasal endoscopy, and PET revealed no space-occupying lesions. In the absence of other identifiable neurological pathology, the observed trigeminal nerve involvement was considered most likely attributable to dermatomyositis, given the established association. Following diagnosis confirmation, the patient was started on standard first-line therapy consisting of prednisone (1.0 mg/kg/day) and methotrexate (12.5 mg weekly). We obtained written informed consent for treatment and publication from the patient. At the 1-week follow-up, she exhibited significant clinical improvement, including markedly increased mouth opening and partial recovery of taste perception. Laboratory findings demonstrated a substantial biochemical response to treatment, with notable reductions in inflammatory markers and muscle enzyme levels. Specifically, ALT decreased to 70 U/L, AST to 60 U/L, LDH to 315 IU/L, and CK to 764 U/L, and creatine kinase-MB (CK-MB) activity declined to 77 IU/L. Inflammatory markers showed notable improvement, with CRP measured at 0.8 mg/L and the erythrocyte sedimentation rate (ESR) returning to within the normal range.

Figure 2.

Skull base MRI showing slightly increased T2 fat-suppressed signals in the left temporalis, masseter, and medial pterygoid muscles. MRI: magnetic resonance imaging.

At the 6-month follow-up, the patient reported complete resolution of pain during mouth opening, disappearance of muscle weakness, and marked improvement of cutaneous lesions. Laboratory tests demonstrated normalization of all previously elevated parameters, including muscle enzyme and inflammatory marker levels. The maintenance regimen consisted of prednisone (10 mg daily) and methotrexate (15 mg weekly).

Discussion

The patient presented with Gottron’s papules and violaceous erythematous rashes on the dorsal aspects of both hands and elbows. However, there were no signs suggestive of systemic sclerosis, such as skin sclerosis or dysphagia. Notable findings included elevated CK levels, extensive symmetrical intramuscular edema of the lower limbs on MRI, myopathic electrical activity without evidence of peripheral neuropathy on electromyography, and positivity for anti-TIF1γ and anti-Ku antibodies. Consequently, a diagnosis of dermatomyositis was established. ⁵ The patient exhibited numbness in the left lateral facial region and restricted mouth opening. Skull base MRI revealed potential inflammation in the left temporalis, masseter, and medial pterygoid muscles. Additionally, MRTA revealed small vessels surrounding the left trigeminal nerve. After multiple consultations with neurology specialists, primary neurological disease was ruled out. The observed inflammation associated with dermatomyositis affected the trigeminal nerve and temporalis muscle.

The association between peripheral neuropathy and connective tissue disease (CTD) is well established; however, the link between nerve involvement and dermatomyositis remains unclear owing to the limited number of relevant studies. The reported prevalence of peripheral neuropathy is 40%–50% in rheumatoid arthritis, 5%–27% in systemic lupus erythematosus, 10%–22% in Sjögren syndrome, and 5%–67% in systemic sclerosis.^6–8 The impact of dermatomyositis on the central or peripheral nerves is not well understood. A retrospective study reported that 18.3% of patients with dermatomyositis developed peripheral neuropathy. Notably, patients with dermatomyositis and peripheral neuropathy exhibited a significantly higher incidence of malignancy. ⁹ Studies have reported that the prevalence of peripheral nervous system lesions in systemic lupus erythematosus and systemic sclerosis ranges from 10.0% to 86.7%. This neuropathy demonstrates variable clinical manifestations, with trigeminal neuropathy in this case representing one such manifestation, with an incidence of 2.6%–32.0%.^10–13 Previous reports have indicated an association between the trigeminal nerve and mixed CTD^14,15 as well as polymyositis. ¹⁶ Furthermore, the association between trigeminal neuropathy and dermatomyositis remains ambiguous, with the underlying mechanisms yet to be elucidated. Inflammatory and potentially fibrotic processes may contribute to the development of inflammatory myositis with trigeminal neuropathy. ¹¹ Another proposed mechanism is that nerve involvement in dermatomyositis may be mediated by the formation of the membrane attack complex (MAC), resulting in nerve injury. Complement-mediated pathogenic mechanisms may play a crucial role in the overall process of nerve injury. ¹⁷

Recent studies have focused on myositis-specific antibodies. Among these, the anti-TIF1-γ antibody has emerged as a potential marker for predicting cancer association in patients with dermatomyositis. ¹⁸ Notably, more than 50% of adult patients with anti-TIF1-γ antibody-positive dermatomyositis are found to have an associated malignancy.^19,20 A study of 349 cases of idiopathic inflammatory myopathies identified gastric, lung, breast, esophageal, and bladder cancers as the most prevalent types associated with anti-TIF1-γ antibody-positive myositis. ¹⁸ Muscle weakness (83%), Gottron’s sign (82.2%), heliotrope rash (73.7%), dysphagia (38.4%), and joint involvement (31.1%) were the most common clinical features observed in patients with anti-TIF1-γ antibody positivity. ²¹ Dermatomyositis is recognized for its association with an increased incidence of malignancy; however, reports of cranial nerve involvement in patients with anti-TIF1-γ antibody-positive dermatomyositis remain limited. ⁹ Anti-Ku antibodies were initially reported as autoantibodies associated with scleroderma–polymyositis overlap syndrome. However, they are also commonly detected in various connective tissue diseases, and their clinical significance remains unclear. ²² Gryga et al. described five patients with anti-Ku antibodies in connective tissue diseases, three of whom exhibited signs and symptoms of transient cranial neuropathy involving the trigeminal and facial nerves. ²³ Autoimmune diseases with anti-Ku antibodies have been associated with peripheral nerve manifestations; however, most studies are limited to case reports of systemic lupus erythematosus, Sjögren syndrome, and scleroderma. Similar reports of anti-Ku antibody-positive dermatomyositis have not been documented.

To the best of our knowledge, this is the first reported case of dermatomyositis with double positivity for anti-TIF1-γ and anti-Ku antibodies, accompanied by trigeminal neuropathy involvement. There are limitations in establishing a direct causal relationship between dermatomyositis and trigeminal neuropathy, as it is challenging to exclude other potential causes of trigeminal neuropathy. However, improvements in the treatment of dermatomyositis appear to correlate with enhanced performance in trigeminal nerve involvement, suggesting a feedback mechanism that may indicate a relationship between the two conditions. Patients with dermatomyositis, particularly those with anti-TIF1-γ antibody-positive dermatomyositis, may concurrently experience trigeminal neuropathy, a phenomenon warranting further investigation. Additional research is needed to validate the correlation between the two conditions.