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A 49 year old woman with polyneuropathy, glomerulonephritis, leucocytoclastic vasculitis, restrictive lung disease, scleroderma-like skin changes, and myalgia, developed progressive myopathy, autoantibodies against voltage gated calcium channels (VGCCs) and a typical electromyographic pattern in accordance with a Lambert-Eaton myasthenic syndrome (LEMS). HLA typing showed that the patient carried the 8.1 ancestral haplotype (HLA-A1, B8, DR3), associated with multiple immunological diseases.1 To our knowledge, this is the first presentation of LEMS occurring in a patient with undifferentiated connective tissue disease.
Our patient initially presented at the age of 32 (in 1987) with sicca syndrome and Raynaud’s phenomenon followed by arthralgia, malaise, and paraesthesia. She subsequently developed leucocytoclastic vasculitis, restrictive lung disease, scleroderma-like skin changes, and proteinuria responsive to steroids. Rheumatoid factor was occasionally positive, while C4 was persistently low to undetectable. SSB and anti-Sm antibodies were once weakly positive (but never thereafter), while low titres of antinuclear antibodies, IgM and IgG immune complexes were increased on several visits. SSA, dsDNA, U1RNP, phospholipid, cANCA, pANCA, Jo-1, and centromere antibodies were negative on several occasions. Thus, her clinical and laboratory investigations did not allow a definite diagnosis at this point.
Starting in 1996–97, the patient noticed slowly progressive loss of strength in the lower extremities (predominantly thighs), rendering her incapable of walking long distances at times. In addition, she had a vasculitic flare, which was eventually controlled with azathioprine. The myopathy, however, persisted for the following years with tolerable symptoms. Various immunosuppressive agents (including methotrexate and ciclosporin A) required for treatment of a progressive polyneuropathy due to epineural vasculitis also did not alter the course of the myopathy. Serum creatine kinase was never raised and multiple clinical and laboratory investigations did not point towards infectious, autoimmune, metabolic, or endocrine causes. In addition, Sjögren’s syndrome associated with the vasculitis was diagnosed in the same year, explaining several, but not all, of her rheumatological symptoms.
In 1999, muscle weakness progressed to the upper extremities, while loss of strength, especially in both hip flexors and extensors, increased significantly (up to paresis grade 2/5 for flexors). A muscle biopsy (M deltoideus) performed 1 year later excluded any inflammatory infiltrates. Steroid induced myopathy was clinically suspected. Stopping the steroid treatment, however, did not relieve the myopathic symptoms. Further, the patient developed fever of unknown origin in 2001 and received netilmicin as part of the antibiotic coverage. This antibiotic (from the class of aminoglycosides known to exacerbate LEMS2) was associated with a dramatic deterioration of her muscle weakness in the lower extremities (especially hip flexors and extensors, but also knee flexors). Electromyographic studies finally showed a pathological increment after stimulation suggestive of LEMS. Positive autoantibodies against VGCCs confirmed the diagnosis, and daily treatment with 3,4-diaminopyridine improved all myasthenic symptoms after the first dose. Extended tumour screening remains negative to date.
In 2002 the patient surprisingly developed symmetric myalgias of the upper extremities not responsive to 3,4-diaminopyridine. These distinctive muscular symptoms evolved after a gastrointestinal infection. Creatine kinase was still in the normal range, but the erythrocyte sedimentation rate was significantly raised. A high dose of steroids promptly relieved these symptoms, suggesting another, possibly vasculitic, cause for her sequelae at this time.
Finally, recent investigations showed a typical HLA pattern associated with multiple autoimmune diseases (HLA-A1, B8, DR3; table 1)1 and increased basal tumour necrosis factor α (TNFα) levels (10.8 pg/ml; normal range 0.1–8.1 pg/ml). Interestingly, raised serum TNFα was measurable, although the patient’s blood was drawn after several weeks of inactive disease defined by lack of signs, symptoms, or laboratory data suggestive of a flare. The patient’s only immunosuppressive drug at this time was azathioprine and tapering doses of steroids.
LEMS is a rare autoimmune disorder of the neuromuscular junction characterised by autoantibodies against VGCCs.2 Cancer is frequently associated and usually detected within 2 years after diagnosis.2 Our patient, however, is a 49 year old, female non-smoker with coexisting systemic autoimmune disease. In addition, HLA-DRB*0301, DQB1*0201, and HLA-B8 are strongly associated with non-neoplastic LEMS, arguing against paraneoplasic mechanisms.3,4
LEMS has been reported in association with only a few systemic autoimmune diseases.5–7 Here we described a patient with undifferentiated connective tissue disease8 and Sjögren’s syndrome before the development of LEMS. The diversity of autoimmune phenomena, including the recent onset of LEMS, prompted us to investigate the patient’s HLA typing. In addition to the notion that this LEMS might be non-neoplastic,3,4 the distinct combination of her HLA alleles indicated the presence of an ancestral haplotype (table 1) which has been associated with various autoimmune conditions.1 Although polymorphisms in HLA molecules are likely to be involved in predisposition to autoimmunity, the striking association of this haplotype might also be partly explained by linkage of disease promoting genes within the central major histocompatibility complex (MHC) region. Of note, a genetically determined high setting of TNFα has been associated with this haplotype.9 Raised levels of TNFα have also been linked to LEMS.10 Our patient indeed showed increased serum levels of TNFα despite inactive disease. Thus, this central cytokine might possibly play a part in the pathogenesis of at least some of the various autoimmune phenomena seen in our patient.
In summary, this report further strengthens the link between autoimmunity to connective tissue and the nervous system, together with a common genetic susceptibility region. It also demonstrates the difficulties of differentiating muscle weakness in patients with systemic autoimmunity.
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