Over a 19-year period, we diagnosed four patients with MG (three patients with CD and one with UC) in our cohort of 606 patients with IBD (prevalence of 0.66%). Patients are currently 45.75±7.29 years old. Mean age at IBD diagnosis was 33.5±2.69 years, mean age at MG onset was 39.5±2.69 years. There were three women and one man. Preliminary results of two cases were reported elsewhere.15 The Prevalence ratio (PR) of having MG in IBD patients vs the proportion of MG among all patients in our center was 8.56 (P<0.0001, CI=3.1-23.5). Considering the lowest and highest reported prevalence of MG worldwide, the PR is 44.00 (P<0.0001, CI:16.3-118.4) and 26.40 (P<0.0001, CI: 9.8-70.6), respectively.
Patient 1 (initial findings previously reported) [15]
A man was diagnosed with UC at age 37. Three years later, he underwent total laparoscopic colectomy sparing the rectum for the treatment of colonic dysplasia. A gastro-colonic fistula identified during the surgery led to a partial gastrectomy and a diagnostic shift to CD. After assuming that he was cured by colectomy, he missed follow-up evaluations and 2 months after tapering off prednisone and azathioprine, he developed quadriparesis with bilateral ptosis, dysphagia and slurred speech over a few weeks. His condition progressed and he was admitted to an intensive care unit, intubated and kept on mechanical ventilation. MG was diagnosed. NCS and EMG were normal. RNS revealed basal compound muscle action potential decrements at the right ulnar nerve up to 22% that improved after exercise (correction) and increased two minutes after forced muscle contraction up to 31%. Anti-acetylcholine receptor antibody (Anti-AchRAB) were elevated up to 10.7. Serum Immuno-electrophoresis revealed polyclonal gammopathy, Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) titers were positive (1:640), Thyroid-stimulating hormone was decreased (0.2) and homocysteine elevated (11.7). Anti-nuclear antibody and rheumatoid factor were negative. Chest computed tomography did not disclose thymoma. Subsequently MG remained well controlled with prednisone, azathioprine and pyridostigmine, except for occasional fatigability. Thymectomy was offered repeatedly in the first years after MG diagnosis, but he refused it. He was also diagnosed with small fiber neuropathy, characterized by distal paresthesias and abnormal skin wrinkling test. He was also diagnosed with osteoporosis and had two bouts of nephritic colic with hydronephrosis.
Patient 2 (initial findings previously reported) [15]
A 35 year-old woman was diagnosed with UC and subsequently developed jaundice, severe anemia, hepatosplenomegaly and was diagnosed with primary sclerosing cholangitis. Five years later, she developed speech impairment, bilateral ptosis, disconjugate gaze, fatigability with sustained vertical movements and mild proximal upper limb weakness. NCS and EMG were normal. Right ulnar RNS demonstrate significant decrement with correction after exercise and worsening three minutes post exercise. Skin wrinkling test was abnormal (mean score of 0.5) and she had mild sensory findings consistent with small fiber neuropathy. Anti-AchRAB were above 20, Anti-nuclear antibody was positive and normal Immunoglobulin G-4 (IgG4) level (87,52). Initial treatment with pyridostigmine and prednisone was successful, but her symptoms progressed in severity. Thymectomy was recommended but could not be performed due to persistent thrombocytopenia (idiophatic thrombocytopenic purpura versus myelodysplastic syndrome). She was subsequently treated with prednisone and Intravenous immunoglobulin infusions, since she could not be treated with azathioprine due to cirrhosis. On 8/2021 she was started on rituximab with good MG control since then.
Patient 3
A 37 year-old woman was diagnosed with CD after a 10-year history of diarrhea, weight loss and abdominal pain. Colonoscopy revealed aphthous ileal, cecal and rectal ulcers (in 2016). She was treated with sulfasalazine and mesalazine and got worse after developing a perianal fistula. She was started on azathioprine on 5/2019, that was stopped due to abdominal pain and elevated aspartate aminotransferase and alanine aminotransferase. She was referred for neurological evaluation of headache and was initially diagnosed with trigeminal neuralgia. She also had dizziness, distal paresthesias and complained of repeated episodes of left facial palsy. She also met the diagnostic criteria of restless leg syndrome and small fiber neuropathy with an abnormal skin wrinkling test (mean score of 1.75). She had been previously diagnosed with fibromyalgia. Neurological exam revealed bilateral (predominant left) facial weakness, hyperreflexia with bilateral Hoffmann sign as well as distal pin loss. On 7/2021 she was diagnosed with Multiple Sclerosis and started on Copaxone s.c., three times/week (Brain MRI findings with normal cervical MRI). She was also diagnosed with anemia (Hemoglobin = 7.2; Hematocrit = 21) and borderline low Vitamin B12 level = 227. On 5/2022 she was found to have worsening of bilateral facial weakness with disconjugate eye movements and fatigability on sustained vertical gaze evaluation, and was diagnosed with myasthenia gravis. Nerve conduction studies and EMG were normal. RNS did not disclose significant decrement and anti-AchR antibodies were negative. She improved with PO pyridostigmine and prednisone (40 mg/day). Chest computed tomography did not reveal thymoma and thymectomy has not been accepted so far.
Patient 4
A 37 year-old woman was diagnosed with CD after a 8-year history of bloody diarrhea and 17-kg weight loss and abnormal colonoscopy. She was initially treated with mesalazine and prednisone and then azathioprine. After developing an anovaginal fistula she was started on inflixamab. She then developed episodic right eye pain and migraine episodes 20 days prior to inflixamab infusions. On 4/2021, she developed left eye ophthalmoplegia and vision loss. She was admitted for inpatient treatment with i.v. methylprednisolone after being diagnosed with orbital apex syndrome due to a posterior variant of orbital pseudotumor. Since vision loss resolved with steroids but she persisted with eye movement abnormalities, including fatigability, she was evaluated for MG. Nerve conduction studies and EMG were normal. RNS disclosed a greater than 10% decrement on facial nerve RNS. Anti-AchR antibodies were normal but anti-muscle specific kinase (anti-MuSK) antibodies were positive (0,09 NMOL/L). Chest Computed tomography did not disclose thymoma and she had a good response to pyridostigmine and PO prednisone. She only had mild generalized weakness that improved with prednisone. IgG4 levels were normal 53,24 (8-140). Anti-aquaporin-4, thyreoglobulin antibodies were negative. Vitamin B12 levels were also low (173) and treated with intramuscular vitamin B12 replacement. She does have mild distal paresthesias consistent with small fiber neuropathy, that was confirmed by abnormal skin wrinkling test (mean score of 0.5).
Literature review
As can be seen in Table 1 and Fig. 1, our systematic literature review disclosed 22 papers and 28 patients with IBD and MG [3,7,16-42]. In several articles, important demographic details were not provided. Seven additional papers describing MG registries where additional autoimmune diseases could be identified were also evaluated.
Eleven patients (five women and four men, two unknown gender) had MG and CD, mean age of CD diagnosis was 44.6±19.17 years. One of them was included but CD diagnosis was not clearly defined at that time. Seventeen patients had UC and MG, mean age of UC diagnosis 27.9±17.01 years, total of eight men and six women. In most cases, the MG diagnosis was made several years after IBD diagnosis, 3-15 years for CD and 0.2 to 13 years for UC. However, in two UC patients and three CD patients, MG was diagnosed 1-4 years prior to IBD diagnosis (one had undefined duration). Fourteen patients had an additional autoimmune disease (other than MG and IBD), four for CD and 10 for UC. One patient had thyroid cancer and another colon cancer.
According to MG Foundation classification, 30.4% were class IV and V. Pure ocular disease (I) and moderate forms (IIIb) occurred in the same proportion (6/23=26% for each), while milder forms of generalized disease (II) affected 17.3% of the patients. Among 21 patients who underwent antibody testing, 18 (18/21=85.7%) were AchRAB+ and three were negative (3/21=14.28%). Only one had anti-muscle specific kinase antibodies (anti-MuSK) testing, that was negative. No one was tested for Lipoprotein receptor related protein-4 (LRP4) or agrin antibodies. Thymectomy led to improvement of MG in the majority of the patients (6/11=54.5%), but in one patient, despite MG remission, Systemic lupus erythematosus (SLE) and UC started after thymectomy. In four patients no information about thymectomy outcome was provided. Among the seven MG registries detailing the occurrence of associated autoimmune conditions, the prevalence of IBD and MG varied from 0.35% among 565 MG patients from Holland to 2.56% among 39 patients older than ³70 years with MG in the USA.
Table 1.