Case 1: New-Onset Arthritis and Lymphadenopathy in a 13-Year-Old Girl With Myasthenia Gravis

Presented here are three patients who have a common chief complaint. All three cases have discussions on presentation, the differential diagnosis, and management that collectively serve as a Review article. Following the three cases, an expert weighs in in a short commentary with 5 questions for CME credit.A 13-year-old girl with myasthenia gravis diagnosed at the age of 2.5 years and absence epilepsy diagnosed 1 year ago presents to the emergency department (ED) with 1 week of right-sided neck swelling and tenderness with associated dysphagia to solids. Over the last few months, she has lost approximately 20 kg, complained of bilateral finger pain, and lost the ability to make fists, which she and her mother attribute to her myasthenia gravis. She also has bilateral knee pain and swelling, diagnosed as patellofemoral pain syndrome a few months prior. The patient and mother deny sick contacts, travel, cat scratches or other animal exposures, or insect bites. She has constipation at baseline but denies nausea, vomiting, and diarrhea. Menarche occurred at age 10; she is not currently menstruating. They deny fevers, but she is febrile on presentation. History is remarkable for thymectomy at age 4. Absence seizures were diagnosed at an outside hospital with an electroencephalogram (EEG) 1 year ago showing 3 Hz spike-and-waves potentiated by sleep and hyperventilation. It is unclear why this EEG was obtained, as the mother reports that the patient was referred to the neurologist for headaches. She has never witnessed behavioral arrest seizures or generalized tonic-clonic seizures. Medication reconciliation confirms the following home medications: ethosuximide, cetirizine, omeprazole, polyethylene glycol, and pyridostigmine. She started ethosuximide and cetirizine within the last year and has been on the other medications for several years. She receives bimonthly intravenous immunoglobulin infusions for myasthenia gravis and is due for an infusion in the next week.In the ED, vital signs include a temperature of 100.9 °F (38.3 °C), heart rate of 146 beats per minute, respiratory rate of 18 breaths per minute, and a blood pressure of 127/78 mm Hg. Review of her growth chart confirms 20-kg weight loss over the last 6 months. On initial examination, she has an approximately 3-cm mobile mass in the right occipital triangle of her neck that is tender to palpation. No other neck tenderness or lymphadenopathy is noted. Her neck is supple and oropharynx is clear, with no mucous membrane lesions. Respiratory, cardiovascular, and abdominal examinations are normal. Neurologic and musculoskeletal examinations show pain with flexion of digits and 4/5 grip strength bilaterally. Otherwise, she has 5/5 motor strength for head flexion and extension, biceps, triceps, deltoids, hip flexion, knee flexion and extension, plantar flexion, and dorsiflexion. Sensation is intact. She walks with short, choppy steps and complains of bilateral knee pain. Muscle tone and bulk appear normal, and no swelling or deformities are noted. Dermatologic examination does not reveal rashes, ulcers, or other lesions. Laboratory tests show C-reactive protein level of 6.2 mg/dL (62 mg/L) (reference range, <0.9 mg/dL [<9 mg/L]), procalcitonin of 0.11 ng/mL (110 ng/L) (reference range, 0.00–0.05 ng/mL [0.00–5000 ng/L]), red blood cell erythrocyte sedimentation rate of 118 mm/hour (118 mm/hour) (reference range, 0–20 mm/hour [0–20 mm/hour]), and white blood cell count of 3800/μL (3.8 × 109/L) (reference range, 6000–17 000/μL [6–17 × 109/L]). Results of a comprehensive metabolic panel are all within normal limits. Mononuclear spot test is negative. Respiratory pathogen polymerase chain reaction (PCR) panel is also negative for the following: adenovirus, coronavirus, SARS-CoV-2, human metapneumovirus, rhinovirus/enterovirus, influenza A, influenza B, parainfluenza 1–4, respiratory syncytial virus, Chlamydia pneumoniae, and Mycoplasma pneumoniae. An ultrasound of the neck shows prominent cervical lymph nodes. Neurology recommends holding pyridostigmine. All other home medications are continued. She is admitted to the hospital for further evaluation.After admission, a computed tomography of the neck and chest is obtained. This demonstrates diffuse lymphadenopathy in the upper and lower cervical chain, mediastinum, and axilla. A core lymph node biopsy is performed, but the specimen is inadequate, precluding assessment of node architecture. Surgical biopsy is not pursued due to risks associated with the procedure in the setting of myasthenia gravis. She continues to have intermittent fevers, tachycardia, and dysphagia. Five days into the hospitalization, she develops a pruritic facial rash. Repeat examination shows an erythematous, papular, nonspecific eruption on the right cheek and arthritis of fingers and bilateral knees, with tenderness in the wrists, digits, and knees and slight thickness of the distal interphalangeal joints. Further evaluation reveals the diagnosis.The differential diagnosis for generalized lymphadenopathy is broad and includes infections (mononucleosis, tuberculosis, cytomegalovirus, HIV), malignancies (leukemias, lymphomas), autoimmune disorders (dermatomyositis, sarcoidosis, systemic lupus erythematosus [SLE]), iatrogenic causes (serum sickness and other drug reactions), and disorders of unknown etiology (Castleman disease, Kikuchi-Fujimoto disease).1 A detailed history is key to narrowing this differential, as unique historical elements are indicative of different etiologies and can help guide diagnostic testing. For instance, fevers, night sweats, and weight loss are worrisome for malignancy. Meanwhile, fevers with associated respiratory or gastrointestinal symptoms are indicative of infection. Rash and arthralgias may suggest an autoimmune process. A history of high-risk sexual activity should lead to consideration of sexually transmitted infections, whereas recent initiation of a new medication points to a medication reaction.1Results of an infectious disease workup are negative, including Epstein-Barr virus (EBV) plasma PCR, cytomegalovirus (CMV) plasma PCR, Coccidioides immitis titers, streptococcal screen, blood culture, and QuantiFERON-TB Gold. EBV viral capsid antigen immunoglobulin M (IgM) and early antigen IgG antibodies are negative, whereas viral capsid antigen IgG and nuclear antigen IgG antibodies are positive, indicating past infection. Similarly, CMV antibody IgM is negative and IgG is positive. Due to concerning progressive symptoms, the patient ultimately does undergo an excisional lymph node biopsy. Microscopic morphology shows increased vascularity, plasmacytosis, and scattered eosinophils. Per the pathologist’s report, these findings are nonspecific but suggestive of an autoimmune or autoinflammatory process. The patient’s laboratory results are remarkable for positive direct Coombs, antinuclear antibody (ANA) titer >1∶2560 (reference range, <1∶80), elevated cardiolipin IgM of 32 (reference range, <13), elevated cardiolipin IgG of 16 (reference range, <15), strong positive histone antibody IgG of 10.1 units (reference range, 0.0–0.9 units), double-stranded DNA IgG titer of 1∶160 (reference range, <1∶10), normal SSA (anti-Sjögren’s syndrome A) and SSB (anti-Sjögren’s syndrome B) IgG, normal Smith IgG, and normal complement C3. Urinalysis shows no hematuria or proteinuria.Given these laboratory results in the setting of arthritis, the patient meets criteria for systemic lupus. Of note, there is an increased incidence of SLE in people with myasthenia gravis, especially after thymectomy.2 Drug-induced lupus (DIL) is included in the differential diagnosis because the arthritis, lymphadenopathy, weight loss, and fevers were not present before initiation of ethosuximide 1 year ago. Due to the concern for DIL, ethosuximide is suspended. An EEG is obtained and shows no abnormalities. The neurology team considers starting levetiracetam but ultimately elects to observe the patient off antiepileptic medications, given the normal EEG and negative history for clinical seizures. They recommend that the patient resume pyridostigmine once she is discharged home. Given her significant weight loss and arthritis, prednisone is initiated during her hospitalization. She notes resolution of her joint pain, along with improvement in her energy level, dysphagia, and lymphadenopathy 1 week after stopping ethosuximide. Thus, her presentation is highly suggestive of DIL. However, SLE cannot be completely ruled out at this point because prednisone treats both DIL and SLE.Drug-induced lupus is a phenomenon in which exposure to a drug leads to the development of lupus-like symptoms. It is the most common iatrogenic autoimmune disease, and it has been estimated that approximately 15 000 to 30 000 new cases of DIL occur every year in the United States. It is most common in middle-aged and older adults, with the exception of minocycline-induced lupus, which presents at a median age of 21 years.3,4 It typically appears months to years after initiation of the offending agent, although there are reports of it occurring after days to weeks. Some research suggests that the risk of DIL increases with higher daily dose and longer duration of therapy.5Hydralazine was the first drug reported to cause a lupus-like syndrome in 1954. Since then, hundreds of other drugs have been implicated in the disease, with the number growing rapidly as new agents are developed.6 Anticonvulsants, statins, biologics (particularly tumor necrosis factor α inhibitors), antiarrhythmics, and antipsychotics are some of the medication classes associated with DIL.5 Recent case reports have shown an association between DIL and proton pump inhibitors, nonsteroidal anti-inflammatory agents, and over-the-counter supplements.7–9 Hydralazine and procainamide make up the highest risk of DIL in 5%-8% and 20% of patients, respectively.6The pathogenesis underlying DIL is likely multifactorial.5 For instance, procainamide competitively inhibits DNA methyltransferase, interrupting the methylation process that suppresses the immune system. Hydralazine inhibits expression of DNA methyltransferase, leading to a similar effect.6,10 Because only a small proportion of individuals exposed to a drug develop disease, genetic factors play a role. HLA-DR4 and HLA-DR2 have been implicated in minocycline-induced lupus. The HLA-DR4 serotype has also been reported in hydralazine, penicillamine, and atorvastatin-induced lupus.11There are no definitive criteria for the diagnosis of DIL, but the following have been proposed: “(a) sufficient and continuing exposure to a specific drug, (b) at least one symptom compatible with SLE, (c) no history suggestive of SLE before starting the drug, and (d) resolution of symptoms within weeks (sometimes months) after discontinuation.”5 The most common presenting symptoms of DIL are fever, weight loss, fatigue, arthralgia and/or arthritis, and myalgia.11,12 Malar rash, photosensitivity, oral ulcers, organ involvement, hypocomplementemia, and hematologic abnormalities are rare in DIL.4,11 Lymphadenopathy is common in some types of DIL, such as hydralazine-induced lupus.4 Autoantibody laboratory results reveal a positive ANA in 90%–100% of cases and positive antihistone antibodies in up to 95%.4,13Anti–double-stranded DNA (dsDNA) antibodies are rare (Table 1).4Treatment depends on diagnosis and identification of the causative drug. Once identified, the offending agent should be discontinued. Corticosteroids are typically initiated if the patient is ill enough to require hospitalization or symptoms persist after drug discontinuation. Major organ involvement warrants immunosuppressive therapy with corticosteroids or disease-modifying antirheumatic drugs.4 Most patients have complete resolution of symptoms within weeks of stopping the medication, and symptoms do not return once immunosuppressive therapy is stopped.3,10The patient was discharged home on oral prednisone. When she presented for follow-up in the rheumatology clinic 1 month after diagnosis, the patient and mother reported resolution of all symptoms. The growth chart showed weight gain, and no lymphadenopathy was detected on examination. Her prednisone dose was tapered and eventually discontinued. At follow-up 4 months later, the symptoms still had not recurred. Double-stranded DNA and complements C3 and C4 were normal. Due to maintenance of remission off prednisone, her diagnosis was determined to be DIL. Although dsDNA can decline and even eventually normalize in SLE, this does not occur rapidly. Thus, the negative dsDNA offers further reassurance of the diagnosis being DIL. The family was instructed to monitor for the development of new joint pain or swelling, as these could indicate the development of SLE. Approximately 1 year after the hospitalization, she followed up in the neurology clinic. She remained seizure free and reported no new rheumatologic symptoms.It is important to review medication history for a patient with constitutional symptoms, generalized lymphadenopathy, and arthralgia or althritis.5Drug-induced lupus typically occurs after chronic exposure to the offending medicine. The latency between drug initiation and symptoms onset makes diagnosis challenging.5More than 100 drugs have been implicated in drug-induced lupus, and this number may continue to grow with the rapid development of new therapies. 6Discontinuation of the causative agent typically leads to full recovery.10Thank you to Dr Sandra Gage for her review of this manuscript.