Treatment of a Myasthenic Dog with Mycophenolate Mofetil

A ten‐year‐old, male castrated Springer Spaniel was presented for dysphagia, ptyalism, and regurgitation. Evidence of megaesophagus and mild aspiration pneumonia were apparent on thoracic radiographs. A diagnosis of focal acquired myasthenia gravis was suspected and subsequently confirmed with a positive serum acetylcholine (ACh) receptor antibody concentration (3.87 nM/L). A gastrostomy tube was placed shortly after presentation; food and drugs (including azathioprine) were administered through the tube. After transient improvement, the dog suddenly deteriorated clinically, experiencing frequent episodes of regurgitation and developing severe aspiration pneumonia. Mycophenolate mofetil (MMF), a novel immunosuppressive drug with relative specificity for lymphocytes, was instituted every twelve hours via the gastrostomy tube. Within four days of beginning MMF therapy, both clinical evidence of pharyngeal/esophageal dysfunction and radiographic evidence of megaesophagus had resolved. Initially, clinical side‐effects of combined MMF/AZA administration were not apparent, but the patient experienced several vomiting episodes during the third week of treatment. The vomiting resolved after decreasing the dose of both drugs. The patient made a full recovery, and a one‐month follow‐up ACh receptor antibody concentration was normal (0.26 nM/L). After one month of combination therapy, the patient was weaned off of AZA and maintained on MMF as the sole immunosuppressive drug. The dog was subsequently weaned off of MMF on two occasions. Mycophenolate mofetil was reinstituted after the first discontinuation due to the development of profound appendicular muscle weakness two days after stopping MMF; the weakness resolved within 24 hours of reinstituting MMF. A positive ACh receptor antibody concentration (0.89 nM/L) after the second MMF weaning prompted the second reinstitution of MMF. Two months following this second MMF reinstitution, the dog was again serologically negative (0.51 nM/L) for myasthenia gravis. At the time of last followup, the dog remained in clinical remission eight months after initial presentation. The use of MMF to treat acquired myasthenia gravis in dogs has not been reported previously. The literature concerning MMF and its potential use in treating patients with autoimmune diseases is discussed.     

Clinical Forms of Acquired Myasthenia Gravis in Dogs: 25 Cases (1988–1995)

The purpose of this project was to investigate the clinical forms of acquired myasthenia gravis in dogs. The medical records from 25 dogs with seropositive acquired myasthenia gravis were reviewed, and the following data were recorded for each patient: signalment, history, clinical findings; results of IV edrophonium chloride administration, repetitive nerve stimulation, and presence or absence of muscle membrane staining by immunocytochemical methods; serum acetyl-choline receptor antibody concentration; treatment; and outcome. Several clinical forms of acquired myasthenia gravis were identified. Nine of the 25 patients (36%) had no historical or clinical evidence of appendicular muscle weakness, and were designated as focal myasthenics. These dogs exhibited focal weakness in one or more of the following muscle groups: facial {3 of 9), pharyngeal (3 of 9), and laryn-geal (3 of 9). The remaining 16 dogs (64%) exhibited appendicular muscle weakness. Four of these 16 dogs had acute onset and rapid development of clinical signs, and were designated as acute fulminating myasthenics. The remaining 12 dogs were classified as generalized myasthenics. All 4 dogs with acute fulminating myasthenia gravis had megaesophagus, 2 had facial muscle weakness, and 1 had pharyngeal muscle weakness. Ten of the 12 dogs with generalized myasthenia gravis had megaesophagus, 4 had facial muscle weakness, 4 had pharyngeal muscle weakness, and 3 had laryngeal muscle weakness. Historical or clinical evidence of exercise-associated appendicular weakness was found in only 6 of the 12 (50%) dogs with generalized myasthenia gravis, and in none of the dogs with acute fulminating myasthenia gravis. Seven of the 12 dogs with generalized myasthenia gravis had weakness primarily (n = 1) or exclusively (n = 6) of the pelvic limbs. Two of the 4 dogs with acute fulminating myasthenia gravis had primarily pelvic limb weakness. Twelve of the 25 dogs (48%) died or were euthanized shortly after admission to the hospital due to aspiration pneumonia. The dogs with acute fulminating myasthenia gravis had a markedly higher 1-year mortality rate in comparison with the other 2 groups. The use of immunosuppressive therapy had a significant positive effect on patient survival, regardless of the type of myasthenia gravis. This investigation demonstrates that acquired myasthenia gravis in dogs is a disorder with a wide spectrum of clinical forms, similar to the analagous disorder in people.     

Combined Gemcitabine and Carboplatin Therapy for Carcinomas in Dogs

Background: Response and adverse reactions to combined gemcitabine (GEM) and carboplatin (CARBO) therapy in dogs with carcinomas are not documented.
Hypothesis: GEM and CARBO are safe for the treatment of dogs with carcinomas.
Animals: Thirty-seven dogs with histologically or cytologically confirmed carcinomas.
Methods: Prospective clinical trial. Dogs were treated with GEM (2 mg/kg, 20–30-minute infusion IV) on Days 1 and 8 and 4 hours later, CARBO (10 mg/kg IV) on Day 1. The cycle was repeated on Day 22.
Results: Thirty-seven dogs (29 with measurable tumor) received a median of 2 cycles (range 0.5–6) for a total of 101 cycles administered. Twelve dogs (32%) developed neutropenia (3 Grade 3, and 5 Grade 4) and 9 (24%) thrombocytopenia (2 Grade 3, and 1 Grade 4). Dogs >20 kg were twice as likely to develop thrombocytopenia ( P = .023). Twenty-seven dogs (73%) had evidence of gastrointestinal (GI) toxicosis, but most signs were of mild to moderate severity and self-limiting. One dog died of treatment-related complications. Overall tumor response rate was 13%. One dog with metastatic prostatic carcinoma achieved a complete remission and 1 dog with intestinal adenocarcinoma and 1 with tonsillar squamous cell carcinoma achieved partial remission. Twelve dogs achieved stable disease for a median of 72 days.
Conclusion and Clinical Importance: GEM and CARBO combination causes mild to moderate hematologic and GI toxicosis in dogs with carcinoma. Response rate in this study was modest, and optimization of dosing of this combination is required.     

Treatment of acquired myasthenia gravis associated with thymoma in two dogs

Two cases of myasthenia gravis associated with thymoma are reported. Both were female German shepherd dogs and the thymoma was surgically resected. Aspiration pneumonia secondary to persistent megaoesophagus was a complication in both cases. The myasthenia gravis did not resolve, but there was a more satisfactory control of clinical signs with anticholinesterase treatment. Corticosteroid therapy was used in one case, but the resulting polydipsia increased the incidence of regurgitation, resulting in recurrent episodes of aspiration pneumonia.     

Epilepsy in Border Collies: Clinical Manifestation, Outcome, and Mode of Inheritance

Background: There is a lack of data on idiopathic epilepsy (IE) in Border Collies (BCs) in the veterinary literature.
Hypothesis: Genetic epilepsy occurs in BCs and is frequently characterized by a severe clinical course and poor response to medical treatment.
Animals: Forty-nine BCs diagnosed with IE.
Methods: Medical records, seizure data, treatment data, and pedigree information of affected dogs were collected. Cases were classified phenotypically as affected or not affected; mild, moderate, or severe clinical course; active epilepsy (AE) or remission; and drug resistant or not drug resistant.
Results: Clinical manifestations were classified as having a moderate (33%) or severe clinical course (49%), characterized by a high prevalence of cluster seizures and status epilepticus. Survival time was significantly decreased in dogs <2 years of age at seizure onset, and in dogs with a severe clinical course. Drug resistance was apparent in 71% of 24 dogs treated with ≥2 antiepileptic drugs. The epilepsy remission rate was 18%. Median age at onset was significantly higher and initial seizure frequency was significantly lower in dogs with remission compared with dogs with AE. Pedigree analyses indicated a strong genetic founder effect in the appearance of epilepsy, resembling autosomal recessive inheritance.
Conclusion and Clinical Importance: The present study confirms the occurrence of genetically mediated epilepsy with a frequent severe clinical course and drug resistance in BCs. The results provide information about the long-term prognosis of IE in BCs for veterinarians and concerned owners, and may benefit breeders as well.     

Efficacy of Combination Chemotherapy for Treatment of Gastrointestinal Lymphoma in Dogs

Background: Chemotherapy for multicentric canine lymphoma has favorable results. The gastrointestinal (GI) tract is the most common extranodal site of canine lymphoma, but there have been no prospective studies to determine outcome when dogs with GI lymphoma are treated with chemotherapy.
Hypothesis: Treatment with a multiagent chemotherapy protocol is associated with a poor outcome in dogs with GI lymphoma.
Animals: Eighteen dogs with histologically confirmed GI lymphoma.
Methods: Prospective clinical trial in which dogs with GI lymphoma were treated with a 20-week combination chemotherapy protocol consisting of induction and consolidation phases.
Results: Thirteen dogs had primary GI lymphoma and 5 had multicentric lymphoma with GI involvement. The majority of the lymphomas (63%) were of T-cell origin. Overall remission rate was 56%; 9 dogs achieved a complete remission for a median of 86 days (range, 22–420 days) and 1 dog achieved a partial remission for 26 days. Overall median survival time was 77 days (range, 6–700 days). Dogs that failed to achieve a remission (10 versus 117 days; P = .002) or had diarrhea at initial presentation (70 versus 700 days; P < .001) had shorter survival times.
Conclusion and Clinical Importance: The response and survival of dogs with GI lymphoma treated with multiagent chemotherapy is poor but long-term survival is possible.     

Epidural Idiopathic Sterile Pyogranulomatous Inflammation Causing Spinal Cord Compressive Injury in Five Miniature Dachshunds

Objective— To characterize the clinical signs, diagnostic and surgical findings, and outcome of dogs with idiopathic sterile pyogranulomatous inflammation (ISP) of epidural fat causing spinal cord compression.
Study Design— Retrospective study.
Animals— Dogs (n=5).
Methods— Dogs with epidural ISP (2002–2006) were identified retrospectively. Inclusion criteria were neurologic examination, myelography, and definitive diagnosis of ISP confirmed by surgery and histopathologic examination of epidural spinal cord compressive tissue.
Results— The most common clinical sign was paraparesis/paraplegia. No abnormalities were detected by laboratory testing or survey spine radiographs. On myelography, extradural spinal cord compressions were focal (dogs 1, 3, and 5) or multifocal (dogs 2 and 4). Surgical decompression of the spinal cord was completed by hemilaminectomy. Epidural fat collected surgically had pyogranulomatous inflammation of unknown cause and was histologically similar to subcutaneous ISP. All dogs had good long-term neurologic outcome (10–45 months follow-up). Some dogs had episodes of ISP at other sites before or after surgical treatment of epidural ISP, suggesting there may be a systemic form of ISP.
Conclusion— Epidural ISP may cause a spinal cord compressive lesion in Miniature Dachshunds, which can be treated by surgical decompression of the spinal cord with or without administration of adjunctive steroids.
Clinical Relevance— Epidural ISP should be considered as a possible cause of thoracolumbar myelopathy for Miniature Dachshunds.     

Acquired Myasthenia Gravis

Serum samples from 152 dogs with a clinical diagnosis of idiopathic megaesophagus without detectable generalized muscle weakness were tested for the presence of antibodies to acetylcholine receptors by immunoprecipitation radioimmunoassay. Positive serum antibody titers (mean, 3.1 nmoL/L; range, 0.77-30 nmoL/L; reference values less than 0.6 nmoL/L) were found in 40 dogs (26%), with German Shepherd dogs (8/25, 32%) and Golden Retrievers (7/20, 35%) having a greater percentage of positive submissions. By immunocytochemical methods, localization of immune complexes at the neuromuscular junction after incubation of serum with normal canine muscle was documented in an additional 17 cases (11% of all samples submitted) that did not have increased antibody titers to acetylcholine receptors. Of the 40 seropositive dogs, 17 (48%) had a clinical improvement or remission of clinical signs associated with decreasing AChR antibody titers. Idiopathic megaesophagus has been associated with a poor prognosis; however, this study demonstrates that a large percentage of the dogs have myasthenia gravis and that with supportive treatment, the clinical signs may improve or resolve.     

Characteristics and outcomes in surgical management of severe acute pancreatitis: 37 dogs (2001–2007)

Objective – Describe clinical characteristics and outcomes associated with canine patients undergoing surgical intervention for treatment of acute pancreatitis.
Design – Retrospective outcome study from 2001 to 2007.
Animals – Thirty-seven dogs.
Interventions – None.
Measurements and Main Results – The following data were collected for dogs who underwent surgical intervention in the course of treatment for severe acute pancreatitis: preoperative clinicopathologic and physical data, ultrasonographic findings, surgical procedure detail, histopathologic findings, and transfusion requirements. The survival rate was 80.8% in dogs with extrahepatic biliary obstruction, 64.3% in dogs undergoing necrosectomy, and 40.6% with pancreatic abscess. Overall survival was 63.6%. Surgical complications included intraoperative and postoperative hemorrhage in 12 dogs, postoperative development of diabetes mellitus in 3 dogs, exocrine pancreatic insufficiency in 1 dog, and bacterial peritonitis in 2 dogs.
Conclusion – Surgical intervention and aggressive postoperative care may be pursued in select dogs with severe acute pancreatitis. In dogs with extrahepatic biliary obstruction secondary to acute pancreatitis, surgical intervention may be associated with a good prognosis whereas dogs with pancreatic abscess formation may have a more guarded prognosis.     

Myasthenia gravis and disorders of neuromuscular transmission.

Myasthenia gravis is a disorder of neuromuscular transmission that occurs in congenital and acquired autoimmune forms. Acquired myasthenia gravis is probably the most common neuromuscular disorder in dogs that can be diagnosed and treated. An early, accurate diagnosis and appropriate therapy is of utmost importance to a good clinical outcome in this disorder. This article focuses on the diagnosis and treatment of acquired myasthenia gravis in dogs and cats with brief discussions of other disorders of neuromuscular transmission, including congenital myasthenia gravis, tick paralysis, botulism, and organophosphate intoxication.     

Dacarbazine as Single-Agent Therapy for Relapsed Lymphoma in Dogs

Background: Multidrug resistance is the most common cause of treatment failure in dogs with multicentric lymphoma. 5-(3,3-Dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) is an atypical alkylator used as standard treatment in human Hodgkin's lymphoma, and has been effective in combination treatment to treat resistant lymphoma in dogs. However, no data are available on the use of DTIC as a single agent in the treatment of relapsed canine lymphoma.
Hypothesis: Single-agent DTIC is effective and safe in treating dogs with lymphoma that relapsed or failed to respond to previous chemotherapy.
Animals: Forty client-owned dogs with relapsed lymphoma.
Methods: Dogs were eligible for the retrospective study if they had a histologically or cytologically confirmed diagnosis of lymphoma and had relapsed. Dogs received DTIC (800–1,000 mg/m² every 2–3 weeks as a 4–5-hour IV infusion) and were evaluated for response rate and duration. Hematologic and gastrointestinal toxicity was assessed.
Results: The overall response rate for dogs being treated with DTIC was 35% (14 dogs) with a median progression-free interval of 43 days. Thirteen dogs had a partial response and 1 dog had a complete response. Stable disease was achieved in 3 dogs. Mild gastrointestinal toxicity was reported in 3 dogs posttreatment. Thrombocytopenia was the principal toxicity observed 7–14 days after the treatment. Treatments were delayed because of thrombocytopenia.
Conclusions: DTIC, when used alone, is effective in the treatment of dogs with relapsed lymphoma.     

Treatment of primary immune‐mediated hemolytic anemia with mycophenolate mofetil in two cats

Objective – To describe the use of oral mycophenolate mofetil (MMF) as an adjunctive therapy in 2 cats with primary immune‐mediated hemolytic anemia. Case Series Summary – Two cats suffering from presumptive primary immune mediated hemolytic were treated with MMF as part of their treatment regimens. Both cats had improved complete blood counts following therapy. New or Unique Information Provided – This is the first reported use of oral MMF as adjunctive treatment for cats with immune‐mediated hemolytic anemia. Outcome was favorable in both cats and no adverse effects were noted from the MMF.     

Noninvasive estimation of cardiac systolic function using continuous-wave Doppler echocardiography in dogs with experimental mitral regurgitation

Objective To evaluate the feasibility of noninvasive estimation of cardiac systolic function using transthoracic continuous-wave Doppler echocardiography in dogs with mitral regurgitation.
Procedure Seven mongrel dogs with experimental mitral regurgitation were used. Left ventriculography and measurement of pulmonary capillary wedge pressure were performed under inhalational anaesthesia. A micromanometer-tipped catheter was placed into the left ventricle and transthoracic echocardiography was carried out. The peak rate of left ventricular pressure rise (peak dP/dt) was derived simultaneously by continuous-wave Doppler and manometer measurements. The Doppler-derived dP/dt was compared with the catheter-measured peak dP/dt in the dogs.
Results Classification of the severity of mitral regurgitation in the dogs was as follows: 1+, 2 dogs; 2+, 1 dog; 3+, 2 dogs; 4+, 1 dog; and not examined, 1 dog. We were able to derive dP/dt from the transthoracic continuous-wave Doppler echocar-diography in all dogs. Doppler-derived dP/dt had a significant correlation with the catheter-measured peak dP/dt (r = 0.90, P < 0.0001).
Conclusion It was demonstrated that transthoracic continuous-wave Doppler echocardiography is a feasible method of noninvasive estimation of cardiac systolic function in dogs with experimental mitral regurgitation and may have clinical usefulness in canine patients with spontaneous mitral regurgitation.     

Azathioprine therapy for acquired myasthenia gravis in five dogs.

Five dogs with acquired myasthenia gravis (MG), verified via positive serum acetylcholine (ACh) receptor antibody concentrations, were treated with a drug protocol including azathioprine (AZA). Four of the five dogs were concurrently treated with pyridostigmine. Azathioprine was used as the sole immunosuppressive agent in four dogs. One dog was temporarily treated with a combination of an immunosuppressive dose of prednisone and AZA, then maintained on AZA as the sole immunosuppressive drug. Three patients experienced complete remission of clinical signs within three months of therapy. In the four dogs for which follow-up serum ACh receptor antibody concentrations were available, initial versus final concentrations decreased substantially (81%), coincident with clinical improvement. One dog died suddenly due to a suspected myasthenic crisis before attaining the target dose of AZA. Two of the four surviving dogs were euthanized approximately one and seven years after diagnosis. One of these two dogs was euthanized because of a rib osteosarcoma, and the other dog was euthanized because of paraparesis of undetermined cause. The remaining two dogs were alive and doing well at the time of final follow-up evaluation, approximately six months and one year after diagnosis. The use of AZA as a therapeutic agent for acquired canine MG has not been investigated. The cases presented in this report suggest a potentially important role for AZA in the treatment of acquired MG in dogs.     

Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune-mediated hemolytic anemia

Objective – To determine the utility of human intravenous immunoglobulin (hIVIG) for the initial treatment of canine immune-mediated hemolytic anemia (IMHA).
Design – Blinded, randomized, clinical trial.
Setting – Veterinary teaching hospital.
Animals – Twenty-eight, client-owned dogs with primary IMHA.
Interventions – At enrollment, after diagnosis of IMHA, dogs were randomly assigned to receive either hIVIG or placebo, in a blinded fashion. For the next 14 days, all dogs received glucocorticoids as the sole immunosuppressant agent. All dogs received low-molecular-weight heparin as an anticoagulant. D-dimer concentrations were evaluated at the beginning and end of the study protocol to monitor for thromboembolic complications.
Measurements and Main Results – Twenty-five of 28 dogs (89%) were discharged from the hospital. Thirteen of those received hIVIG and 12 received placebo. Twenty-four dogs (86%) were alive 14 days after enrollment, and of these 13 received hIVIG and 11 received placebo. D-dimer concentrations were elevated in 86% of all dogs at the time of diagnosis.
Conclusions – For initial treatment of dogs with IMHA, the addition of hIVIG to corticosteroid treatment did not improve initial response, nor did it shorten hospitalization.     

Coagulation effects of low molecular weight heparin compared with heparin in dogs considered to be at risk for clinically significant venous thrombosis

Objective – Compare the effects of 3 anticoagulation protocols on anti-factor Xa activity (AXa).
Design – Prospective, randomized, double-blind study.
Setting – University veterinary teaching hospital.
Animals – Eighteen dogs considered to be at risk for venous thrombosis.
Interventions – Each dog was randomly assigned to 1 of the following 3 groups ( n =6/group) and was treated for 24 hours: low-dose heparin (LDH), high-dose heparin (HDH), and dalteparin (DP). Dogs in the LDH group received a constant rate infusion (CRI) of unfractionated heparin (UFH) at 300 U/kg/d, the HDH group received a bolus of 100 U/kg of UFH IV, then a CRI of 900 U/kg/day, and the DP group received 100 U/kg DP SC at 0, 12, and 24 hours.
Measurements and Main Results – A total of 54 samples for activated partial thromboplastin time (aPTT) and AXa assays were collected at 0, 4, and 28 hours. Six samples had an AXa >0.1 U/mL, 5 of those were from the HDH group at hour 4. Two samples from the HDH group at hour 4 had a prolonged aPTT (93 and 200 seconds) and the highest AXa (0.6 and 1.0 U/mL, respectively). Four additional dogs in the HDH group did not complete the study due to hemorrhage; none of the dogs completing the study showed signs of hemorrhage.
Conclusions: Neither DP nor LDH increased AXa to values considered therapeutic in humans (0.5–1 and 0.35–0.75 U/mL, respectively), and both protocols appear to be inadequate to increase AXa in dogs with clinical illness. HDH increased AXa to this range in 2 of 6 dogs, but had unpredictable effects on aPTT and resulted in hemorrhage in some dogs.     

Diseases of the horse: the centennial of a great book

A 7-year-old Saint Bernard developed muscular weakness 1 year after right forelimb amputation and adjuvant cisplatin chemotherapy for osteogenic sarcoma. Clinical and laboratory findings supported a diagnosis of myasthenia gravis, and the dog had clinical improvement in response to prednisone treatment. Two additional dogs with myasthenia gravis and osteogenic sarcoma were identified by review of the medical records of the University of California Veterinary Medical Teaching Hospital. Findings indicated that myasthenia gravis or other neuromuscular transmission disorders may be associated with muscular weakness in dogs with osteogenic sarcoma.     

0–7–21 Radiation Therapy for the Treatment of Canine Oral Melanoma

Eighteen dogs with malignant melanoma of the oral cavity were treated with high-dose per fraction (0–7–21) radiation therapy. Eight hundred cGy was administered on days 0, 7, and 21 for a total dose of 2,400 cGy in 3 weeks. Of 17 dogs evaluated, 9 (53%) had a complete remission and 5 (30%) achieved a partial remission with an overall response rate of 83%. Local failure occurred in 2 of the 9 dogs where a complete response was initially observed. One dog died of intercurrent disease, and one died of metastatic disease without evidence of local recurrence. Five dogs are alive and free of disease 9 to nineteen months from the initiation of therapy. The 0–7–21 protocol was well-tolerated, and acute radiation reactions were low-grade and limited to the skin. The results of this study demonstrate that oral melanomas in dogs are responsive to radiation. 0–7–21 radiation therapy offers a viable alternative to radical excision, especially when tumor volume or location would require cosmetically or functionally debilitating surgery.     

Megaoesophagus and glucocorticoid-deficient hypoadrenocorticism in a dog

A seven-year-old German shepherd dog was referred for acute onset regurgitation. Muscle weakness and severe dermatological disease were present. Thoracic radiographs revealed generalised megaoesophagus. Diagnostic testing revealed glucocorticoid deficiency, and rapid resolution of the megaoesophagus followed appropriate supplementation. The dog made a full recovery. Unique features of this case include a transiently positive antinuclear antibody titre and clinical features of myasthenia gravis.     

Immune‐mediated myasthenia gravis in a methimazole‐treated cat

A 12‐year‐old female neutered ragdoll crossbred cat was presented for investigation of generalised weakness and regurgitation. The cat was being treated with transdermal methimazole for hyper‐thyroidism, which had been diagnosed 10 weeks previously. An acetylcholine receptor antibody titre was consistent with acquired myasthenia gravis. Withdrawal of methimazole and treatment with pyridostigmine was followed by resolution of clinical signs and reduction of the acetylcholine ‐receptor antibody titre. Medical control of hyperthyroidism was subsequently achieved with carbimazole, administered in conjunction with pyridostigmine, and no recurrence of clinical signs was observed. Myasthenia gravis is an uncommon but clinically significant adverse effect of methimazole therapy in cats, and may be caused by immunomodulatory properties of this drug. An adverse drug reaction should be considered in cats receiving methimazole that develop myasthenia gravis, and potentially also other immune‐mediated disorders.