Steroid responsive findings -orbital pseudotumor, -Tolosa-Hunt syndrome -sarcoidosis, -Langerhans’-cell histiocytosis, and -Hodgkin’s and -non-Hodgkin’s lymphomas. -IgG4 disease Tolosa-Hunt Syndrome - described in 1961 -granulomatous inflammation of the cavernous sinus HD NHL Burkitts lymphoma Case 2-2022: A 70-Year-Old Man with a Recurrent Left Pleural Effusion DDx. PMR (PMR, GCA, RA, Hematologic malignancies) This patient’s initial symptoms of pain in the shoulders and hip girdle were diagnosed as poly- myalgia rheumatica. Polymyalgia rheumatica is a misnomer, since this condition does not primar- ily involve muscle or cause weakness. Specifical- ly, symptoms of pain or stiffness associated with polymyalgia rheumatica are caused by interspi- nous, subacromial, and trochanteric bursitis. The symptoms are extremely responsive to treatment with low-to-moderate doses of glucocorticoids; however, gradual reduction of treatment over a period of many months is usually necessary be- fore symptoms fully resolve. In suspected cases, it is important to maintain a high index of sus- picion for concurrent diseases. In approximately 10 to 20% of patients who have polymyalgia rheumatica, giant-cell arteritis can develop.1 This patient had no symptoms or vascular abnormalities that were suggestive of a concomitant large-vessel vasculitis. Polymyalgia rheumatica can be a harbinger of rheumatoid arthritis; however, this patient had no features of peripheral arthritis. Musculoskeletal symptoms within the spectrum of polymyalgia rheumatica have been reported in association with various cancers, particularly hematologic neoplasms. DDx. Auricular Chondritis (Relapsing polychondritis, GPA, Mycobacterial infections) The differential diagnosis for systemic diseases that are manifested by symptoms of auricular chondritis is limited. 1. Relapsing poly-chondritis is an inflammatory disease character- ized in part by cartilaginous inflammation of the ear, nose, airway, and joints, eye.2 Chondritis of the nose and airway can be subtle and over- looked. It is important to obtain additional in- formation from the patient, including whether he had nasal pain, difficulty breathing, cough, neck tenderness, or chest-wall pain. Given the morbidity and mortality associated with chon- dritis of the airway, the presence of symptoms involving the airway warrants further evaluation for subglottic stenosis and tracheobronchomala- cia by direct visualization of the airway or non- invasive imaging. Concomitant myelodysplastic syndromes have been reported in association with a spectrum of inflammatory diseases, including relapsing poly- chondritis among older men. 2. Cartilaginous inflammation of the ear, nose, and airway is also a feature of granulomatosis with polyangiitis (GPA). The clinical features of GPA overlap with those of relapsing polychon- dritis. The absence of detectable ANCAs and of kidney involvement in this patient is more con- sistent with relapsing polychondritis than with GPA. This patient subsequently had scleritis, which is a feature of both GPA and relapsing polychondritis. 3. Although infections (including mycobacterial infections) also cause chondritis of the ear in rare instances, they are unlikely to be the cause of this patient’s presentation be- cause of the chronic, relapsing nature of the ear pain, with a reduction in symptoms noted in response to glucocorticoid therapy. DDx. Exudative Pleural Effusion (SLE, RA, GPA, FMF, TNFRAPS) Seven months before this patient’s current pre- sentation, he had a left pleural effusion. Analysis of the pleural fluid revealed a sterile, exudative effusion without cytologic evidence of cancer. Exudative pleural effusions are associated with certain rheumatologic diseases. 1. Serositis is common in patients with systemic lupus erythematosus; however, this diagnosis can essentially be ruled out in this case, given the patient’s undetectable levels of antinuclear antibodies and absence of other supporting features. 2. Pleural effusions in patients with rheumatoid arthritis are characteristically associated with a low pH and low glucose level in pleural fluid4; we are not given the pH of this patient’s pleural fluid, but the level of glucose was not low. 3. Exudative effusions occur rarely in patients with GPA but are not a feature of relapsing polychondritis. 4. It is important to consider autoinflammatory diseases, such as familial Mediterranean fever and tumor necrosis factor receptor–associated periodic syndrome, in cases of recurrent serositis with systemic inflammation and musculoskeletal pain. The development of an exudative pleural effusion later in the disease course expands, rather than narrows, the differential diagnosis in this case. DDx. Neutropenia / Macrocytic Anemia / MGUS (MDS, Tocilizumab, CYC, MTX, concomitant Relapsing polycondritis, SLE, Felty syndrome, concomitant PMR) Concomitant myelodysplastic syndromes have been reported in association with a spectrum of inflammatory diseases, including relapsing poly- chondritis among older men.5,6 Toxic effects re- sulting from medication use are the most com- mon cause of neutropenia in patients with rheumatologic diseases; however, neutropenia may be a feature of systemic lupus erythemato- sus or Felty’s syndrome. Finally, monoclonal gammopathy suggests the possibility of multiple myeloma, a condition that can occur simultane- ously with polymyalgia rheumatica. VEXAS Syndrome In late 2020, a new disease entity that was re- ferred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was re- ported.7 VEXAS syndrome is caused by somatic mutations in UBA1 (the gene that encodes ubiqui- tin-like modifier activating enzyme 1), which initiates the first step of cellular ubiquitylation. The mutations arise later in life and are con- fined to hematopoietic precursor cells in bone marrow and myeloid cells (e.g., neutrophils and monocytes) in peripheral blood. Since UBA1 is an X-linked gene and women are protected by a second allele, VEXAS syndrome occurs almost exclusively in men. The majority of disease- defining mutations are missense mutations in codon 41 in UBA1, which impairs translation and function of the cytoplasmic isoform of the UBA1 enzyme. Patients with VEXAS syndrome can have in- flammatory symptoms that mimic rheumato- logic diseases.8 Specifically, patients with VEXAS syndrome can meet diagnostic or classification criteria for one or more diseases, including re- lapsing polychondritis, polyarteritis nodosa, giant- cell arteritis, Sweet’s syndrome, ANCA-associated vasculitis, systemic lupus erythematosus, and adult-onset Still’s disease.7,9,10 This patient had several clinical features that were consistent with VEXAS syndrome. Chondritis is a common clini- cal feature in patients with VEXAS syndrome, is typically confined to the ear or nose, and can be transient and subtle without resultant damage.7 Fever and cutaneous manifestations that reflect neutrophilic dermatosis, leukocytoclastic vascu- litis, or medium-vessel vasculitis are common in patients with VEXAS syndrome but were not present in this case.7 Pulmonary involvement can occur, often in the later stages of disease. Sterile neutrophilic alveolitis is the most common pul- monary manifestation, but exudative pleural ef- fusions have been reported in a minority of pa- tients. Musculoskeletal conditions that can mimic polymyalgia rheumatica have been described. Re- current thromboembolic disease, in the absence of traditional risk factors for hypercoagulability, is common in patients with VEXAS syndrome. Inflammation can be severe and difficult to treat, and only glucocorticoids have shown con- sistent effectiveness in ameliorating symptoms In addition to systemic inflammatory disease, progressive bone marrow failure is a defining feature of VEXAS syndrome. Mutations in UBA1 in bone marrow stem cells and in hematopoietic progenitor cells, with subsequent clonal expan- sion, result in hematologic abnormalities. Macro- cytosis is the most common hematologic mani- festation and is typically an early feature of disease. Progressive cytopenias, especially throm- bocytopenia and lymphopenia, occur in the later phases of disease.12 Bone marrow biopsies that are performed in patients with VEXAS syndrome. typically reveal hypercellular marrow with my- eloid predominance. Numerous cytoplasmic vacu- oles in erythroid and myeloid precursor cells are present in the bone marrow aspirate in almost all patients with VEXAS syndrome.8 Monoclonal gammopathy has been reported in approximate- ly 20% of patients.7 Serial bone marrow biopsies may reveal progression to myelodysplastic syn- drome or to multiple myeloma. A simple clinical algorithm to identify patients with VEXAS syndrome with near-perfect accuracy has been proposed.13 Men with chondritis of the ear or nose are likely to have VEXAS syndrome if the mean corpuscular volume is greater than 100 fl or if the platelet count is greater than 200,000 per microliter. When the algorithm is applied to this patient, the findings suggest that genetic testing will confirm a diagnosis of VEXAS syndrome. A bone marrow biopsy should be performed to rule out hematologic cancer; however, genetic testing for VEXAS syndrome may be performed on either bone marrow or peripheral-blood cells, since mutational burden is typically high in both compartments. Summary The episodic nature of the syndrome and responsiveness to glucocorticoids were sug- gestive of an autoimmune or autoinflammatory disease process, and the concurrence of inflam- matory musculoskeletal pain, recurrent chondri- tis, scleritis, and pleural effusion supported the idea that all the features were linked by a single process. The most salient aspect of this patient’s presentation was the profound refractoriness to multiple immunosuppressive agents. Paired with the smoldering and progressing macrocytosis, the primary diagnostic consideration was an auto- inflammatory process caused by underlying my- elodysplastic syndrome. Case 4-2022: A 55-Year-Old Man with Bilateral Hearing Loss and Eye Redness Syphilis This 55-year-old man presented with progressive hearing loss, imbalance, and ocular inflammation. A headache involving the left temple had occurred 8 weeks earlier. These symptoms were superimposed on a 6-month his- tory of weight loss, a 2-month history of body aches and fatigue, and the occurrence of a non- pruritic rash on the torso (Fig. 2). During the evaluation, the erythrocyte sedimentation rate and C-reactive protein level were elevated. On the basis of this constellation of findings, I will focus my initial differential diagnosis on the conditions that cause
Temporal Pain The development of clinically significant tempo- ral pain prompts consideration of temporal arte- ritis, a specific phenotype of giant-cell arteritis. Although hearing loss and elevations in the erythrocyte sedimentation rate and C-reactive protein level are consistent with this condition, the patient is young for the development of tem- poral arteritis; the mean age at onset is 72 years.1,2 In addition, there was no jaw claudica- tion or vision loss, and the lack of a response to glucocorticoids and the normal retinal examina- tion make this possibility unlikely.3 The history of shingles suggests the possibility of a recurrence of herpes zoster oticus. How- ever, there were no vesicles on the auricle or posterior auditory canal; the eye redness, with- out vesicles, crossed the midline to affect both eyes; and the rash on the torso was not in a dermatomal distribution. Audiovestibular symptoms can be a manifestation of herpes zoster oticus, but this patient did not have facial nerve paresis, which often occurs. In addition, herpes zoster oticus does not affect both labyrinths. Asymmetric Sensorineural Hearing Loss and Dizziness Upper respiratory infection can lead to the acute onset of progressive hearing loss, known as sudden sensorineural hearing loss. However, the hearing loss would not involve both ears. A posterior fossa mass, such as a vestibular schwannoma, can cause both asymmetric senso- rineural hearing loss and dizziness, and such tumors can occur bilaterally in patients with neurofibromatosis type 2. Leptomeningeal infiltration from lymphocytic leukemia, carcinomatosis, or neurosarcoidosis can also cause asymmetric sensorineural hearing loss.4,5 Inner Ear and Ocular Involvement Condi- tions associated with both inner ear and ocular involvement and with systemic symptoms fall under three main categories:
systemic vasculitides and rheumatologic diseases, Systemic lupus erythematosus can cause episcleritis and uveitis, but it typically affects the retinal vasculature, and such involvement was not observed in this patient. In addition, patients with lupus typically have high-frequency hearing loss, whereas this patient had low-frequency hearing loss.8 Patients with relapsing polychondritis can have both ocular inflammation and inner ear dysfunction. However, this patient did not have any joint involvement or inflammation of carti- lage in the nose, auricle, trachea, or bronchus, features that would suggest a diagnosis of relapsing polychondritis. Ankylosing spondylitis can cause hearing loss, but the hearing loss is usually mild and conductive in nature. In addition, patients with ankylosing spondylitis usually have uveitis in one eye at a time.9 Granulomatosis with polyangiitis is a disor- der that causes tissue necrosis and vasculitis involving small and medium-sized vessels. Al- thoughthemiddleearandnearlyeverystructure in the eye can be involved, this patient did not have any lesions in the lungs, kidneys, or sinuses, features that would suggest a diagnosis of granulomatosis with polyangiitis. Cogan’s syndrome causes hearing loss, dizzi- ness, and bilateral eye findings that were origi- nally referred to as “nonsyphilitic keratitis.” The eye findings include bilateral ocular inflamma- tion, photophobia, and eye pain and may involve interstitial keratitis, episcleritis, scleritis, and uveitis. The onset of hearing loss, tinnitus, and vertigo is typically sudden and occurs within 3 to 4 months after the eye findings develop.10 Tem- poral bone studies have shown osteoneogenesis of the cochlea.11 Constitutional symptoms such as fever, fatigue, weight loss, myalgias, and ar- thralgias occur within 2 months after the onset of the illness. The erythrocyte sedimentation rate and C-reactive protein level are elevated.10,12,13 Cogan’s syndrome may have cardiovascular manifestations, such as aortitis. The incidence is increased in persons with HLA-B17, HLA-A9, HLA-Bw35, and HLA-Cw4. Anti-HSP70 antibod- ies have been reported to be present in 92.5% of patients with Cogan’s syndrome and have also been found in patients with autoimmune inner ear disease and rapidly progressive sen- sorineural hearing loss. This remains a top DDx as most features were present. Autoinflammatory Conditions Susac’s syndrome causes both ocular inf lammation and sensorineural hearing loss. However, the condition is characterized by encephalopathy and retinal-artery occlusion, which were absent in this patient. Patients with Behçet’s syndrome can present with anterior and posterior uveitis, hearing loss, and tinnitus. However, this patient did not have skin, oral, or genital ulcerations, which are hallmarks of this condition. Paraneoplastic syndromes, which are due to an altered immune response to an underlying cancer, can also cause inner ear and eye defi- cits.16 These syndromes occur in 8% of pa- tients with cancer and are most frequently associated with lung, breast, hematologic, medul- lary thyroid, gynecologic, and prostate cancers. This patient did not have a known underlying cancer. Infection: TB, Lyme disease, Neurosyphilis In summary, the list of systemic disorders as- sociated with eye and ear involvement and with constitutional signs and symptoms is broad.22 However, this patient’s presentation is most con- sistent with Cogan’s syndrome or a spirochetal infection — either syphilis or Lyme disease. Among these entities, syphilis is the best clinical fit in this case. To establish the diagnosis of syphilis, I would perform a lumbar puncture with cerebrospinal fluid (CSF) analysis to look for pleocytosis and to conduct the Venereal Disease Research Laboratory (VDRL) test and the fluorescent treponemal-antibody absorption (FTA-ABS) test.23 Case 33-2021: A 68-Year-Old Man with Painful Mouth Ulcers Leukemia This 68-year-old man presented with a 6-week history of progressively worsening painful mouth ulcers associated with weight loss and the development of scaly papules on the skin. He had been treated with acyclovir, colchi- cine, prednisone, and amoxicillin–clavulanate, but the oral ulcers had not abated. Evaluation of Oral Ulcers Evaluation of oral ulcers begins with determina- tion of whether the patient has a single lesion or multiple lesions and whether the process is epi- sodic or continuous (Fig. 3). This patient had multiple ulcers that had developed abruptly, with subsequent resolution of some ulcers and devel- opment of others at the same time, so that he was never ulcer-free. This combination of find- ings rules out conditions associated with a sin- gle episodic ulcer, including traumatic ulcers, which usually result from a defined traumatic event; solitary progressive ulcers due to cancer; and recurrent idiopathic aphthous ulcers, a com- mon condition that almost always begins in the second or third decade of life and is character- ized by ulcers that measure less than 1 cm in size.  The presence of oral ulcers is one of the defining criteria of Behçet’s disease, but the oral ulcers associated with this disease tend to wax and wane and often respond to colchicine and glucoorticoid therapy.2 In addition, this patient did not have genital, ocular, or typical cutaneous symptoms of Behçet’s disease. Although HLA typing was positive for the HLA-B51 allele, this test is not highly specific for Behçet’s disease and is positive in approximately 18% of the gen- eral population. Case 3: Froedtert Middle aged man with AIN as presentation , not responding to steroid DDX of systemic ds SLE and GPA have AIN in bxp along with classic GN. Rarely, it may be present alone in both. Most common systemic cause though is sarcoidosis. Other rare cause: IgG4 related disease, anti TBM ab related disease |
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