Shane Pahlavan, M.D.
July 24, 2008
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by physicians and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No warranties, either express or implied, are made with respect to accuracy, completeness or timeliness of this material. This material does not necessarily reflect the current or past opinions of the faculty of Baylor College of Medicine and should not be used as a basis for diagnosis or treatment, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
For today’s presentation, I will go through the background and the initial presentation in the literature and discuss the challenges of diagnosing relapsing polychondritis. I will go into some depth regarding the pathophysiology of what is proposed to be the underlying disease process and talk about some of the current treatments of the disease and prognosis.
For the background of relapsing polychondritis, we will start with the definition. It is defined as an episodic systemic disorder characterized by the recurrent, widespread, and potentially destructive inflammatory lesions involving cartilaginous structures. The cardiovascular system can be involved, as well as organs of special sense including the eyes and the ears.
The first note of relapsing polychondritis in the literature comes from 1923 from Dr. Jaskch-Wartenhorst of Austria. He gave the first description in the Vienna Archives of Internal Medicine, and he called the disorder “polychondropathia.” His described a 24-year-old male, a young brewery worker, who presented with repeated fever and painful arthritic swellings. Several months later, this same patient presented and had developed painful swelling in both auricles and a saddle-nose deformity. This was his first patient who had this conglomeration of symptoms. His conclusion at the end of his paper that he published was that relapsing polychondritis, or what he called “polychondropathia,” was related to excessive quantities of alcohol consumption in this young brewery worker.
In 1936, Dr. Marburg described chondromalacia after performing an autopsy on a 14-year-old boy, who had destruction of larynx, ears, nose, ribs, and multiple joints. Many years later in 1960, Dr. Pearson introduced the term “relapsing polychondritis” after reviewing 12 cases of the disorder and noted that, based on histology, after a few episodes of inflammation, the cartilage had been replaced by fibrous connective tissue.
The clinical presentation of this disease is varied and can be quite a challenge to the diagnostician. It is classified among the other autoimmune connective tissue disorders because of its clinical and mechanistic similarity. There is a preponderance for head and neck symptom manifestations that are oftentimes the initial symptoms at presentation. As a result, the otolaryngologist is the first physician to evaluate these patients. The age of onset is typically in the fourth to fifth decade, and there is no race or sex discrimination. However, some literature does suggest that there is a slight female predominance as related to other autoimmune phenomena.
Presenting symptoms of the disorder can be varied but 89% of the patients will present with auricular chondritis. So the auricle in relapsing polychondritis is classically painful, erythematous and is associated with the characteristic sparing of the lobule. With repeated bouts of the disorder, the disease process can result in a cauliflower ear when the cartilaginous portion has been compromised. Polyarthritis can present in 81% of patients. Patients complain of walking and difficulty using their hands. Most commonly, their ribs and elbows are affected. There is nasal chondritis in 72% of patients. This can present in a multitude of ways. Most commonly, it will present with an acute chondritis, but can also present with rhinorrhea, epistaxis, or as a saddle-nose deformity due to cartilaginous loss at the bony-cartilaginous junction of the dorsum. Ocular manifestations are commonplace as well in over half of patients. This can present in a myriad of ways, most commonly an episcleritis, but can also present as conjunctivitis or scleritis.
Respiratory tract involvement occurs in about 56% of patients. This can be from just a mild cough to a patient presenting in acute distress with stridor. Tracheobronchial involvement is one of the most feared complications of relapsing polychondritis and must be evaluated in a timely fashion. Audiovestibular symptoms have been shown to occur in 46% of patients. This is thought to be as a direct result of a cochlear sensorineural hearing loss due to arteritis of the internal auditory artery.
Cardiac manifestations include valvular disease as well as aneurysms of the aortic arch. A multitude of skin lesions can also be a presenting symptom.
So, how do we diagnose these patients? On clinical presentation, there is no specific laboratory test that exists to help us with the diagnosis. Most are nonspecific in nature. The serological tests that have been recommended include erythrocyte sedimentation rate, which will be elevated in 86% of patients. This has also been shown to help to monitor the progression or resolution of the disease in patients. The ESR will decline as the disease entity is treated.
Anemia is present in 57% of patients. Most commonly, it is a monocytic anemia. Our patient had a microcytic anemia due to other medical problems as well. Our patient did have a leukocytosis, which presents in 38% of patients. There will also be an elevated ASO titer in 29% of patients. ANA and RF (rheumatoid factor) can be positive in 18% and 17% of these patients, respectively.
The wide spectrum of the disease makes the presenting complaints and episodic nature very difficult to diagnose and results in a significant delay in diagnosis. A study by Trentham and Le in 1998 in the Annals of Internal Medicine reviewed 66 patients with relapsing polychondritis. The mean delay in diagnosis of these patients was 2.9 years; 68% were diagnosed after more than one year. Shockingly, five or more physicians had been seen consulted for diagnosis in a third of the patients.
The diagnostic criteria for relapsing polychondritis were first proposed by Dr. McAdam and have been modified several times. He also recommended performing a biopsy only if the clinical criteria are in question with a risk of creating a wound and the potential for an infectious sore. McAdam’s criteria for diagnosis of relapsing polychondritis must include three of the six following clinical features: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage.
The criteria have been modified several times since Dr. McAdam. Drs. Damiani and Levine recommended the use of one of the three following conditions to be met to make the diagnosis of relapsing polychondritis: either three of the McAdam criteria, one of McAdam criteria plus histology–proven disease, or two McAdam criteria plus a therapeutic response to corticosteroid or dapsone administration.
Dr. Michet modified it slightly further where two of his conditions needed to be met to make the diagnosis: either proven inflammation in two of the three of the auricular, nasal, or laryngotracheal cartilages, or proven inflammation in one of the three cartilages plus two other signs including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.
The pathophysiology of relapsing polychondritis is largely unknown at this point. There have been multiple studies trying to elucidate the underlying disease process, although an autoimmune response, as I mentioned, is strongly suspected. There have been antibodies to type II collagen that have been found to be implicated in this disease. This reaction results in an inflammatory infiltration and a lysosomal enzyme release, eventually resulting in destruction of the cartilage. The established therapeutic response to steroid also hints at an autoimmune etiology.
Dr. Foidart, in the New England Journal of Medicine, presented a study to test the hypothesis that that are immunologic mechanisms involved in the pathogenesis of relapsing polychondritis. He analyzed the serum of 15 patients with the diagnosis. Antibodies, specifically to type II collagen which is found in cartilage most commonly, were found in the serum of five of the patients at the time of acute symptoms. There were no antibodies detected to cartilage proteoglycan or to any of the other cartilaginous types. He did also note the presence of circulating immune complexes detected in the serum of the patients. His conclusion was that these findings supported immunologic involvement in this condition, specifically of the antibodies to type II cartilage as well as the pathway creating immune complex deposition.
Dr. Hansson, in Sweden, presented a paper on the use of an animal model using mice to investigate the role of Matrilin-1 which is a noncartilaginous collagen matrix protein. Monoclonal matrilin-1-specific antibodies were injected into neonatal mice bound specifically to the cartilage of the respiratory tract. These mice were then sacrificed, and they were noted to have developed erosive chondritis of the respiratory tract. His conclusion was, therefore, that the relapsing polychondritis can be ameliorated by the pathway involving these tissue-specific antibodies and complement activation.
How do we treat these patients? No controlled trials of therapy for relapsing polychondritis have been published. Most treatment protocols are anecdotal or based on retrospective studies and analyses. Anti-inflammatory agents or NSAIDs are indicated for mild disease or for symptomatic care. Corticosteroids are the mainstay of therapy for more severe cases including IV steroids in patients who present with respiratory compromise. Immunosuppressants such as methotrexate, CZT, cyclophosphamide, and cyclosporin A have been used very successfully. Oftentimes, patients will be started on a corticosteroid initially and then be started on methotrexate to bridge that gap as patients are weaned off the steroids. Dapsone and minocycline have been used in mild disease with little effect. Dapsone was used historically and the proposed mechanisms is inhibition of the lysozyme enzyme.
Medical care must include assessment and treatment for other concurrent autoimmune disorders, which is why it is important to evaluate these patients for rheumatoid factor and other autoimmune diseases which can be found in approximately in one-fourth of these patients.
What is the prognosis of this disease? Natural history is somewhat unpredictable, unfortunately, and repeated bouts of the inflammation of the cartilage can result in permanent destruction of the involved tissues resulting in significant disability. This is especially detrimental in those patients with endotracheal or bronchial involvement and subglottic stenosis. Destruction of the nose or ear cartilage can result in cosmetic deformity and functional deformity. The five-year survival rate has been cited between 70% and 84%, with the most common cause of death in these patients being pneumonia from respiratory involvement.
To follow up on our patient, the Rheumatology Service was consulted and they agreed with the diagnosis of relapsing polychondritis. The patient was started on indomethacin. She immediately started to notice resolution of her symptoms. The pain as well as the tenderness of the ear resolved. She was switched over to prednisone and methotrexate prior to discharge as she had an elevation in her serum creatinine, which was believed to be secondary to the indomethacin. Her lab values were rechecked, and her ESR came down appropriately to a level of 49 and her CRP came down to 1.11 showing resolution of her disease. She has had no reported recurrences to date.
In conclusion, I would characterize relapsing polychondritis as an uncommon, chronic disorder of the cartilage with varying presentations that can be a difficult and challenging diagnosis. It is characterized by recurrent episodes of painful inflammation. It can involve all parts of cartilage. Studies have shown a link to an autoimmune etiology. There are no specific tests for diagnosing relapsing polychondritis. A high index of suspicion is necessary to make a diagnosis in a timely fashion to avoid long-term sequelae such as saddle-nose deformity or cauliflower ear. Treatment currently involves some sort of cortisone-related medications and the course of symptoms in the patient is often unpredictable.
The patient is a 52-year-old African American female with a PMH of DM, HTN, OA, diabetic neuropathy, allergic rhinitis, and a recent episode of left auricular perichondritis one month earlier that resolved completely with PO Ciprofloxacin. She presents now with a 3 day history of extreme pain in the right ear. No history of trauma but admits to q-tip use. She denied hearing loss, tinnitus, vertigo, and otorrhea. She does complain of an occasional cough and scratchy voice. She denied fevers and chills. Review of symptoms was negative for pulmonary, cardiovascular, or neurological symptoms
Physical exam was remarkable for right auricular erythema and edema sparing the lobule. The ear was warm and extremely tender. The external auditory canal and tympanic membranes were clear bilaterally. The left auricle was within normal limits. The nose, nasopharynx, oral cavity, larynx, and neck were within normal limits.
The patient was admitted for further evaluation and the Rheumatology Service was consulted. The erythrocyte sedimentation rate was significantly elevated. On further questioning, she admitted to repeated bouts of nasal dorsum pin that resolved spontaneously. Upon further evaluation the patient was diagnosed with relapsing polychondritis and started on indomethacin. She improved clinically and the right auricular erythema, edema, and tenderness gradually resolved. Due to an increase in her serum creatinine, she was switched to prednisone and methotrexate prior to discharge. Her erythrocyte sedimentation rate slowly normalized and she has had no recurrences to date.
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