Jerome H Herman, MD Mar 21, 2000

It is difficult to predict the clinical course of relapsing polychondritis (RPC) because there is a marked interpatient variability. (See "Clinical manifestations of relapsing polychondritis"). The patterns that may be seen include:

• Episodic disease activity.
• Smoldering disease with ever-changing severity.
• A fulminant downhill course resulting in death.
• A relatively benign course that is free of clinically evident visceral involvement and is easily managed. It is not possible to estimate the prevalence of this self-limited pattern, since it is likely that many of these cases are not diagnosed.

In addition to the variable course, other issues that may affect therapeutic decisions are concurrent systemic symptoms, the sites of involvement, the duration of disease activity, the initial response to therapy, and the frequency of relapse.

GENERAL PRINCIPLES OF THERAPY — The relative rarity of RPC has not permitted clinical trials to determine the efficacy and safety of different therapies. The pharmacologic approach in current use is largely empiric, being based upon a large series of anecdotal single or multiple case reports. No form of therapy has been shown to modify the natural history of the disease, although successful suppression of the clinical features can be achieved.

The inability to predict patient response is particularly frustrating and limits our understanding of the relevance of certain pathophysiologic mechanisms. As an example, the administration of immunosuppressive agents is one of the mainstays of therapy in severe disease (see below). However, de novo RPC has been reported in a renal transplant recipient (in whom the cause of end-stage renal disease was unknown) despite potent immunosuppression with prednisone, cyclosporine, and azathioprine [1].

Decisions about therapy should not be made until potential subclinical disease involving major visceral sites has been appropriately investigated. Active cardiac, tracheobronchial, and large artery involvement, which generally indicate the need for aggressive therapy, are at times asymptomatic or difficult to detect. We therefore recommend the following evaluation prior to the institution of therapy:

• Careful cardiac auscultation and electrocardiography. Consideration should also be given to echocardiography to look for possible aortic or mitral valve thickening or regurgitation if there is clinical evidence or suspicion of valvular disease.

• A chest radiograph and baseline pulmonary function testing.

• If clinically indicated, CT scanning to determine the site and degree of suspected airway stenosis.

In addition, careful and continuous long-term monitoring is indicated. It is important to appreciate that patients in apparent clinical remission may have ongoing and important subclinical disease activity. One patient, for example, developed aortic valve inflammation despite apparent remission of RPC [2]. This observation has raised the question of whether early prophylactic treatment with a second-line immunosuppressive agent should be considered in all patients.

MEDICAL MANAGEMENT — The type of medical therapy given varies with the clinical estimate of disease activity and severity (show figure 1).

Lack of visceral involvement — Some patients have active disease which does not significantly compromise organ function. They can present with features such as auricular or nasal chondritis and peripheral or axial arthritis. A nonsteroidal antiinflammatory drug (NSAID) may be sufficient in this setting if it is given in sufficient quantity to suppress the inflammation. Analgesic supplementation may be necessary.

There are several choices if an adequate response is not achieved within seven to 10 days, usually beginning with dapsone or prednisone which appear to be equally effective in patients without visceral involvement. Both drugs decrease disease activity and reduce the incidence of recurrence. A response is evident in the majority of patients within one to two weeks.

• Institution of dapsone (a sulfone), based upon its presumed enzyme inhibitory and immunomodulatory properties [3,4]. We initiate therapy at a dose of 50 to 100 mg, once daily. The dose is increased, if necessary, in 25 mg increments every one to two weeks to a maximum dose 200 mg/day. In one small series, for example, improvement was seen in all seven patients treated with dapsone [4]. The average dose was 75 mg/day for four months (range 25 mg to 200 mg/day, duration, one week to two years). Once the desired response is obtained, the dose should be gradually tapered to the lowest effective maintenance level. An attempt should be made to discontinue the drug if there has been persistent clinical stabilization and normalization of laboratory parameters such as the erythrocyte sedimentation rate (ESR).

The physician should be alert for potential side effects, particularly hemolytic anemia, blood dyscrasias, hypersensitivity reactions, exfoliative dermatitis, peripheral neuropathy, hepatic damage, or changes in mental status. Dapsone should not be used if there be a history of allergy to sulfonamides, severe anemia, or glucose-6-phosphate dehydrogenase deficiency or if the patient is pregnant or breast feeding.

• Corticosteroids are also effective, with the initial dose being dependent upon the severity of the disease [4,5,6]. Most patients respond to 30 to 60 mg/day of prednisone (or its equivalent) in divided doses. Once the disease activity has remitted, the dose should be tapered to the lowest maintenance level and eventually discontinued.

Alternate-day dosing is not recommended in RPC. The possible use of a second-line agent with potential steroid-sparing activity should be considered in patients requiring continued steroid therapy (see below). On occasion, an intraarticular steroid injection may be efficacious.

• Patients who do not respond to initial therapy with dapsone or prednisone can be treated with a combination of these two drugs. Alternatively, a second-line agent such as cyclophosphamide, azathioprine or methotrexate can be given, either as monotherapy or in conjunction with dapsone and/or prednisone (see below).

There are sporadic reports of the use of other drugs to manage the more benign forms of RPC. However, their efficacy is uncertain. An initial report describing a beneficial response to colchicine awaits further documentation [7]. We have not used this agent in the management of RPC.

Organ-threatening disease — A less conservative approach should be taken in the presence of laryngotracheal, bronchial, cardiovascular, renal, ocular or neurologic disease. Patients with relatively mild organ involvement should be started on prednisone (60 to 100 mg/day in divided doses), followed by gradual tapering to a maintenance level of 7.5 to 10 mg/day; in contrast, those with compromised organ function should also be begun on a second-line agent (see below).

Relapses tend to occur when the prednisone dose is reduced too rapidly or if prednisone is prematurely discontinued. Although an attempt should be made to withdraw medication once clinical and laboratory parameters have stabilized, this may not be possible without concomitant use of a second-line agent (see below). Because of the unpredictable relapsing nature of RPC, there are no definitive guidelines indicating how long maintenance therapy with steroids or alternative agents should be continued before attempting withdrawal. We empirically initiate a conservative pattern of tapering leading to discontinuation once the clinical course has remained stable for at least three months and laboratory parameter, such as the ESR, are normal. Medication should be reinstituted or the dosage increased should symptoms recur.

The role of dapsone in patients with organ-threatening disease has not been clearly defined. Preliminary observations suggest that it may be less effective than prednisone in these patients [4,8].

Second-line drugs — A number of immunomodulatory and antiinflammatory drug regimens have been used as an adjunct to steroids in RPC. The response to these agents cannot be predicted and the potential benefit must be weighed against possible toxicity.

A second-line agent should be added in the following settings:

• The severity of involvement significantly compromises organ function (such as laryngotracheobronchial involvement), posing the potential of irreversible damage. The second-line agent should be given with prednisone at the initiation of therapy in such patients.

• A satisfactory clinical response to prednisone is not achieved within one to two weeks.

• The required maintenance dose of steroid is excessive and a steroid-sparing effect is desired.

The choice of agent is largely empiric, since there is insufficient published evidence to strongly support one regimen versus another in RPC. Nevertheless, some recommendations can be provided based upon usage in RPC and in other forms of autoimmune and connective tissue disease in which comparable pathophysiologic mechanisms are thought to be operative.

The major second-line drugs in RPC include cyclophosphamide, azathioprine, cyclosporine, pulse methylprednisolone, methotrexate, and other newer therapies. Newly released antiinflammatory/immunomodulatory compounds with potential efficacy, such as leflunomide, soluble tumor necrosis factor receptor (etanercept) or anti-tumor necrosis factor antibody (infliximab), have not yet been evaluated.

Cyclophosphamide — Cyclophosphamide, in an oral dose of 1 to 2 mg/kg per day for two weeks, is the preferred second-line agent primarily because of its proven value in the management of systemic necrotizing vasculitis, rather than evidence from controlled studies demonstrating its efficacy in RPC [9,10]. If a favorable clinical response is seen, the dose is kept at this level with readjustment to maintain a total white blood cell count above 3000 per mm3 with a total neutrophil count of 1000 to 1500 mm3. If, on the other hand, there is no clinical response, the daily dose should be increased in 25 mg increments every two weeks until a response is achieved or drug toxicity is apparent. (See "Mechanism of action and general toxicity of alkylating agents"). An attempt should be made to reduce the dose to a stable maintenance level once the disease activity is controlled (as defined by clinical and laboratory parameters, such as a significant reduction in the usually elevated erythrocyte sedimentation rate). Although definitive guidelines have yet to be established, we prefer to continue maintenance therapy for at least one year following clinical and laboratory evidence of disease remission.

There is insufficient information on the efficacy of monthly intravenous pulse cyclophosphamide therapy [11,12], a regimen that appears to be effective in lupus and is of uncertain efficacy in Wegener's granulomatosis. (See "Treatment of lupus nephritis-I" and See "Treatment of Wegener's granulomatosis-I"). The possible efficacy of chlorambucil, another alkylating agent, is uncertain.

Azathioprine — Azathioprine, in an oral dose of 2 mg/kg per day, is a potentially effective alternate to cyclophosphamide [13,14]. A clinical response should be evident within three to four weeks. Once the disease is controlled, the dose should be tapered to a maintenance level of 50 to 75 mg/day. The dose must be adjusted according to the degree of myelosuppression and the duration of therapy is similar to that recommended with cyclophosphamide.

Cyclosporine — Cyclosporine, in a dose of 5 mg/kg per day, should be considered if the patient fails to respond to cyclophosphamide or azathioprine [15]. A clinical response should be seen within one month. If clinical and laboratory parameters have remained stable over a three month period, an attempt should be made to achieve a lower maintenance dose to minimize nephrotoxicity. (See "Cyclosporine and tacrolimus (FK506) nephrotoxicity"). Cyclosporine may be particularly useful in the treatment of refractory ocular disease, especially nodular sclerosing relapsing scleritis [16]. The optimal duration of therapy is uncertain. Individual case reports have indicated both successful discontinuation after one year as well as the need for continued maintenance for more than two years.

Pulse methylprednisolone — Limited observations suggest that intravenous pulse methylprednisolone (1 gm bolus per day for three consecutive days) may be beneficial in selected patients with RPC [17]. This approach should be considered as an adjunct in patients refractory to the above immunosuppressive measures.

Methotrexate — Pulsed weekly methotrexate has been successfully used in the management of rheumatoid arthritis with a relative paucity of severe side effects. The limited information currently available is discordant as to its benefit in RPC, although it may have a steroid-sparing effect [18,19]. Methotrexate should be initiated in refractory cases at a dose of 5 to 7.5 mg per week, increasing by 2.5 mg increments every four to six weeks until the desired clinical response is achieved or a level of 25 mg per week is reached. Maintenance therapy may be required for a period of years. A disease flare should be managed by the addition of supplemental prednisone or by adjusting the dose of methotrexate. (See "Use of methotrexate in the treatment of rheumatoid arthritis" for a review of the pharmacokinetics and dosing of this drug).

Anti-CD4 antibody — The monoclonal anti-T cell anti-CD4 antibody has been reported to induce disease regression in two severe and refractory patients without significant side effects [20,21]. Unfortunately, follow-up of this promising approach is restricted because of lack of availability of this antibody for use in an orphan disease such as RPC, even on a compassionate basis.

Others — Sporadic reports have evaluated the use of penicillamine, plasmapheresis, and total nodal irradiation [22]; however, these modalities remain of unproven benefit. The administration of oral minocycline reportedly induced improvement in a patient with methotrexate toxicity [23].

GENERAL MEASURES — Patients with RPC are at increased risk for infection, which is a leading cause of death in this disorder. At least two factors contribute to this problem: the use of immunosuppressive drugs; and obstruction associated with inherent features of the disease, such as laryngotracheal and bronchial involvement, leading to abnormal drainage of respiratory secretions and ineffective cough due to dynamic upper airway collapse. Consideration should be given to the administration of influenza and pneumococcal vaccines in the presence of immunosuppressive therapy or significant laryngotracheobronchial disease.

Although increasing the dose of steroid may be sufficient for control of an exacerbation of many features of disease, delay in its onset of action poses a particular hazard in patients with airway compromise due to inflammation. The use of nebulized racemic ephedrine may be effective in this setting [24], while there is insufficient information concerning the use of inhaled steroids. In some cases, tenacious secretions may contribute to the airway obstruction and should be treated appropriately [25].

Few surgical options are available for patients with diffuse respiratory tract disease (see below); in this setting, the use of nasal continuous positive airway pressure may represent an effective, although temporary, therapy [26]. (See "Compliance and management problems with nasal CPAP").

Hematopoietic stem cell transplantation — The use of hematopoietic stem cell transplantation in conjunction with myeloablation has been suggested in patients with RPC (and other putative autoimmune diseases) and reversible life or organ threatening disease [27]. Major advances in this technique (such as the use of growth factors and/or pulse cyclophosphamide, aggressive supportive care prior to cellular reconstitution, and refinement in the cryopreservation of blood products) have significantly reduced the mortality associated with this procedure. (See "Engraftment and supportive care after stem cell transplantation").

SURGICAL THERAPY — Surgery may be indicated for some of the visceral manifestations of RPC.

Airway obstruction — Laryngotracheal and bronchial chondritis can cause potentially fatal airway narrowing. Three factors can contribute to this problem: inflammation; fibrosis-induced contractures; and/or loss of cartilaginous structural support which results in dynamic airway collapse during forced inspiration (larynx) or expiration (trachea). Involvement of glottic, subglottic, and upper tracheal regions may necessitate tracheostomy. It is important to appreciate, however, that tracheostomy may be ineffective in patients with more distal focal or diffuse airway narrowing. Furthermore, tracheostomy, by inducing inflammation, may increase the tendency to fatal airway obstruction.

Regions of segmental collapse, due to tracheomalacia, refractory stenosis, and inflammatory masses, may be surgically resected or treated with an expandable metal stent [28,29,30,31]. Stents eventually become epithelialized, preventing migration and permitting continued ciliary activity. Significant complications of stenting include airway inflammation, stent migration, airway erosion and stent fracture and collapse. The use of BiPAP after surgical management may help keep narrowed airways from collapsing, especially at night [32]. (See "Airway stents" and see "Noninvasive positive pressure ventilation in acute respiratory failure").

More extensive tracheobronchial collapse may require tracheal reconstruction with any of a variety of techniques. These include external tracheal fixation by suspension to the vascular adventitia of the aorta using pericardium, dura, or Gore-Tex implants [33], the use of sialastic tube prostheses, or esophageal tracheoplasty [34]. Localized inflammatory and mucosal fibrotic lesions leading to severe main stem bronchial obstruction have been successfully treated with NdYAG laser ablation [35].

Reported results of laryngotracheal reconstruction procedures are poor [36]. If such techniques are to be considered for isolated segments of tracheal or subglottic stenosis, timing of the operation is critical. Surgery should only be contemplated when the disease is well-controlled or in remission. There must be meticulous pre- and postoperative medical management of the disease process to avoid complications.

Valvular and aortic disease — Valve replacement or valvuloplasty should be considered in the presence of intractable heart failure due to valvular involvement in RPC [37,38]. Aortic aneurysms have also been successfully resected. However, a high incidence of surgical failure has been reported, perhaps due to contiguous active inflammation at operative sites or even induction of activity in regions of surgical trauma [37].

The management of valvular problems remains controversial because the preferred procedures and the optimal time for surgical intervention remain unclear [39]. Since 'silent inflammation' progresses both in the aortic wall and the aortic or mitral annuli despite corticosteroid treatment, the complete replacement of the ascending aorta using a composite graft and reimplantation of the coronary arteries in patients with disease involving the ascending aorta has been recommended. Optimal medical control of inflammation must be obtained prior to performing such elective surgery.

Although corticosteroids may be efficacious in cardiac complications such as acute inflammatory heart block, the development of an atrioventricular block late in the course of disease may require placement of a permanent pacemaker. (See "Indications for permanent cardiac pacing").

Anesthesia considerations — There are a number of settings in which general anesthesia may be required in the management of RPC including bronchoscopy, tracheostomy, and the surgical procedures noted above. Laryngeal or tracheobronchial disease can cause major anesthesiologic problems [29,40]. As an example, a small glottis destroyed by inflammation may lead to difficulty with intubation. There is also concern that intratracheal manipulation can lead to life-threatening post-anesthetic deterioration of the respiratory system by inducing additional glottal or subglottal inflammation. Local and regional anesthetics are therefore preferred. If general anesthesia be indispensable, a surgical standby should be available for emergency cricothyrotomy, especially if laryngeal obstruction is suspected.

PROGNOSIS — The pattern of case reporting in RPC prevents an accurate assessment of the overall prognosis. Among the problems are often incomplete documentation in single or a limited series of patients, large series derived from tertiary care centers to which more severely ill patients are referred, and the under reporting, lack of reporting, or failure of recognition of milder forms of the disease. The limited information available suggests what may be an unnecessarily ominous outlook.

Although the course of RPC can on occasion be rapidly fatal, the more frequent patterns reflect either a relatively benign or chronic indolent disease process, extending over many years with ultimate death stemming from unrelated causes. Some form of disability is common in later stages of RPC; this may include visual impairment, audiovestibular dysfunction, and cardiopulmonary disease.

The largest study reported a comprehensive analysis of 112 patients followed for approximately six years [41]. Intermittent inflammatory manifestations were noted by 86 percent of patients, with a median of five episodes per patent; the remaining 14 percent had continuous disease activity. The median survival from the time of diagnosis was 11 years, with 5- and 10-year probabilities of survival 74 percent and 55 percent, respectively (show figure 2).

However, a more favorable prognosis was reported in a more recent series [19]. In this review of 66 patients with an average disease duration of eight years, the survival rate was 94 percent.

The age at presentation appears to predict mortality. The death rate in younger patients (< 50 years of age) with aggressive disease ranges from 28 to 50 percent [42,43]. The most frequent causes of death are infection, laryngotracheal or bronchial involvement (especially stricture or collapse with resultant respiratory failure or superimposed pneumonia), and vasculitis.

Valvular heart disease — Additional adverse prognostic features include valvular heart disease with intractable heart failure, renal disease, intercurrent malignancy, and anemia. A recent literature review of valvular heart disease in 440 patients with RPC made the following observations [44]:

• The mean time from the onset of RPC to the need for operative intervention was 6.5 years (range five months to 21 years.

• Surgery was performed an average of one year after the diagnosis of valvular incompetence.

• Reoperation was required in 24 percent of cases in the first four postoperative years. The primary problem was leakage around the prosthetic valve due to friability at the site of prosthesis anchorage and aneurysm formation.

• Fifty three percent of patients died of a cardiovascular event during this four year period.