Version May 2024
INTRODUCTION — Relapsing polychondritis (RPC) is a systemic immune-mediated condition associated with inflammation in cartilaginous structures and other tissues throughout the body, particularly the ears, nose, eyes, joints, and respiratory tract (table 1). Classic features include auricular inflammation, saddle-nose deformity, and other features of cartilage destruction, but clinical manifestations can vary between patients, and the cardiovascular, renal, and nervous systems may also be affected. Another disorder is also present in association with RPC in approximately one-third of patients, usually some form of systemic vasculitis or a systemic rheumatic disease.
The diagnosis of RPC is frequently delayed due to its episodic and diverse symptoms and a lack of familiarity with the disease among clinicians. The course of RPC also varies considerably between patients and is difficult to predict. Disease may be episodic, relatively benign and free of clinically evident major organ involvement, continuously active but with fluctuating severity, or exhibit a fulminant and progressive course resulting in death.
The treatment of patients with RPC is presented here. The etiology and pathogenesis, pathology, clinical manifestations, and diagnosis of this disease are presented separately. (See "Etiology and pathogenesis of relapsing polychondritis" and "Pathology of relapsing polychondritis" and "Clinical manifestations of relapsing polychondritis" and "Diagnostic evaluation of relapsing polychondritis".)
GENERAL PRINCIPLES OF THERAPY — The type of medical therapy varies with the clinical estimate of disease activity and severity. Effective suppression of the clinical features can generally be achieved using immunosuppressive and immunomodulatory medications, although no form of therapy has been proven to modify the natural history of the disease (see 'Prognosis' below). Procedural interventions, including surgery, are sometimes required.
The relative rarity of relapsing polychondritis (RPC) has prevented the systematic evaluation of potential drug therapies for their efficacy and safety in randomized trials [1]. Thus, the approach to pharmacologic therapy is largely based upon observations in case series, multiple case reports, and clinical experience [1-5].
Factors that may affect therapeutic decisions include the disease course and severity, concurrent systemic symptoms, the sites of involvement, the duration of disease activity, the initial response to therapy, and the frequency of relapse. Importantly, treatment choices may also be influenced by the therapies required for associated comorbid conditions, requiring modification of the treatment approaches described here to optimize efficacy while minimizing adverse effects.
Several general principles apply to the treatment of RPC, despite the limitations of the available evidence regarding therapy:
●Extent and severity of disease – Decisions about therapy require the identification or exclusion of potential subclinical disease involving major organs, although active cardiac, tracheobronchial, and large artery involvement, which generally indicate the need for aggressive therapy, are sometimes asymptomatic or difficult to detect. The following testing, described in more detail separately, should be performed in all patients diagnosed with RPC prior to the institution of therapy (see "Diagnostic evaluation of relapsing polychondritis", section on 'Overview of post-diagnostic testing'):
•Otolaryngology consultation
•Baseline pulmonary function testing
•Chest radiography
•Electrocardiography
•Renal function (serum creatinine) and urinalysis
•Antineutrophil cytoplasmic antibody (ANCA) panel
Additional studies should be obtained in selected patients, depending upon the patient's history and findings; the indications for these studies are described in detail separately and may include additional imaging, such as computed tomography (CT), positron emission tomography (PET)/CT [6], and magnetic resonance imaging (MRI); bronchoscopy; echocardiography; autoantibody testing; and other laboratory investigations. (See "Diagnostic evaluation of relapsing polychondritis", section on 'Subsequent testing'.)
●Monitoring and duration of therapy – Attentive and continuous long-term monitoring is indicated in patients with RPC. Patients in apparent clinical remission may have ongoing and important subclinical disease activity. Moreover, the duration of required therapy can vary significantly depending on the degree of clinical involvement. (See 'Monitoring and duration of therapy' below.)
For patients with simple auricular, costochondral, or nasal chondritis, intermittent therapy for periodic flares is often sufficient. For severe manifestations, such as laryngotracheal involvement, prolonged immunosuppression is often necessary, and distinguishing active disease from permanent damage can be challenging.
AURICULAR OR NASAL CHONDRITIS, ARTHRITIS, AND LACK OF MAJOR ORGAN DISEASE
Initial treatment with NSAIDs — In patients with relapsing polychondritis (RPC) who have nasal or auricular chondritis and those with peripheral or axial arthritis but no major organ-threatening involvement (ie, no major airway inflammation, stenosis, or collapse; cardiac disease; vasculitis; ocular, renal, or neurologic disease attributable to RPC), we suggest initial treatment with a nonsteroidal antiinflammatory drug (NSAID) at a full antiinflammatory dose (eg, naproxen 500 mg twice daily or ibuprofen 800 mg three to four times daily). Once the desired response is achieved, the medication should be used in the lowest dose and for the shortest duration necessary.
In our experience and described in case series, an NSAID may be sufficient in this setting if it is given in adequate doses to suppress clinical evidence of inflammation; use of an NSAID may help to avoid other drugs with potential adverse effects such as glucocorticoids or dapsone [7,8]. As the frequency and severity of flares of chondritis may vary widely in patients, clinical judgment is necessary to determine if NSAID therapy alone is sufficient to treat limited disease. A trial of dapsone, low-dose prednisone, or methotrexate should be considered in patients who remain symptomatic with auricular or nasal chondritis despite regular NSAID use. (See 'Dapsone' below and 'Systemic glucocorticoids' below and 'Resistant to glucocorticoids' below.)
Brief analgesic supplementation with tramadol (50 to 100 mg two to four times daily) or hydrocodone/acetaminophen (5/500 mg two to four times daily) can be added if required but should be used in the lowest doses necessary and stopped once the flare of chondritis is resolving.
In patients in whom NSAIDs are contraindicated, a glucocorticoid or dapsone should be used, using the same approach as in patients who are resistant to NSAIDs. (See 'Resistant to NSAIDs' below.)
Resistant to NSAIDs — In patients with an inadequate response to at least 7 to 10 days of treatment with an NSAID in an antiinflammatory dose, who have nasal or auricular chondritis and/or peripheral or axial arthritis but no major organ-threatening involvement, we suggest glucocorticoids rather than continued trials of different NSAIDs (see 'Systemic glucocorticoids' below). Another potentially effective option in patients with these disease characteristics is dapsone. (See 'Dapsone' below.)
Both glucocorticoids and dapsone can decrease disease activity and reduce the frequency of recurrence. A response is evident in the majority of patients given one of these agents within one to two weeks. We generally prefer glucocorticoids because they have fewer contraindications and are often better tolerated than dapsone, which may be associated with cutaneous eruptions and hemolysis. However, for mild, non-deforming chondritis, dapsone may be used as an alternative to glucocorticoids in patients with relative contraindications to glucocorticoids, such as diabetes.
Intraarticular glucocorticoids may be of benefit in patients with one or a few involved joints, and, in patients whose other manifestations respond to NSAIDs, such treatment may help to avoid the need for glucocorticoid or dapsone therapy. (See 'Resistant mono/oligoarthritis' below.)
Systemic glucocorticoids — The initial dose of glucocorticoids depends upon the severity of the disease [9-11]. 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 as tolerated. Alternate-day dosing is not recommended in RPC.
The effectiveness of glucocorticoids in this population has been shown in case reports and case series and is consistent with our experience [9-11].
Long-term, low-dose glucocorticoid therapy (eg, prednisone 5 to 7.5 mg daily) may be necessary to suppress flares. If the dose cannot be tapered to this level, the addition of a glucocorticoid-sparing agent is advised. (See 'Resistant to glucocorticoids' below.)
The adverse effects of glucocorticoids and the approach to prevention of glucocorticoid-induced osteoporosis are described in detail separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Dapsone — In patients being treated with dapsone, 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 of 200 mg daily. 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).
Dapsone may be effective for primary manifestations of RPC, including auricular and nasal chondritis. However, in patients who respond to dapsone, long-term therapy is sometimes necessary to suppress flares.
Dapsone should not be used as monotherapy in patients with sudden hearing loss, vertigo, or laryngotracheal involvement; these patients require a more intensive treatment approach. (See 'Life- or organ-threatening disease' below.)
Potential side effects of dapsone include hemolytic anemia, blood dyscrasias, hypersensitivity reactions, exfoliative dermatitis, peripheral neuropathy, hepatic damage, and changes in mental status. Dapsone should not be used if there is a history of allergy to sulfonamides, severe anemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, or if the patient is pregnant or breastfeeding.
The efficacy of dapsone has been shown in case reports and case series and is consistent with our clinical experience. As an example, in one small series, improvement was seen in all seven patients treated with dapsone [9]. The average dose was 75 mg/day for four months (range 25 mg to 200 mg/day, duration one week to two years). Dapsone (a sulfone) is thought to act through its presumed enzyme inhibitory and immunomodulatory properties [9,12].
Resistant mono/oligoarthritis — An intraarticular glucocorticoid injection may be beneficial in patients with mild chondritis who respond to NSAIDs, glucocorticoids, or dapsone, but who have persistent arthritis in one or only a few joints that is resistant to those therapies. Precautions, dosing, and adverse effects are the same as in patients with rheumatoid arthritis and other inflammatory arthritides. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Intraarticular therapy' and "Joint aspiration or injection in adults: Technique and indications" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?" and "Joint aspiration or injection in adults: Complications".)
Resistant to glucocorticoids — In patients with auricular, nasal, or joint involvement who do not remit with glucocorticoids within a month of starting therapy, a second agent should be added. In mild to moderate disease, we typically use methotrexate (MTX) for this purpose. MTX is used in a similar fashion to its use in mild to moderate organ and tissue involvement and for maintenance therapy of life- or organ-threatening disease. (See 'Initial control of disease' below and 'Maintenance therapy' below.)
As an alternative, patients who do not respond to initial therapy with dapsone or prednisone can be treated with a combination of these two drugs. Although a combination of dapsone and prednisone has also been used in patients presenting with auricular and nasal chondritis that is complicated by sudden hearing loss or vertigo, more reliably tolerated and effective choices have been preferred as more experience has been gained in RPC with other glucocorticoid-sparing strategies. In addition to MTX, other alternative second-line agents include azathioprine and leflunomide, which, like MTX, can be given as either monotherapy or in conjunction with dapsone and/or prednisone, as well as other options. Cyclophosphamide may be useful in patients with organ-threatening disease. (See 'Life- or organ-threatening disease' below.)
There have been sporadic reports of the use of other drugs to manage the more benign forms of RPC. However, their efficacy is uncertain.
Treatment of relapse — In patients who relapse during subsequent tapering to a low maintenance dose of glucocorticoids (eg, prednisone 5 to 7.5 mg daily), we treat as in patients who do not improve adequately with glucocorticoids, usually with the addition of MTX, while temporarily increasing the dose of glucocorticoids to regain disease control. (See 'Resistant to glucocorticoids' above.)
LIFE- OR ORGAN-THREATENING DISEASE — In patients with life- or organ-threatening disease, which may include ocular, inner ear, laryngotracheal, bronchial, cardiovascular, renal, or neurologic disease, the initial treatment is determined by the assessment of disease severity.
●Patients with mild to moderate disease are typically begun on high-dose oral glucocorticoids, with the addition of a second agent, usually methotrexate (MTX), if glucocorticoids are inadequate to control disease. (See 'Mild to moderate organ involvement' below.)
●Patients with more severe disease, which is generally defined as that which is life-threatening or which has the potential to result in significant organ and tissue damage, are treated initially with a combination of glucocorticoids and another agent, typically cyclophosphamide. (See 'Life- or organ-threatening disease' below.)
Mild to moderate organ involvement
Initial control of disease — Treatment depends upon the nature and severity of organ involvement and the response to therapy:
●Initial management – In patients with mild to moderate organ involvement, we suggest initiating prednisone (1 mg/kg daily by mouth in divided doses for three to four weeks). These patients include those with ocular, inner ear, laryngotracheal, bronchial, or cardiovascular disease but whose disease is not life- or organ-threatening and who lack significant organ and tissue damage.
●Resistant to initial glucocorticoids – In patients with mild to moderate disease who do not remit with glucocorticoids within a month of starting treatment, we suggest the addition of MTX; other alternative second-line agents include azathioprine, leflunomide, and others. (See 'Alternatives to cyclophosphamide' below and 'Cyclophosphamide use and dose adjustment' below.)
The efficacy of MTX in relapsing polychondritis (RPC) and evidence of its glucocorticoid-sparing effect are supported by case reports and case series and are consistent with our clinical experience [2,3,13]. There have not been any randomized trials to compare MTX with other immunosuppressive/immunomodulatory drugs in this condition.
Once-weekly MTX is administered as 15 mg weekly by mouth or by subcutaneous injection initially and advances to 20 to 25 mg weekly, if necessary, as tolerated; the drug is generally well tolerated. The approach to the use of MTX is the same as is described for the treatment of rheumatoid arthritis; preventive measures, including appropriate drug monitoring, treatment with daily folic acid supplementation, and the adverse effects of MTX used in this fashion are described in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease" and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)
Maintenance therapy and glucocorticoid taper — Tapering of medications in patients with mild to moderate disease typically occurs in two stages:
●During the first stage of tapering, once disease control is established, an effort to reduce glucocorticoids to 5 to 7.5 mg daily is made, with the addition of MTX or an alternative agent if needed to achieve that goal (see 'Initial control of disease' above and 'Treatment of relapsed mild to moderate organ involvement' below). In patients who respond to therapy, an attempt should be made to gradually reduce the dose of glucocorticoids once clinical and laboratory parameters have stabilized.
The clinical monitoring and testing should focus in particular on the affected organs and tissues together with nonspecific markers reflecting inflammation, such as the erythrocyte sedimentation rate (ESR). The glucocorticoid should be gradually tapered, as long as disease remains under control, to a maintenance level of 5 to 7.5 mg daily. In patients in whom a higher maintenance dose of glucocorticoid is required to control disease activity, a second immunosuppressive drug (eg, MTX) should be added for greater efficacy and to provide a glucocorticoid-sparing effect. (See 'Initial control of disease' above and 'Treatment of relapsed mild to moderate organ involvement' below.)
●Once a stable dose is achieved and treatment has been maintained for three months without recurrent disease, an effort is made to further reduce and discontinue the medications. In patients in whom the clinical course has then remained stable for at least three months and laboratory parameters, such as the ESR, continue to remain normal, we further taper the medications gradually, with a goal of discontinuing the medications. Medications should be reinstituted or the dose increased should symptoms recur during this taper.
Relapses tend to occur when the prednisone dose is reduced too rapidly or if prednisone is prematurely discontinued. Relapses may occur unpredictably, and there are no proven or formal consensus guidelines indicating how long maintenance therapy with glucocorticoids or alternative agents should be continued before attempting withdrawal. Our approach is based upon published case series and our clinical experience and is consistent with approaches to the use of these medications in other systemic immune-mediated disorders [4,14,15]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)
Decisions regarding the dose and duration of therapy and other drug choices need to be individualized, depending upon the response to therapy and the severity of disease, and some patients will require maintenance therapy for months to years to prevent relapses.
Given the toxicities of prolonged glucocorticoid use, prophylactic treatments should be provided for bone loss (eg, calcium and vitamin D or, if appropriate, a bisphosphonate). (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Treatment of relapsed mild to moderate organ involvement — In patients with mild to moderate disease who relapse during or following subsequent tapering to a low maintenance dose (eg, prednisone 5 to 7.5 mg daily), we suggest the addition of MTX; other alternative second-line agents include azathioprine, leflunomide, mycophenolate, and cyclosporine. In patients with very mild disease, hydroxychloroquine has been used. Management of these patients follows the same approach as in patients with an inadequate response to initial treatment with glucocorticoids. (See 'Initial control of disease' above.)
Life- or organ-threatening disease
Initial therapy — In patients with life-threatening disease or significant organ damage, we suggest a combination of prednisone (usually 1 mg/kg daily) combined with oral cyclophosphamide (initially at 2 mg/kg daily by mouth). Such patients include those with severe laryngotracheal involvement, renal or neurologic involvement (especially glomerulonephritis or central nervous system [CNS] disease), or necrotizing scleritis. Selected patients with more acute or especially severe or critical presentations may benefit from pulse intravenous glucocorticoids when therapy is initiated. We take the following approach to the dosing and administration of each medication:
●Glucocorticoids – We typically initiate glucocorticoid treatment with prednisone (1 mg/kg administered orally once daily). The dose can be split to administer the same daily total over two doses daily in patients whose inflammation is not suppressed by the once-daily dosing regimen. Prednisone should be maintained at the initial starting dose for the first month, then tapered gradually, once disease activity is controlled, to 7.5 mg or less daily by six months. The response to therapy is assessed by resolution of the clinical and laboratory manifestations of active disease.
In patients with an acute, systemic presentation with complications such as sudden sensorineural hearing loss, systemic vasculitis, or severe laryngotracheal chondritis, we use pulse intravenous methylprednisone (1 g bolus per day for three consecutive days) as an adjunct to other therapies. Limited observations suggest that intravenous pulse methylprednisolone may be beneficial in selected patients with RPC [16].
●Cyclophosphamide – We typically use orally administered cyclophosphamide (initiated at a dose of 2 mg/kg daily). We prefer cyclophosphamide in this population because of evidence from case series and case reports in RPC and its proven value in the management of systemic necrotizing vasculitis, rather than evidence from controlled trials demonstrating its efficacy in RPC, which are lacking. (See 'Cyclophosphamide use and dose adjustment' below.)
Intravenous monthly bolus cyclophosphamide is another option for administration of this medication but with less published evidence of benefit compared with oral administration [17,18].
As in other systemic rheumatic diseases where cyclophosphamide is used, the safest strategy is to use it for induction therapy with a plan to transition the patient to another medication for maintenance within three to six months.
Cyclophosphamide use and dose adjustment — In patients with a favorable clinical response (control of symptoms, signs of disease, and laboratory markers of inflammation), the dose of cyclophosphamide is kept at the initial level of 2 mg/kg by mouth with readjustment to maintain a total white blood cell (WBC) count above 3000 per mm3 with a total absolute neutrophil count (ANC) of 1000 to 1500 mm3. In patients in whom there is no response after two weeks of treatment, the cyclophosphamide dose may be increased by 25 mg increments every two weeks, to a maximum of 200 mg daily, until a response is achieved or drug toxicity limits further dose escalation (see "General toxicity of cyclophosphamide in rheumatic diseases"). The same parameters for total WBC and ANC should be followed.
The use of cyclophosphamide or another alternative immunosuppressive (second-line) agent (see 'Alternatives to cyclophosphamide' below) in RPC is based upon case series and case reports [4,19,20], clinical experience, and efficacy in systemic vasculitis, including disorders that are sometimes associated with RPC, such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and in other autoimmune and systemic rheumatic disorders in which comparable pathophysiologic mechanisms are thought to be operative (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach'). There is insufficient published evidence to strongly support the use of one regimen over another. The potential benefit of any agent must be weighed against possible toxicities.
Given the toxicities of cyclophosphamide, prophylactic therapy should be provided for Pneumocystis pneumonia. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Cyclophosphamide may cause amenorrhea in women of childbearing age and bladder cancer. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity' and "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Bladder toxicity'.)
Alternatives to cyclophosphamide — A number of other immunomodulatory and antiinflammatory drugs have also been used in RPC as less toxic alternatives to cyclophosphamide, usually as an adjunct to glucocorticoids; these include MTX, azathioprine, and cyclosporine, as well as other therapies:
●Methotrexate – MTX is an alternative for patients who are unable to take cyclophosphamide or wish to avoid the adverse effects of cyclophosphamide, such as increased risk of infertility after drug discontinuation. It should not be used in patients with nephritis. (See 'Initial control of disease' above.)
●Azathioprine – Azathioprine, in an oral dose of 2 mg/kg per day, is a potentially effective alternate to cyclophosphamide that can be used in patients with glomerulonephritis and renal disease, unlike MTX [21-23]. 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. (See 'Initial therapy' above.)
Further information regarding the use and adverse effects of azathioprine is described in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)
●Other agents – The response to other antiinflammatory/immunomodulatory compounds with potential efficacy, such as cyclosporine, leflunomide, mycophenolate mofetil, soluble tumor necrosis factor (TNF)-alpha receptor (etanercept) or anti-TNF antibody (eg, infliximab, adalimumab), anti-interleukin (IL)-1 receptor (anakinra), anti-IL-6 receptor antibody (tocilizumab), and T-cell costimulatory inhibition (abatacept), have been largely limited to individual case reports and small case series [24,25]. Rituximab has not been shown to be reliably effective. (See 'Biologic therapies in relapsing polychondritis' below.)
Maintenance therapy — The choice of maintenance therapy, in place of cyclophosphamide, depends upon whether the patient has renal involvement:
●Without nephritis – In patients without nephritis, we use MTX as a maintenance therapy in place of cyclophosphamide once the patient's disease is well controlled after three to six months of treatment with cyclophosphamide. The duration of cyclophosphamide therapy is individualized within this range based upon the rapidity and completeness of the response and the severity of the disease. MTX is preferred because it is generally well tolerated and effective. MTX is usually begun at or titrated to 15 mg once weekly by mouth or by subcutaneous injection, then advanced to 20 to 25 mg weekly if necessary and tolerated. (See 'Initial control of disease' above.)
●With nephritis – In patients with nephritis, maintenance therapy should be with azathioprine or mycophenolate, similar to the approach to AAV. (See 'Alternatives to cyclophosphamide' above and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)
Multiple medications have been reported as glucocorticoid-sparing agents, including MTX, azathioprine, cyclosporine, mycophenolate, and leflunomide, but the evidence supporting any of these drugs as the preferred choice is limited. Their use is based upon case reports, small case series [3], clinical experience, and inference from their efficacy in other disorders, including AAV. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)
Full-dose cyclophosphamide is reinstituted in place of the immunosuppressive maintenance drug should a significant flare occur despite ongoing therapy.
Resistant to initial therapy — In patients who have not responded adequately to the combination of either cyclophosphamide, azathioprine, or MTX with high-dose oral glucocorticoids, we use one of the biologic agents (eg, a TNF inhibitor or tocilizumab) or cyclosporine (5 mg/kg per day) as a further treatment option [4,26,27]. (See 'Biologic therapies in relapsing polychondritis' below.)
In patients on cyclosporine, 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 nephrotoxicity"). Cyclosporine may be particularly useful in the treatment of refractory ocular disease, especially for nodular sclerosing relapsing scleritis [28]. 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.
In patients resistant to initial therapies (eg, cyclophosphamide, azathioprine) and to cyclosporine, we use pulse intravenous methylprednisone (1 g bolus per day for three consecutive days) as an adjunct to other therapies. Limited observations suggest that intravenous pulse methylprednisolone may be beneficial in selected patients with RPC [16].
In patients with severe or life-threating disease who have not responded to cyclophosphamide and glucocorticoids, there is no agent that has been proven to be the reliable next choice. Although cyclosporine 5 mg/kg has been used in this setting, it is not known if it is more effective than another drug such as azathioprine, mycophenolate, MTX, or a TNF inhibitor, as there have been no direct comparisons. Unlike in patients with AAV, rituximab has not been demonstrated to be an alternative to cyclophosphamide. Other biologics, while showing efficacy in case reports, are also unproven. (See 'Biologic therapies in relapsing polychondritis' below.)
Biologic therapies in relapsing polychondritis — Information regarding the benefit of biologic agents is limited to case reports and small series influenced by positive-result publication bias, and successful responses have been reported with infliximab, etanercept, adalimumab, tocilizumab, abatacept, anakinra, rituximab, and tofacitinib [29-44]. However, because of the rarity of RPC, there are no randomized trials of these agents.
The largest experience with biologics has been reported by the French RPC multicenter study group [45]. This 14-year retrospective cohort of 41 patients exposed to 105 biologics evaluated clinical disease activity response, glucocorticoid dose reduction, and clinical remission after six months of drug exposure. The overall rate of disease activity reduction was approximately 63 percent, but only 19 percent achieved complete remission. There was a high six-month drug dropout rate due to inefficacy, loss of efficacy, and adverse drug reactions. Tocilizumab, TNF inhibitors, particularly adalimumab or infliximab, and rituximab resulted in the highest frequency of clinical responses (60 to 71 percent). Abatacept and anakinra each had response rates of 50 percent. Analysis of organ-specific responses revealed that TNF inhibitors, tocilizumab, and abatacept had the greatest impact on most of the serious respiratory involvement in RPC.
Overall, tocilizumab was the most effective drug for all disease manifestations in the French cohort but was associated with a withdrawal rate for adverse drug reactions of 23.5 percent. Anakinra was the least beneficial biologic and was also associated with a high rate of withdrawal due to adverse drug reactions. The study confirmed clinical experience that RPC related to myelodysplastic syndrome tended to have a lower clinical response to biologics.
ADDITIONAL MEASURES FOR AIRWAY DISEASE — Patients with upper and/or lower airway disease benefit from further interventions in addition to systemic pharmacotherapy of the immune/inflammatory disease process, including particular attention to immunizations (to prevent respiratory infection), management of secretions, and inhaled medications for acute and subacute airway management. Management principles are the same as those that apply to other patients with obstructive airway disease and immune compromise.
Patients with relapsing polychondritis (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. Although use of immunosuppressive drugs precludes the use of live vaccines and may impair the antibody response to other vaccinations, we suggest the administration of influenza and pneumococcal vaccines for patients with significant laryngotracheobronchial disease.
Although increasing the dose of glucocorticoids 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 [46], while there is insufficient information concerning the use of inhaled glucocorticoids [47]. In some cases, tenacious secretions may contribute to the airway obstruction and should be treated appropriately [48].
Few surgical options are available for patients with diffuse respiratory tract disease (see 'Surgical therapy' below). In such patients, nasal continuous positive airway pressure may represent an effective, although temporary, therapy [49]. (See "Assessing and managing nonadherence with continuous positive airway pressure (CPAP) for adults with obstructive sleep apnea".)
SURGICAL THERAPY — Surgery may be indicated for some of the organ and tissue manifestations of relapsing polychondritis (RPC), including saddle nose deformity, airway obstruction, and valvular heart disease. There are special considerations that should be addressed in patients requiring general anesthesia.
Saddle nose deformity repair — Surgical repair of saddle nose deformity can be considered once the patient is in a sustained remission. Nasal septal repair is usually performed using a costal cartilage graft; however, in RPC patients, there has been concern for a possible relapse in a cartilage graft. Some reconstructive surgeons have successfully used bone grafts instead to avoid this potential complication.
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.
Regions of segmental collapse, due to tracheomalacia, refractory stenosis, or inflammatory masses, may be surgically resected or treated with an expandable metal stent, although the results of stenting vary and this approach is sometimes ineffective, in our experience [50-53]. 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 airway collapse proximal and distal to the stent. Some patients do not tolerate this intervention and may require removal of the stent soon after its insertion. This complication is often related to collapse of the airway distal to the stent. The use of bilevel positive airway pressure (BiPAP) after surgical management may help keep narrowed airways from collapsing, especially at night [54]. (See "Airway stents" and "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications".)
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 [55]; the use of silastic tube prostheses; or esophageal tracheoplasty [56]. Localized inflammatory and mucosal fibrotic lesions leading to severe main stem bronchial obstruction have been successfully treated with Nd:YAG laser ablation [57].
Reported results of laryngotracheal reconstruction procedures are poor [58]. 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 — Patients should be referred for surgical consultation for valve replacement or valvuloplasty in the presence of intractable heart failure due to valvular involvement in RPC [59,60]. 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 [59].
The management of valvular problems remains controversial because the preferred procedures and the optimal time for surgical intervention remain unclear [61]. Since "silent inflammation" progresses both in the aortic wall and the aortic or mitral annuli despite glucocorticoid 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 [62]. Optimal medical control of inflammation must be obtained prior to performing such elective surgery.
Although glucocorticoids 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 "Permanent cardiac pacing: Overview of devices and indications".)
Anesthesia considerations — Local, regional, or epidural anesthesia is generally preferred, while in patients who require general anesthesia, a surgical standby should be available for emergency cricothyrotomy, especially if laryngeal obstruction is suspected. Laryngeal or tracheobronchial disease can cause major anesthetic problems [51,63]; endotracheal intubation of patients with RPC may be difficult or impossible. As examples, a small glottis destroyed by inflammation may lead to difficulty with intubation and intratracheal manipulation can lead to life-threatening postanesthetic deterioration by causing further glottal or subglottal inflammation.
However, there are a number of settings in which general anesthesia may be required in the management of RPC, including bronchoscopy, tracheostomy, and other surgical procedures. (See 'Saddle nose deformity repair' above and 'Airway obstruction' above and 'Valvular and aortic disease' above.)
MONITORING AND DURATION OF THERAPY — In patients with limited cartilage involvement such as just auricular inflammation, follow-up is determined by the requirement of maintenance therapies. If the disease remains quiescent after several months of treatment, tapering therapy should be considered. In patients with an associated systemic disease such as vasculitis or myelodysplasia, the associated condition will determine the frequency and requirements of follow-up. In patients with laryngotracheal involvement, ongoing monitoring by the rheumatologist, otolaryngologist, and pulmonologist is necessary. At a minimum, annual spirometry and visualization of the upper airway is usually indicated. Follow-up CT or other advanced airway imaging is done on a case-by-case basis.
Duration of required therapy can vary significantly depending upon the degree of clinical involvement. For patients with simple auricular, costochondral, or nasal chondritis, intermittent therapy for periodic flares is often sufficient (see 'Auricular or nasal chondritis, arthritis, and lack of major organ disease' above). For severe manifestations, such as laryngotracheal involvement, prolonged immunosuppression is often necessary (see 'Life- or organ-threatening disease' above and 'Additional measures for airway disease' above). In the latter setting, in particular, distinguishing active disease from damage is challenging and may require periodic direct visualization of the airway by otolaryngology or pulmonary specialists. The role of positron emission tomography (PET)/CT scanning as a noninvasive method for following active airway inflammation is a potentially attractive option that needs further formal evaluation. A relapsing polychondritis (RPC) disease activity index has been developed but will require longitudinal evaluation to determine its utility [64].
PROGNOSIS — The pattern of case reporting in relapsing polychondritis (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 underreporting, lack of reporting, or failure of recognition of milder forms of the disease. The limited information available thus suggests a more ominous outlook than is necessarily likely.
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. Effective suppression of the clinical features can generally be achieved using available medications, although no form of therapy has been shown to modify the natural history of the disease. Some form of disability is common in later stages of RPC; this may include visual impairment, audiovestibular dysfunction, and cardiopulmonary disease.
The largest study, published in 1986, reported a comprehensive analysis of 112 patients followed for a median duration of approximately six years (range of one month to 20 years) [7]. Intermittent inflammatory manifestations were noted by 86 percent of patients, with a median of five episodes per patient; 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 of 74 and 55 percent, respectively.
However, a more favorable prognosis was reported in 1998 in a subsequent series [2]. 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 reported in younger patients (<50 years of age) with aggressive disease ranges from 28 to 50 percent during the follow-up period in various series [65,66]. 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.
Additional adverse prognostic features include valvular heart disease with intractable heart failure, renal disease, intercurrent malignancy, and anemia. A 1995 literature review of valvular heart disease in 440 patients with RPC made the following observations [59]:
●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.
SUMMARY AND RECOMMENDATIONS
●The treatment of patients with relapsing polychondritis (RPC) is largely based upon observations in case series, multiple case reports, and clinical experience and is tailored based upon the extent and severity of disease. Pretreatment evaluation is necessary to assess symptomatic and subclinical disease and includes otolaryngology consultation, baseline pulmonary function testing, chest radiography, electrocardiography, renal function testing and urinalysis, and testing for antineutrophil cytoplasmic antibody (ANCA). Additional studies should be obtained in selected patients, depending upon the patient's history and findings. (See 'General principles of therapy' above.)
●In patients with nasal or auricular chondritis and those with peripheral or axial arthritis but no major organ involvement (ie, no major airway inflammation, stenosis, or collapse; cardiac disease; vasculitis; ocular, renal, or neurologic disease attributable to RPC), we take the following approach:
•We suggest initial treatment with a nonsteroidal antiinflammatory drug (NSAID) (Grade 2C). The NSAID should be used initially in a full antiinflammatory dose. (See 'Auricular or nasal chondritis, arthritis, and lack of major organ disease' above.)
•In patients with an inadequate response to at least 7 to 10 days of an NSAID, we suggest oral glucocorticoids (prednisone or equivalent) (Grade 2C). Prednisone is administered at a dose of 30 to 60 mg daily depending upon severity of disease and tapered once disease activity is controlled to the lowest level necessary to maintain remission. Dapsone (initial dose 50 to 100 mg/day) is an alternative agent that may be effective for some patients. (See 'Resistant to NSAIDs' above and 'Systemic glucocorticoids' above and 'Dapsone' above.)
•In patients who do not remit with glucocorticoids within a month of starting therapy, a second agent should be added. In mild to moderate disease, we typically use methotrexate (MTX; 15 to 25 mg once weekly) for this purpose. Alternatives to MTX in these patients include azathioprine (2 mg/kg daily) and leflunomide (20 mg daily), which, like MTX, can be given either as monotherapy or in conjunction with dapsone and/or prednisone. (See 'Resistant to glucocorticoids' above.)
●In patients with mild to moderate organ involvement, which includes those with ocular, inner ear, laryngotracheal, bronchial, or cardiovascular disease, but whose disease is not life- or organ-threatening and who lack significant organ and tissue damage, we take the following approach:
•We suggest initiating prednisone (1 mg/kg daily by mouth in divided doses for three to four weeks) (Grade 2C), rather than using an additional immunosuppressive drug initially. (See 'Initial control of disease' above.)
•In patients who do not remit with glucocorticoids within a month of starting treatment, we suggest the addition of MTX (Grade 2C). MTX is used at a dose of 15 to 25 mg once weekly. Alternative second-line agents include azathioprine, leflunomide, and others. (See 'Initial control of disease' above.)
•Once disease control is established, an effort to reduce glucocorticoids to 5 to 7.5 mg daily is made, with the addition of MTX or an alternative agent (if not already required) if needed to achieve that goal. Once a stable dose is achieved and maintained for three months without recurrent disease, an effort should be made to further reduce and discontinue the medications. In patients who remain stable for at least three months and whose laboratory indices remain normal, we further taper the medications gradually, with a goal of discontinuing the medications. (See 'Maintenance therapy and glucocorticoid taper' above.)
●In patients with life-threatening disease or significant organ damage, which includes those with severe laryngotracheal involvement, renal or neurologic involvement (especially glomerulonephritis or central nervous system [CNS] disease), or necrotizing scleritis, we take the following approach:
•We suggest a combination of prednisone (usually 1 mg/kg daily) combined with oral cyclophosphamide (initially at 2 mg/kg daily by mouth) (Grade 2C). Prednisone should be maintained at the initial starting dose for the first month, then tapered gradually, once disease activity is controlled, to 7.5 mg or less daily by six months. In patients with an acute, systemic presentation with complications such as sudden sensorineural hearing loss, systemic vasculitis, or severe laryngotracheal chondritis, we use pulse intravenous methylprednisone (1 g bolus per day for three consecutive days) as an adjunct to other therapies. (See 'Life- or organ-threatening disease' above and 'Initial therapy' above.)
In patients with a favorable clinical response, the dose of cyclophosphamide is kept at the initial level of 2 mg/kg by mouth with readjustment to maintain a total white blood cell (WBC) count above 3000 per mm3, with a total absolute neutrophil count (ANC) of 1000 to 1500 mm3. (See 'Cyclophosphamide use and dose adjustment' above.)
Other immunomodulatory and antiinflammatory drugs that are alternatives to cyclophosphamide, usually also as an adjunct to glucocorticoids, include MTX, azathioprine (2 mg/kg per day, subsequently tapered to a maintenance level of 50 to 75 mg/day), and cyclosporine (5 mg/kg per day, subsequently tapered to a lower maintenance dose), as well as other therapies. (See 'Alternatives to cyclophosphamide' above and 'Resistant to initial therapy' above.)
•In patients without nephritis, we use MTX as a maintenance therapy in place of cyclophosphamide once the patient's disease is well controlled after three to six months of treatment with cyclophosphamide. In patients with nephritis, maintenance therapy should be with azathioprine or mycophenolate. (See 'Maintenance therapy' above.)
•In patients who have not responded adequately to the combination of either cyclophosphamide, azathioprine, or MTX with high-dose oral glucocorticoids, we use one of the biologic agents (eg, a tumor necrosis factor [TNF] inhibitor or tocilizumab) or cyclosporine (5 mg/kg per day) as a further treatment option. (See 'Resistant to initial therapy' above and 'Biologic therapies in relapsing polychondritis' above.)
●Airway obstruction may require surgical intervention. Involvement of glottic, subglottic, and upper tracheal regions may necessitate tracheostomy. Regions of segmental collapse due to tracheomalacia, refractory stenosis, and inflammatory masses may be resected or treated with expandable metal stents. The use of bilevel positive airway pressure (BiPAP) after surgical management may help prevent airway collapse. Surgical management may also be necessary for intractable heart failure due to valvular regurgitation and for aortic aneurysms. (See 'Airway obstruction' above and 'Valvular and aortic disease' above.)
●Endotracheal intubation of patients with RPC may be difficult or impossible. In addition, intratracheal manipulation can lead to life-threatening postanesthetic deterioration by causing further glottal or subglottal inflammation. Local and regional anesthesia is preferred. When general anesthesia is unavoidable, surgical standby should be available for emergency cricothyrotomy. (See 'Anesthesia considerations' above.)
●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 most frequent causes of death are infection, laryngotracheal or bronchial involvement (especially stricture or collapse with resultant respiratory failure or superimposed pneumonia), and vasculitis. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clement J Michet, MD, who contributed to an earlier version of this topic review.
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