The low prevalence of RP prevents controlled clinical trials of drug therapy. Consequently, there is no standard medical therapy which remains empiric and varies with the extent and severity of disease manifestations. Some patients have milder disease, with symptoms limited to auricular or nasal chondritis with or without peripheral/axial arthritis. In these patients, nonsteroidal anti-inflammatory drugs, low-dose colchicine, and analgesics, either alone or in combination, may be effective in controlling symptoms (40). For patients who fail to respond within one to two weeks, dapsone should be initiated at 50mg/day and increased by 25 mg every one to two weeks to a maximum dose of 200 mg/day. With control of symptoms and normalization of acute phase reactants, dapsone can be tapered to the lowest effective dose that maintains the response. Dapsone should not be used in patients with a sulfonamide allergy or glucose-6-phosphate dehydrogenase deficiency. Side effects include nausea, headaches, hemolytic anemia, severe rashes, peripheral neuropathy, hepatitis, and mental status changes.
Patients with minor manifestations that fail to respond to dapsone should be treated with low-dose corticosteroids (0.5 mg/kg/day prednisone equivalent). Patients who present with or later develop major disease manifestations including laryngotracheal, bronchial, or ocular involvement, systemic vasculitis, or cardiovascular, renal, or neurologic disease should be treated immediately with high-dose corticosteroids (1.0 mg/kg/day prednisone equivalent). Severe presentation such as acute airway obstruction should be treated with intravenous pulse methylprednisolone (1000 mg/day for three days) and nebulized racemic ephedrine (41,42).
Once the disease symptoms are controlled, corticosteroids should be tapered to the lowest dose that maintains control of visceral disease manifestations, to lessen the chance of side effects.
Several immunosuppressive drugs have been used empirically in patients who fail to respond to corticosteroids, have intolerable corticosteroid side effects, or would benefit from a corticosteroid-sparing regimen. Cyclophosphamide, methotrexate, azathioprine, chlor-ambucil, cyclosporin A, leflunomide, and plasmapheresis have all been used with reported success. Of these, the most experience has been with cyclophosphamide and methotrexate. Due to RP's frequent association with vasculitis, cyclophosphamide in a daily oral dose of 1 to 2 mg/kg/day is the preferred drug for severe disease (42). To induce remission, daily oral dosing is more effective than monthly intravenous pulse therapy. Patients are started on 50 mg/day and the dose is increased by 25 mg every two weeks to a maximum of 2 mg/kg/ day (usually 150 mg/day) or until the patient is brought into remission or experiences drug toxicity. The total white blood cell count should be kept above 3500 to 4000/mm3 to help avoid infectious complications. Once remission is achieved, prednisone is tapered. After six months of remission, cyclophosphamide is tapered by 25 mg/mo to the lowest effective dose that maintains remission, as evidenced by the clinical symptoms and a normal sedimentation rate/C-reactive protein. For less severe disease in patients with normal renal function, weekly methotrexate (7.5-25 mg/wk) with folate (1 mg/day) has been an efficacious and well-tolerated, steroid-sparing medication regimen. Trentham and Le reported that 23 of 31 patients receiving methotrexate at an average weekly dose of 17.5 mg responded to therapy and were able to taper their prednisone from 19 to 5 mg/day (20). Methotrexate is started at 7.5 to 15 mg/wk and increased by 2.5 to 5.0 mg monthly to clinical response, drug toxicity, or a maximum dose at 25 mg/wk. Subcutaneous methotrexate should be used at doses higher than 20 mg/wk for better absorption. Many physicians will use cyclopho-sphamide initially for three to six months to bring RP under control and then switch to methotrexate to maintain remission. A combination with dapsone is also used for added therapeutic effect and for Pneumocystis carinii pneumonia prophylaxis. Patients who fail to initially respond or maintain their response, or who develop severe hematologic or other toxicities on cyclophosphamide or methotrexate, should be considered for cyclosporine (5 mg/kg/day) or biologic therapy (43). Due to significant potential side effects, all of these medications should be administered and monitored by a physician familiar with their use. Administration of the pneumococcal vaccine, evaluation and therapy of osteoporosis, and treatment of hyperlipidemia and hypertension to prevent accelerated atherosclerosis must be done by the treating physician.
Biologic therapies have been used successfully in RP patients who do not respond to or cannot tolerate standard therapy. The anti-TNF-a agents have been increasingly reported to be effective in such patients in isolated case reports. Infliximab, at doses of 5 mg/kg every eight weeks after loading doses, has been reported to be effective in two case reports of treatment-resistant RP, while etanercept (25 mg subcutaneously twice a week) has been used in one patient (44,45). The major concerning side effect for these agents is infection, particularly in patients with tracheobronchial disease who are prone to developing pneumonia. Finally, autologous stem cell transplant has resulted in complete remission in one patient with refractory RP (46).
Patients who develop cardiorespiratory complications despite medical therapy may require surgery. Tracheostomy or stenting may be required to alleviate localized or extensive tracheobronchial disease (47). The use of BiPAP® (Respironics, Murrysville, Pennsylvania, U.S.A.) after surgery may help keep narrowed airways from collapsing. Localized lesions in a main stem bronchus have been successfully treated with NdYAG laser ablation. Severe tracheobronchial collapse that is too severe for stenting may require tracheal reconstruction, although reported results are poor (48). Up to 33% of patients with valvular regurgitation will need valve replacement due to intractable heart failure. Frequent postoperative complications include perivalvular leak and dehiscence resulting from valvular ring dilatation and friable tissue from chronic inflammation (26). Patients with valvular disease frequently have involvement of the aortic root and ascending aorta with aneurysm formation. Complete replacement of the ascending aorta using a graft with reimplantation of the coronary arteries may be necessary. Irrespective of the type of surgery, optimum results are obtained only if the inflammation is maximally controlled with immunosuppressive medications. If possible, surgery should be delayed until this is accomplished, in order to avoid complications (49). In addition, the anesthesiologist should be alerted that tracheal intubation will be difficult in patients with laryngotracheal involvement (50).
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