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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen expressed by B cells, is now considered an effective second-line therapy in various systemic diseases. We describe here the effects of rituximab in patients with relapsing polychondritis.

Methods

This was a retrospective study of 9 patients with relapsing polychondritis who received different regimens of rituximab in addition to their ongoing therapies. Clinical, laboratory, physiologic, and radiologic indicators were used to assess disease activity. We also examined their corticosteroid doses and any change in immunosuppressive agents. We then compared disease activity in the 6 months preceding rituximab administration and at 6 and 12 months after.

Results

At 6 months, 2 patients showed partial improvement, 4 were stable, and 3 had worsened disease; however, no patient had complete remission. At 12 months (after exclusion of the 3 patients whose disease had worsened at 6 months), 2 patients remained stable and 4 had worsened disease; however, there were no partial or complete remissions. B cells were counted in 8 patients during the first 6 months after treatment, and B cell depletion was observed in all of the patients.

Conclusion

Although we cannot rule out the possibility that rituximab had a small effect, our patients' clinical courses did not improve significantly with this treatment.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Relapsing polychondritis is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilage, particularly involving the external ears, nose, and respiratory tract (1). Joints, inner ears, eyes, skin, cardiac valves, and blood vessels may also be involved (2–5). An association with myelodysplastic syndromes or less frequently with lymphoma has been reported (2, 6–10). Preliminary elucidation of the pathogenesis of relapsing polychondritis suggests that a role is played by an inappropriate immune response involving B cells (11).

No single treatment is uniformly effective in relieving symptoms or preventing disease progression, although corticosteroids are the mainstay of treatment. Other drugs, including nonsteroidal antiinflammatory drugs, dapsone, and colchicine, have been proposed for mild cases. Immunosuppressants such as cyclophosphamide, azathioprine, cyclosporine (12), mycophenolate mofetil (13), and anti–tumor necrosis factor (anti-TNF) (14) have been used for severe manifestations of refractory relapsing polychondritis with varying degrees of efficacy. Other therapies such as plasmapheresis, anti-CD4 monoclonal antibodies (15), and autologous stem cell transplantation (16) have also been reported in a few cases.

Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen expressed by B cells, is considered an effective second-line therapy in various systemic diseases, including rheumatoid arthritis, systemic lupus erythematosus, thrombocytopenic purpura, and systemic vasculitis (17). To our knowledge, there are no published reports on the use of rituximab in patients with relapsing polychondritis. We describe here the course of 9 patients who received rituximab for refractory relapsing polychondritis (n = 8) or associated malignant lymphoma (n = 1).

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Patients.

We retrospectively reviewed the medical records of 9 patients followed in our department for relapsing polychondritis who received rituximab between September 2003 and January 2007. Relapsing polychondritis was diagnosed according to the criteria defined by Michet et al (2). All patients had a documented history of inflammatory episodes involving at least 2 of either ear, nose, or laryngotracheal cartilage, or involving 1 site and 2 other manifestations, including ocular inflammation, hearing loss, vestibular dysfunction, or seronegative inflammatory arthritis. Histologic proof was not required for inclusion, but 4 patients had a biopsy sample result compatible with the diagnosis (patients 1, 5, 7, and 8). Patients 1, 3, 5, and 6 were tested for antibodies to type II collagen before and 6 months after receiving rituximab; no patients had such antibodies. Antibodies to matrilin 1 were not determined. The patients also met the criteria defined by Damiani and Levine (18).

Two patients had sicca syndrome without anti-SSA antibodies (patients 3 and 5). All patients were tested for antineutrophil cytoplasmic antibodies (ANCAs) and antinuclear antibodies (ANAs); no patients had cytoplasmic ANCAs and 2 patients had ANAs.

Rituximab regimens.

Rituximab was administered as follows: 1,000 mg 2 weeks apart (patients 2, 6, 7, 8, and 9), 375 mg 2 weeks apart (patient 3), or 375 mg/m2 per week for 4 weeks (patients 1 and 4; patient 4 missed the last injection due to an infection). Patient 5 received 375 mg/m2 per week for 6 weeks combined with a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen. All patients received 40 mg of methylprednisolone with each rituximab infusion.

Assessment of disease activity.

The assessment of disease activity considered clinical evaluations, C-reactive protein levels, spirometry, thoracic computed tomography (CT) scans, the patient's steroid regimen, and any modification of their immunosuppressant regimen. Maximal expiratory and inspiratory flow volumes were studied for the followup, as recommended by Mohensifar et al (19). The thoracic CT scans were reviewed by a radiologist experienced in relapsing polychondritis.

The first day of rituximab infusion was defined as day 0. We then compared disease activity observed during the 6 months before day 0 with disease activity observed during the following two 6-month periods (months 1–6 and 7–12). Clinical symptoms present in the month after day 0 were not considered.

Complete remission was defined as the absence of any clinical symptoms. Partial remission was defined as an incomplete improvement in disease activity, stability was defined as unchanged disease activity, and worsening was defined as either an aggravation of disease activity or the institution of a new immunosuppressive agent regimen necessitated by the change in the patient's clinical status.

Monitoring B cell depletion.

The B cell count was assessed during the first 6 months and between 6 and 12 months after rituximab treatment began. B cell depletion was defined as a peripheral CD19+ B lymphocyte count less than 0.005 × 109/liter.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Patient characteristics.

Table 1 shows the characteristics of the 9 patients included in this study (6 women and 3 men, mean ± SD age 57.2 ± 9.7 years). Mean ± SD disease duration at day 0 was 13.6 ± 9.7 years. Signs of relapsing polychondritis involved cartilage from the nose (n = 9, with saddlenose deformity in 3 cases), larynx (n = 8), ears (n = 8), ribs (n = 6), and tracheobronchial tract (n = 4). Other manifestations included joints (n = 9), eyes (n = 6), skin (n = 5), inner ear (n = 2), and cardiac valves (aortic insufficiency in 1 case and mitral insufficiency in 2 cases each). Two patients had associated hematologic disorders: myelodysplasia (patient 4) and large B cell lymphoma (patient 5).

Table 1. Demographic characteristics*
PatientAge, yearsSexSigns of RPDisease duration, yearsPrevious treatments
  • *

    RP = relapsing polychondritis; IV = intravenous; MMF = mycophenolate mofetil; MI = mitral insufficiency; TNFα = tumor necrosis factor α; AI = aortic insufficiency; ASCT = autologous stem cell transplantation.

  • Including saddlenose deformity.

162MEars, nose, larynx, ribs, respiratory tract, joints, eyes19IV steroids, cyclophosphamide, methotrexate, dapsone
241MNose, larynx, respiratory tract, ribs, joints, eyes4IV steroids, cyclophosphamide, azathioprine
353FEars, nose, larynx, ribs, joints, hearing loss10IV steroids, methotrexate, azathioprine
476MEars, nose, larynx, respiratory tract, ribs, joints, skin8IV steroids, cyclophosphamide, methotrexate, azathioprine, MMF
563FEars, nose, joints, eyes, skin, MI1Dapsone
649FEars, nose, larynx, joints, eyes, skin, MI22IV steroids, cyclophosphamide, methotrexate, azathioprine, TNFα, IV immunoglobulins
757FEars, nose, larynx, ribs, joints, skin, hearing loss, AI32IV steroids, methotrexate, azathioprine, MMF, dapsone
858FEars, nose, larynx, respiratory tract, joints, eyes10IV steroids, cyclophosphamide, methotrexate, azathioprine, MMF, TNFα, cyclosporine, ASCT, thalidomide, dapsone
956FEars, nose, larynx, ribs, joints, eyes, skin16IV steroids, methotrexate, azathioprine, TNFα, sulfasalazine, dapsone

In addition to long-term oral steroids, patients had previously received the following treatments: high-dose intravenous pulse methylprednisolone (n = 8), methotrexate (n = 7), azathioprine (n = 7), cyclophosphamide (n = 5), dapsone (n = 5), mycophenolate mofetil (n = 3), infliximab (n = 3), intravenous immunoglobulins (n = 1), cyclosporine (n = 1), thalidomide (n = 1), sulfasalazine (n = 1), and autologous stem cell transplantation (n = 1).

Indications for rituximab and concomitant drug administration.

Rituximab was administered for severe refractory relapsing polychondritis (n = 8) or associated lymphoma (n = 1). It was given in combination with oral steroids (n = 9), methotrexate (n = 4), mycophenolate mofetil (n = 1), azathioprine (n = 3), and CHOP (n = 1), which were all initiated at least 8 months before the rituximab except in patients 2 and 4, who had begun azathioprine and methotrexate 4 months earlier.

Assessment of treatment efficacy at 6 months.

At 6 months, 2 patients were in partial remission (patients 1 and 8), 4 were stable (patients 2, 3, 5, and 6), and 3 had worsened disease (patients 4, 7, and 9), 2 of whom needed a new immunosuppressive agent (at 3 months for patient 4 and at 5 months for patient 9), and 2 of whom needed an increase in their corticosteroid dose (patients 4 and 7); however, no patient was in complete remission. Patient 1 was considered to be in partial remission because he had no relapse of ear cartilage symptoms, his dyspnea improved, he had only 2 episodes of bronchitis compared with 6 during the 6 months before rituximab treatment, and his maximal expiratory and inspiratory flow volumes increased. The worsening of the lung symptoms visible on the CT scan and the inflammatory syndrome may have been related to an infection on the day of evaluation. Patient 2 was classified as stable despite a worsening of the spirometric results. At 6 months, the results of the CT scan showed upper lobe opacities without aggravated malacia, findings considered more compatible with a pulmonary infection than a disease flare. The patient's clinical course was favorable with antibiotics. Control spirometry at 12 months confirmed the return to the preinfection values.

Assessment of treatment efficacy at 12 months.

Because the 3 patients whose disease was aggravated during the first 6 months required intensified treatment, they were excluded from the analysis at 12 months.

At 12 months, none of the remaining 6 patients had either a complete or partial response. Two remained stable (patients 2 and 5; patient 5 received rituximab in association with CHOP) (Table 2) and 4 grew worse (patients 1, 3, 6, and 8). Two patients received a second course of rituximab at 12 months for relapses, patient 8 after initial improvement and patient 3 after initially remaining stable. Specifically, although classified as stable at 6 months, patient 3 presented no signs of relapsing polychondritis from 4 to 11 months and relapsed only at 11 months with manifestations in the ears, nose, and joints, as well as with costochondritis and sensorineural hearing loss. The other 2 patients whose disease worsened received a new immunosuppressive agent (at 9 months for patient 6 and at 12 months for patient 1). Patients 2 and 5 were classified as stable; their steroid doses were decreased according to the scheduled tapering and their clinical symptoms were very stable.

Table 2. Followup characteristics*
PatientChondritisHearing lossJointsSystemic signsResp tractSkinEyesClinician assessmentSpirometryCRP levelCT scanPred dose, mg/dayAssociated immunCD19, %Eval of efficacy
EarsNoseRibsLarynxFEV1FIV1
  • *

    Resp = respiratory; FEV1 = forced expiratory volume in 1 second; FIV1 = forced inspiratory volume in 1 second; CRP = C-reactive protein; CT = computed tomography; pred = prednisone; immun = immunosuppressive agents; eval = evaluation; AB = abnormal; MTX = methotrexate; I = improvement; W = worsening; PR = partial remission; CYC = cyclophosphamide; AZA = azathioprine; S = stable; NA = not available; NL = normal; IV = intravenous; TNFα = tumor necrosis factor α; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; MMF = mycophenolate mofetil.

  • In liters.

  • In mg/liter.

  • §

    The worsening of the CT scan included bilateral interstitial infiltrates.

1                   
 Day 0X--X---X---1.371.45<4AB12MTX--
 M6---X---X--I1.741.9648W12MTX0PR
 M12---X---X--W1.331.537W12CYC0W
2                   
 Day 0-XX--X-X-X-1.272.6522AB15AZA--
 M6-X---X-X--S0.941.6137S15AZA0S
 M12-X---X-X--S1.222.488S15AZA0S
3                   
 Day 0XXXX-X-----NANA<4NL20AZA--
 M6XXXX-X----SNLNL<4NA15AZA0S
 M12XXX-XX----WNLNL<4NA60IV steroids, AZA, anti-CD200W
4                   
 Day 0XX-X-XX-X--NANA30AB15MTX--
 M6------XX-XWNANA77W§60TNFαNAW
5                   
 Day 0X----------NLNL<4NL17CHOP--
 M6X---------SNANA<4NL12.5-0S
 M12X---------SNANA<4NA10-2S
6                   
 Day 0-----X--XX-NLNL6NL25MTX--
 M6-----X--X-SNANANANA23MTX0S
 M12X----X--X-WNANA17NA17MMF0W
7                   
 Day 0-X---XX----NLNL9NA17MMF--
 M6-X---XX---SNANA8NA27MMF0W
8                   
 Day 0XX---XX----2.21NA39AB12---
 M6XX--------I2.28NA47S9-0PR
 M12X----XX---WNANA43S9Anti-CD204W
9                   
 Day 0-----X-----NANA4NA25AZA, MTX--
 M6---X-X----WNANA4NA25MMF0W

B cell depletion.

During the first 6 months, B cells were counted in 8 patients, and B cell depletion was observed in all patients. At 12 months, B cell depletion persisted in 4 patients (patients 1, 2, 3, and 6) among the 6 we could analyze (after excluding the 3 patients whose disease had worsened at 6 months), but repopulation of the peripheral B cell compartment had started for patients 5 and 8.

Adverse reactions.

Hypotension was not observed within 24 hours of the first infusion, nor was fever, urticaria, or joint pain. Patient 4 did not receive the final planned rituximab infusion because of sepsis related to a cutaneous abscess. The relapsing polychondritis remained uncontrolled and the patient received a TNF antagonist at 3 months. He later had Escherichia coli sepsis and finally died at 7 months with uncontrolled relapsing polychondritis and septic shock related to lung infection by Pseudomonas aeruginosa and emphysematous cystitis. Finally, no patient developed progressive multifocal leukoencephalopathy.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

To our knowledge, this study of 9 patients is the first report of rituximab use in patients with relapsing polychondritis. At 6 months, only 2 patients showed a partial clinical improvement, 4 were stable, and disease worsened in 3. Results at 12 months showed persistent stability in 2 patients and aggravated disease in 4 (after excluding the 3 patients with aggravated disease at 6 months from the 12-month analysis because of their intensified treatment). We did not observe complete remission at 6 or 12 months in any patient. Although partial response was observed in a few cases, rituximab did not seem to significantly improve the clinical course of the disease. The frequent association of rituximab with other immunosuppressive agents would most likely lead to overestimating rather than underestimating its effects.

Results of recent clinical studies indicate that rituximab is a major advance in the treatment of systemic autoimmune diseases (17, 20, 21). In contrast, our results present no strong evidence for its use in patients with relapsing polychondritis. A likely explanation is that CD20 cells are not a good treatment target in relapsing polychondritis. B cell depletion was observed in all patients tested for B cells, but clinical improvement was rare. We did not observe any correlation between clinical course and CD20 depletion: disease worsened in 3 patients at 12 months despite persistent complete B cell depletion (patients 1, 3, and 6), and 1 patient showed B cell repopulation without any clinical aggravation (patient 5). These findings agree with recent reports of patients with rheumatoid arthritis that suggest there is no consistent relationship between the absolute number of B cells and disease activity in individual patients (22).

Only one patient had severe infections, and he had received other immunosuppressive agents. Therefore, it is difficult to link sepsis to anti-CD20 therapy. Treatment was otherwise well tolerated and we did not observe any previously reported adverse events (22, 23).

Three limitations of our study should be underlined. First, because it is retrospective, the patients received different regimens of rituximab. Protocol regimens for the use of rituximab in autoimmune disorders are not currently standardized (17). They are most often based either on the schedule proposed for rheumatoid arthritis (1,000 mg 2 weeks apart) (21) or for lymphoma (375 mg/m2 per week for 4 weeks) (24). There is also a question about whether or not we should have followed the procedure used by Keystone et al for rheumatoid arthritis (22) and administered a second course at 6 months to the patients with partial response who had considerable residual disease activity.

The second limitation is difficulty in assessing the activity of relapsing polychondritis. Its polymorphic manifestations, the unpredictability of its relapses, and particularly the absence of any validated score of disease activity make it difficult to evaluate treatment. Laboratory markers of inflammation usually increase both during disease flares and infections (2). Moreover, bronchial involvement may lead to subsequent segmental or lobar pulmonary infection (19). The followup of antibodies to type II collagen or matrilin 1 is not helpful in assessing disease activity, given that they are not routinely monitored and no useful reason for such routine monitoring has been shown. Moreover, their sensitivity for relapsing polychondritis is low: antibodies to type II collagen have been identified in 33% of patients in the literature for this disease, predominantly in untreated patients (25). Antibodies to matrilin I have been detected in only 13% of patients (26). Among the 4 patients we tested, none had antibodies to type II collagen, a finding consistent with the numerous treatments that these patients have undergone, including steroids.

The third limitation of our study is the selection of patients treated with rituximab. Except for patient 5, who received rituximab in association with CHOP for malignant lymphoma, all of the patients had very severe forms of relapsing polychondritis that involved the larynx and sometimes the tracheobronchial tree, required long-term high-dose steroids, and were refractory to various immunomodulating agents (including TNF antagonists for 3 patients). In our experience with more than 300 cases, such refractory cases account for approximately 5% of all patients with relapsing polychondritis. Therefore, the rather disappointing results reported here might not apply to less severe forms of the disease.

In conclusion, to our knowledge, this is the first study describing rituximab use in patients with severe refractory relapsing polychondritis. Although we cannot rule out the possibility of a small positive effect, our patients' clinical courses did not improve significantly after rituximab treatment.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Dr. Costedoat-Chalumeau had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Leroux, Costedoat-Chalumeau, Piette.

Acquisition of data. Leroux, Costedoat-Chalumeau, Brihaye, Cohen-Bittan, Amoura, Haroche, Limal, Bletry, Piette.

Analysis and interpretation of data. Leroux, Costedoat-Chalumeau.

Manuscript preparation. Leroux, Costedoat-Chalumeau, Limal, Piette.

Statistical analysis. Leroux, Costedoat-Chalumeau.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The authors thank Dr. Beigelman-Aubry for reviewing the thoracic computed tomography scans.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES