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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Objective

The primary objective of this study was to evaluate the safety of rituximab in antiphospholipid antibody (aPL)–positive patients with non-criteria manifestations of antiphospholipid syndrome (APS). The secondary objectives were to evaluate the effect of rituximab on the aPL profile and to evaluate the efficacy of rituximab treatment for non-criteria manifestations of APS.

Methods

In this 12-month, phase II pilot study, adult aPL-positive patients with thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and/or cognitive dysfunction received 2 doses of rituximab (1,000 mg) on days 1 and 15. Antiphospholipid antibody profiles and clinical outcome measures, which were categorized as complete response, partial response, no response, or recurrence, were analyzed at preset time points.

Results

Two of 19 patients experienced infusion reactions, resulting in early termination. Twelve serious adverse events and 49 nonserious adverse events were recorded. All patients who had positive results of lupus anticoagulant, anticardiolipin, and anti–β2-glycoprotein I antibody tests at baseline had positive results at 24 weeks and 52 weeks. The numbers of patients with a complete response, a partial response, no response, and recurrence for the clinical outcome measures at 24 weeks were as follows: for thrombocytopenia, 1, 1, 2, and 0, respectively; for cardiac valve disease, 0, 0, 3, and not analyzed, respectively; for skin ulcer, 3, 1, 0, and 1, respectively; for aPL nephropathy, 0, 1, 0, and 0, respectively; and for cognitive dysfunction, 3, 1, 1, and not analyzed, respectively.

Conclusion

The results of this uncontrolled and nonrandomized pilot study suggest that the safety of rituximab in aPL-positive patients is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS.

The updated Sapporo classification criteria define antiphospholipid syndrome (APS) as vascular thromboses and/or pregnancy morbidity occurring in persons with persistent positivity for antiphospholipid antibodies (aPL) (lupus anticoagulant [LAC], anticardiolipin antibody [aCL], and anti–β2-glycoprotein I antibody [anti-β2GPI]) (1). Patients with aPL positivity may experience the development of thrombocytopenia, cardiac valve disease (CVD), aPL nephropathy, skin ulcer, or cognitive dysfunction, which are collectively referred to as non-criteria manifestations of APS (1, 2). Very few studies address the pathogenesis and treatment of non-criteria manifestations of APS, which usually are not responsive to anticoagulation.

Based on in vitro experience, B cells are known to be involved in aPL-related clinical events (3, 4), BAFF blockade can prevent disease onset and prolong survival in murine APS (5), and CTLA-4Ig prevents the initiation but not the development of APS in (NZW × BXSB)F1 mice (6).

Rituximab is a chimeric monoclonal antibody that binds to CD20 antigen, resulting in a rapid and sustained depletion of the peripheral B lymphocyte lineage (7–9). Only a limited number of case reports have been published regarding rituximab treatment of aPL-positive patients (mostly for hematologic manifestations of aPL and mostly in combination with other agents) (10–15). However, it is currently unknown whether rituximab treatment eliminates clinically significant aPL or whether rituximab is truly effective against aPL manifestations.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Study design.

RITuximab in APS (RITAPS) is an investigator-initiated, single-center, open-label, prospective, phase II descriptive pilot trial of rituximab therapy for non-criteria manifestations of APS. The primary objective was to evaluate the safety and tolerability of rituximab for up to 12 months. The secondary objectives were to evaluate the effect of rituximab on the aPL profile for up to 12 months and to evaluate the efficacy of rituximab for non-criteria manifestations of aPL for up to 6 months. The exploratory objective was to evaluate the biologic effects of rituximab in aPL-positive patients, as assessed by serum rituximab levels and human antichimeric antibody (HACA) assays at 6 months and 9 months, and the number of circulating B cells (CD19+ lymphocytes) in peripheral blood at baseline, 2 weeks, and 6, 9, and 12 months.

Inclusion criteria.

Patients who were ≥18 years of age, did not have other systemic autoimmune diseases, and fulfilled at least one of the laboratory criteria and one of the clinical criteria were eligible for inclusion in the study. The laboratory criteria were defined as positive results of a LAC test, as defined by the International Society on Thrombosis and Haemostasis (16), positive aCL IgG/IgM/IgA isotype (≥40 units), and/or positive anti-β2GPI IgG/IgM/IgA isotype (≥40 units) on 2 or more occasions, at least 12 weeks apart. The clinical criteria were defined as 1) persistent thrombocytopenia (platelet count <100 × 109/μl on at least 2 occasions 12 weeks apart; 2) CVD (regurgitation, stenosis, thickening, and/or nodules as diagnosed by echocardiography within 12 months of study entry); 3) skin ulcer (noninfected, livedoid vasculitis– and/or pyoderma gangrenosum–like, for at least 1 month prior to screening); 4) aPL nephropathy (as diagnosed by kidney biopsy within 12 months of study entry, and urinary protein:creatinine ratio of ≥1.0 at screening); and/or 5) cognitive dysfunction (significant memory symptoms were evaluated at baseline and 6 months using the battery of cognitive tests recommended by the American College of Rheumatology [ACR] [17], for which reliability and validity have been established [18]). The methods used to detect aPL and information regarding other inclusion and exclusion criteria are shown in Supplement 1, which is available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.

Exclusion criteria.

Patients were considered ineligible if any of the following criteria were fulfilled: fulfilling the ACR classification criteria (≥4 of the 11 criteria components) for systemic lupus erythematosus (SLE) (19), other systemic autoimmune diseases, acute thrombosis, or history of stroke (only for patients with cognitive dysfunction). Additional information is available in Supplement 1.

Study interventions.

The study was approved by the local institutional review board and complied with the Health Insurance Portability and Accountability Act. An independent Data and Safety Monitoring Board reviewed all safety issues on a quarterly basis or more frequently if required.

Baseline data collection included demographics, general and aPL-specific medical history, medications, complete blood cell (CBC) count, complete metabolic panel (CMP), erythrocyte sedimentation rate (ESR), hepatitis profile, aPL profile, urinalysis (UA), urine pregnancy test for women of childbearing age, chest radiography, electrocardiography, ACR revised criteria for the classification of SLE (19), Short Form 36 (SF-36) questionnaire (20), patient's global assessment of disease activity, and physician's global assessment of disease activity. After the screening visit (within 5–10 days), all eligible patients received 2 doses of rituximab intravenously (1,000 mg; provided by Genentech) on days 1 and 15, with 1,000 mg of acetaminophen orally, 50 mg of diphenhydramine orally, and 100 mg of methylprednisolone (Solu-Medrol) intravenously 30–60 minutes prior to the start of each infusion. Patients were followed up on day 30, then monthly for 6 months (for safety, aPL, and clinical outcome measures), and then every 3 months for up to 1 year (for safety and aPL). During each followup visit, patients were reassessed for general and aPL-specific medical history, medications, selected blood tests (CBC, CMP, ESR, UA), adverse events, SF-36 score, patient's global assessment, and physician's global assessment.

Patients continued to receive their regular medications throughout the study, with the following restrictions during the first 6 months: 1) no initiation, dose change, or discontinuation of immunosuppressive, antiplatelet, or anticoagulant agents (unless indicated for new bleeding or thrombosis); and 2) no initiation or dose increase of corticosteroids unless indicated for reactions to rituximab or other comorbidities. For all patients with aPL nephropathy who were not already receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, such therapy was initiated at the time of screening.

Outcome measures.

The safety of rituximab (primary end point) was evaluated during and immediately after rituximab administration for up to 52 weeks. An adverse event (AE) was defined as any unfavorable medical occurrence, regardless of causality. A serious adverse event (SAE) was defined as an AE meeting ≥1 of the following criteria: death, life-threatening, requiring or prolonging inpatient hospitalization, disabling, or resulting in a congenital anomaly.

The efficacy of rituximab (secondary end points) was evaluated using aPL tests (LAC test, aCL enzyme-linked immunosorbent assay [ELISA], and anti-β2GPI ELISA), scored as complete response, partial response, and/or no response at 4, 16, 24, 36, and 52 weeks, and specific clinical outcome measures scored as complete response, partial response, and no response at 24 weeks only in patients with baseline positivity for that specific clinical outcome measure. Recurrence was evaluated at 24 weeks in patients with baseline positivity for selected clinical outcome measures (thrombocytopenia, skin ulcers, and aPL nephropathy) and who had complete response for that clinical outcome measure at 12 weeks.

For thrombocytopenia, complete response was defined as a platelet count of ≥150 × 109/μl, partial response as 100–149 × 109/μl, and no response as <100 × 109/μl. For CVD, complete response was defined as the disappearance of echocardiographic lesions, partial response as >50% improvement of echocardiographic lesions, and no response as no change or worsening of echocardiographic lesions. For skin ulcer, complete response was defined as disappearance by physical examination and digital imaging, partial response as >50% improvement, and no response as no change or worsening of skin ulcers. For aPL nephropathy, complete response was defined as a normal serum creatinine level, inactive urinary sediment, and urinary protein:creatinine ratio <0.5; partial response as a serum creatinine level ≤15% above baseline, red blood cells (RBCs) per high-power field ≤50% above baseline with no RBC casts, ≥50% improvement in the urinary protein:creatinine ratio, and estimated glomerular filtration rate <10% above baseline; and no response as the absence of complete or partial response. For cognitive dysfunction, complete remission was defined as normalization of the cognitive impairment index with ≥50% improvement, partial response as abnormal cognitive impairment index with ≥50% improvement, and no response as no change or worsening of the cognitive impairment index.

The biologic effects of rituximab were assessed by measurement of serum rituximab levels, rituximab-specific IgG HACA assays, and the number of circulating B cells (see Supplement 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131). Patients were followed up until their B cell levels returned to baseline levels or to the lower limit of normal values.

Statistical analysis.

Clinical characteristics, safety data (primary end point), and efficacy data (secondary end points) were reported in a descriptive manner, using the mean ± SD and range. The proportion of patients who achieved response (complete response and partial response) in aPL profiles (4, 16, 24, 36, and 52 weeks) and clinical outcome measures (12 and/or 24 weeks) was analyzed as a categorical variable. Selected laboratory values, SF-36 domains, patient's global assessment, and physician's global assessment were compared with baseline values using Student's t-test or one-way analysis of variance.

The cognitive impairment index was calculated using 12 selected tests from the short neuropsychological test battery described by the ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature (17). Each test score was converted to T scores using demographically corrected normative data (21), and T scores <40 were considered abnormal. Cognitive dysfunction was defined as ≥4 abnormal T scores (cognitive impairment index ≥4 [range 0–12], with a higher value representing greater cognitive impairment).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Of 149 self- or physician-referred patients, 69 (46%) met the inclusion criteria, and 19 (28%) of 69 participated in the RITAPS trial. Of 19 patients enrolled, 3 were withdrawn from the study during the first 6-month period, and 1 was withdrawn during the second 6-month period (see Supplement 2, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131).

Baseline characteristics.

The mean ± SD age of the patients was 40.5 ± 13.8 years, 11 patients (58%) were female, and 17 patients (89%) were white. Eleven patients (58%) fulfilled the updated Sapporo criteria for APS (1) (Table 1). Seventeen patients (89%) were positive for LAC, 15 patients (79%) were positive for aCL IgG/IgM/IgA, and 15 patients (79%) were positive for anti-β2GPI IgG/IgM/IgA (Table 2). Single, double, and triple aPL positivity was observed in 4 patients (21%), 3 patients (16%), and 12 patients (63%), respectively.

Table 1. Baseline characteristics of and clinical outcomes in the study patients*
Patient/ age/sexAPSInclusion criteria/durationPrevious medicationsConcomitant medicationsResponse at 24 wksObservations at 24–52 wks§Observations after 52 wks (duration from study completion to time of report)
  • *

    APS = antiphospholipid syndrome; PG = pyoderma gangrenosum–like ulcer; CS = corticosteroids; WAR = warfarin; LMWH = low molecular weight heparin; AZA = azathioprine; ASA = aspirin; PTX = pentoxifylline; HCQ = hydroxychloroquine; MMF = mycophenolate mofetil; RC = recurrence; NR = no response; ET = early termination; IVIG = intravenous immunoglobulin; WinRho = Rho immune (D) globulin; CR = complete response; PM = pregnancy morbidity; PR = partial response; VE = arterial/venous thrombosis; LV = livedoid vasculitis-like ulcer; STN = statin; TPO = thrombopoietin receptor agonist; ACE = angiotensin-converting enzyme.

  • Medications administered for the antiphospholipid (aPL)–related manifestation(s) under investigation.

  • Medications related to aPL at the time of the screening.

  • §

    Relevant clinical observations are reported only if patients had not received inclusion criterion–specific treatment during the 24–52-week safety period.

  • Relevant clinical observations are shown only if they were reported by patients and/or their physicians and if patients had not received any inclusion criterion–specific treatment after study completion.

  • #

    Diagnosed with batteries of neuropsychological tests performed at screening; the duration represents the period of time when the patients had been reporting significant memory problems.

  • **

    Not included in the 36-week and 52-week analyses due to repeat rituximab prescribed by the patient's physician between 24 weeks and 36 weeks.

  • ††

    Thrombocytopenia was included in the 24-week analysis as “no response.”

  • ‡‡

    Resolution of aortic valve vegetation and mitral valve thickness.

  • §§

    Resolution of mitral valve thickness.

1/61/MNoSkin ulcer (PG)/36 mosCS, WAR, LMWH, AZAASA, PTX, HCQ, MMFRCActive ulcers
2/25/MNoCardiac valve disease/3 mosNRNo change (6 mos)
3/32/MNoThrombocytopenia/3 mosASA, HCQET
  Cardiac valve disease/1 wk  ET
  Cognitive dysfunction/48 mos# ET
4/40/FNoThrombocytopenia/6 mosCS, IVIG, WinRhoCRNo changeRecurrence (4 mos)
5/38/FPMThrombocytopenia/8 mosCS, IVIGASA, HCQPRNo change
  Cognitive dysfunction/24 mos#  CR
6/24/FVEThrombocytopenia/5 mosCS, WinRhoWARNR
7/61/FNoCognitive dysfunction/6 mos#ASA, HCQ, STNCR
8/53/MNoCognitive dysfunction/10 mos#WAR, HCQ, MMFPR
9/46/FVE + PMCognitive dysfunction/12 mos#CSASA, WARCR
10/20/FVESkin ulcer (LV)/2 mosCSHCQ, STN, WARCRNo change
11/45/MVESkin ulcer (PG)/5 mosCS, IVIGWARCR**Active ulcers
12/46/FVE + PMThrombocytopenia/12 yrsCS, TPOHCQ, CPG, WARET††
  Cardiac valve disease/3 mos  ET
13/52/MVECardiac valve disease/1 moSTN, WARNRImproved (17 mos)‡‡
14/38/MVESkin ulcer (PG)/1.5 mosHCQ, WARCRNo change
15/22/MNoaPL nephropathy/2 mosCSACE inhibitorET
16/61/FVESkin ulcer (PG)/22 mosCSASA, STNPRRecovered
17/20/FNoaPL nephropathy/35 mosCS, MMFACEPRNo change
18/45/FPMCognitive dysfunction/3 mos#ASA, HCQNR
19/41/FPMCardiac valve disease/25 mosASANRImproved (5 mos)§§
Table 2. Numbers of aPL-positive patients at baseline who had complete response, partial response, and no response during followup*
 Baseline4 wks16 wks24 wks36 wks52 wks
  • *

    Values are the number (%). Percentages for values less than 5 are not shown. For the lupus anticoagulant (LAC) test, we defined complete response (CR) as a negative test result and no response (NR) as a positive test result; for the anticardiolipin antibody (aCL)/anti–β2 glycoprotein I (anti-β2 GPI) enzyme-linked immunosorbent assay, CR was defined as a titer of <20 units, partial response (PR) was defined as a titer of 20–39 units, and NR was defined as a titer of ≥40 units. When the change in baseline low-titer (20–39 units) aCL IgG, aCL IgM, aCL IgA, anti–β2 IgG, anti-β2GPI IgM, and anti-β2GPI IgA was analyzed, the CR rates at 24 weeks were 100% (n = 1), 66% (n = 3), 0% (n = 3), 75% (n = 4), not applicable, and 50% (n = 4), respectively, and the CR rates at 52 weeks were 100% (n = 1), 66% (n = 3), 0% (n = 2), 66% (n = 3), not applicable, and 33% (n = 3), respectively.

  • Of 70 LAC tests analyzed in 15 patients with baseline positivity, only 1 test result was negative at 36 weeks.

  • Of 80 aCL IgG/IgM/IgA tests analyzed in 11, 5, and 1 patients, respectively, with baseline positivity, only 1 patient had 5 negative aCL IgM test results during followup (the baseline aCL IgM level was 40 units).

  • §

    Of 71 anti-β2GPI IgG/IgM/IgA tests analyzed in 8, 5, and 2 patients, respectively, with baseline positivity, 1 patient had 3 negative anti-β2GPI IgM test results at 24, 36, and 52 weeks (the baseline anti-β2GPI IgM level was 45 units), and another patient had 2 negative anti-β2GPI IgA test results at 16 and 24 weeks (the baseline anti-β2GPI IgA level was 40 units).

LAC      
 No. of patients171515141313
 CR00010
 NR15 (100)15 (100)14 (100)12 (92)13 (100)
aCL IgG      
 No. of patients1311111099
 CR00000
 PR10111
 NR10 (91)11 (100)9 (90)8 (89)8 (89)
aCL IgM      
 No. of patients555555
 CR11111
 PR11112
 NR33332
aCL IgA      
 No. of patients211111
 CR0000 
 PR0000 
 NR1111 
Anti-β2GPI IgG§      
 No. of patients1087777
 CR00000
 PR02212
 NR8 (100)5 (71)5 (71)6 (86)5 (71)
Anti-β2GPI IgM§      
 No. of patients555555
 CR00111
 PR11000
 NR44444
Anti-β2GPI IgA§      
 No. of patients322222
 CR01100
 PR00011
 NR21111

Safety.

During a mean ± SD observation period of 12.5 ± 4.8 months (17.8 patient-years), there were 12 SAEs and 49 AEs in 17 patients. Among the 12 SAEs involving hospitalization in 7 patients, 5 were neurologic, 3 were infectious, 2 were vascular, 1 was cardiac, and 1 was allergic (Table 3). There were no infusion-related SAEs.

Table 3. Serious and nonserious adverse events in the RITAPS trial*
  • *

    RITAPS = Rituximab in antiphospholipid syndrome; EEG = electroencephalography; ET = early termination; MRI = magnetic resonance imaging.

  • Patient responded to stopping the medication and supportive measures; had recurrence with the repeat infusion (counted as 2 events in the same patient).

  • Patient responded to stopping the medication and supportive measures; did not receive further treatment.

Serious (hospitalization) (n = 12) 
 Neurologic 
  Antiepileptic drug adjustment (history of seizure disorder)1
  Brain surgery (history of seizure disorder)1
  Subdural hematoma1
  New-onset focal motor seizure due to previous stroke1
  48-hour EEG monitoring and new-onset partial sensory seizure1
 Infection 
  Pneumonia2
  Viral gastroenteritis/dehydration/cellulitis1
 Vascular 
  Recurrent deep vein thrombosis1
  Post-phlebitic syndrome1
 Cardiac 
  Multifocal atrial tachycardia due to resolving pneumonia1
 Allergy 
  Trimethoprim/sulfamethoxazole treatment1
Nonserious during or within 24 hours of rituximab infusion (n = 8) 
 Cardiovascular 
  Chest pain with fever, chills, and low back pain (ET)2
  Transient chest pressure3
 Dermatologic 
  Diffuse severe erythematous rash (ET)1
  Facial rash1
 Gastrointestinal 
  Nausea1
Nonserious >24 hours after rituximab infusion 
  (n = 41) 
 Cardiovascular 
  Transient palpitations (recurrence)1
  Deep vein thrombosis (recurrence)1
  Raynaud's phenomenon (new)1
 Dermatologic 
  Rash (diffuse) within 1 week of rituximab infusion (new)1
  Rash (local) within 1 week of rituximab infusion (new)1
  Rash (local) due to nail glue allergy (new)1
 Gastrointestinal 
  Gastrointestinal reflux disease (new)1
 Hematologic 
  Epistaxis (recurrence)1
 Infection 
  Upper respiratory tract infection6
  Tonsillitis, otitis, sinusitis (n = 1 each)3
  Urinary tract3
  Bronchitis2
  Acute gastroenteritis2
  Cellulitis1
  Herpes zoster infection within 2 weeks of rituximab infusion (new)1
  Herpes zoster infection while noncompliant with prophylaxis1
   (recurrence)
 Musculoskeletal 
  Arthralgia (local) (new)2
  Arthritis (diffuse) within 1 week of the infusion (new)2
  Arthralgia (diffuse) within 2 weeks of the infusion (new)1
  Arthralgia (local) (recurrence)1
  Carpal tunnel syndrome (recurrence)1
  Gout flare (recurrence)1
  Shoulder dislocation (new)1
  Elbow incidental MRI metallic artifact finding (new)1
 Neuropsychiatric 
  Seizures (history of partially controlled seizures) (recurrence)1
  Depression (new)1
  Migraine (new)1
  Headache (severe, transient) (new)1

Of 49 nonserious AEs, 8 occurred during or within 24 hours of the infusion in 6 patients, and 41 occurred more than 24 hours after the infusion in 15 patients (including 19 infections in 11 patients) (Table 3). The rate of serious infections was 16.9 per 100 patient-years.

Antiphospholipid antibody profile.

Table 2 shows the number of patients with positive aPL test results at baseline and during followup, as well as the number of patients who had complete response, partial response, or no response at weeks 4, 16, 24, and 52. All patients with baseline positivity for LAC, aCL, and anti-β2GPI IgG remained positive at 24 and 52 weeks (see Supplement 3, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN) 1529-0131).

Clinical outcome measures.

Excluding 2 patients who were withdrawn from the study due to infusion reactions, the numbers of patients with complete response, partial response, no response, and recurrence at 24 weeks were as follows: for thrombocytopenia, 1, 1, 2, and 0, respectively; for cardiac valve disease, 0, 0, 3, and not analyzed, respectively; for skin ulcer, 3, 1, 0, and 1, respectively; for aPL nephropathy, 0, 1, 0, and 0, respectively; and for cognitive dysfunction, 3, 1, 1, and not analyzed, respectively.

Of the 5 patients with baseline thrombocytopenia, 4 were included in the 12- and 24-week analyses, and 1 terminated early due to infusion reaction. Three of 5 patients with cardiac valve disease were included in the 24-week analysis (1 withdrew early due to an infusion reaction, and 1 patient had early termination due to intravenous immunoglobulin treatment for worsening concomitant thrombocytopenia). All 5 patients with skin ulcers were included in the 12- and 24-week analyses. One of 2 patients with aPL nephropathy was included in the 12- and 24-week analyses (the other patient withdrew early due to an infusion reaction). Five of 6 patients with cognitive dysfunction were included in the 24-week analysis (1 patient withdrew early due to an infusion reaction). Details of the clinical outcome measures are shown in Supplement 4, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.

Clinical observations that were made after the first 6 months of the study are shown in Table 1. The mean followup SF-36 scores (combined or stratified by a specific aPL manifestation) at 4, 12, and 24 weeks were not significantly different compared with those at the baseline visit. The mean ± SD scores for patient's global assessment at baseline and 24 weeks were 42.8 ± 27.9 and 27.6 ± 20.8, respectively (P = 0.08). The mean ± SD scores for physician's global assessment at baseline and 24 weeks were 47.7 ± 17.4 and 21.7 ± 23.5, respectively (P = 0.001).

Biologic effects of rituximab.

No patients had detectable rituximab levels at baseline (normal <500 ng/ml). At 24 weeks and 36 weeks, 6 (38%) of 16 patients and 1 (7%) of 15 patients had detectable rituximab levels (mean 2,330 ng/dl at 24 weeks and 512 ng/dl at 36 weeks). One patient had positive results of a HACA test at baseline. Based on the analysis of 17 patients who received 2 rituximab infusions, 5 (29%) of 17 patients and 9 (56%) of 16 patients developed HACAs at 24 weeks and 36 weeks, respectively. Two patients with infusion reactions resulting in early terminations did not develop HACAs (patients received only 254 mg and 166 mg of rituximab, respectively). Four (67%) of the 6 patients with no response and 5 (45%) of the 11 patients with partial response, complete response, or recurrence developed HACAs (P = 0.61).

CD19+ lymphocytes were detected in all patients at baseline. Based on the analysis of 17 patients, the mean ± SD percentage of CD19+ lymphocytes at baseline was 11.8 ± 3.72 (normal range 6–29%). Rituximab treatment resulted in rapid B cell depletion in all except 1 patient, which occurred by 2 weeks after the first infusion (mean ± SD 0.29 ± 1.21%). The mean ± SD percentages of CD 19+ lymphocytes at 4, 24, 36, and 52 weeks were 0.24 ± 0.97%, 2.64 ± 4.26%, 4.4 ± 4.58%, and 6.56 ± 4.19%, respectively. B cell levels returned to baseline or normal levels after 6 months in 4 patients, 9 months in 3 patients, 12 months in 6 patients, 15 months in 1 patient, and 24 months in 2 patients.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Based on our prior retrospective experience (12), we designed the prospective pilot RITAPS trial, the results of which suggest that the safety of rituximab in aPL-positive patients is consistent with the known safety profile of rituximab, rituximab does not cause a substantial change in aPL profiles, and rituximab may be effective in controlling some but not all non-criteria manifestations of APS.

There are no systematic safety data on patients with persistent aPL positivity who are receiving rituximab. This study is the first to demonstrate the safety profile of rituximab in such patients. In a pooled analysis of 2,578 patients with rheumatoid arthritis who were receiving rituximab for up to 24 weeks (5,014 patient-years), 32% experienced an adverse reaction during or within 24 hours of the first infusion, and 39% experienced any type of infection. The rate of serious infections was 4.31 per 100 patient-years (8). The results of an analysis of 99 patients with antineutrophil cytoplasmic antibody–associated vasculitis who were receiving rituximab for up to 24 weeks (47.6 patient-years) showed that 12% of the patients experienced an adverse reaction during or within 24 hours of the first infusion, and 62% experienced an infection of any type. The rate of serious infections was 25 per 100 patient-years (8). In the RITAPS trial, 26% of patients experienced an adverse reaction during or within 24 hours of the first infusion, and 58% experienced any type of infection; the rate of serious infections was 16.9 per 100 patient-years.

Although there are anecdotal reports of LAC negativity or aCL/anti-β2GPI down-regulation in patients treated with rituximab, these reports “did not uniformly document the response of aPL levels or profiles to treatment” (13). In addition, no case report has described a patient with a clinically significant aPL profile switching to a negative aPL (LAC, aCL, and anti-β2GPI) profile following treatment with rituximab without other immunosuppressive agents or plasmapheresis. Our study demonstrated no substantial change in aPL profiles during 12 months of followup, which may explain why some patients have a limited clinical response. Rituximab has no effect on memory B cells or long-lived plasma cells. However, B cells also have effector functions independent of antibody production (22, 23), which may explain why some patients have a clinical response without a substantial change in the aPL profile.

Rituximab has been used to treat severe thrombocytopenia in aPL-positive patients, with various responses ranging from no remission (24, 25) to complete remission (10, 26, 27); this finding is consistent with the 50% response rate to rituximab among patients with idiopathic thrombocytopenic purpura (28, 29). The RITAPS results confirm that some, but not all, aPL-positive patients respond to rituximab.

Although there is one case report of complete resolution of mitral valve vegetation following warfarin therapy (30), a 5-year transesophageal echocardiographic followup study of 12 patients with primary APS showed that treatment with oral anticoagulation and aspirin is ineffective for CVD (31). In RITAPS, although the secondary end point was not met at 24 weeks, 2 of 3 patients had improvements on later echocardiography.

Although there have been reports of successful oral anticoagulation and/or antifibrinolytic therapy for skin ulcers (32), many patients do not respond to such treatment. Costa et al recently reported successful use of the combination of rituximab and plasma exchange for aPL-related cutaneous necrosis (33). In RITAPS, the most dramatic improvement was seen for skin ulcers, confirming the observations in our retrospective study (12).

There is no consensus on the management of aPL nephropathy. Tsagalis et al recently reported stabilization of renal function and proteinuria with rituximab and plasma exchange (34); here, we report another patient with a partial response to rituximab.

Because of the limited understanding of the pathogenesis of cognitive dysfunction (35), the efficacy of antithrombotic or immunosuppressive treatment has been neither hypothesized nor demonstrated. RITAPS is the first attempt to investigate the role of immunosuppression in the management of cognitive dysfunction in aPL-positive patients without other systemic autoimmune diseases. Although the sample size is small and practice effects cannot be ruled out without a comparable disease control group, our findings indicate improvement in aspects of attention, visuomotor speed, and flexibility.

The RITAPS study has several limitations and strengths. First, because RITAPS is a pilot study with a small sample size and a relatively short followup, the safety data may not be comparable with those from other large rituximab trials. Second, although the cohort includes patients with a variety of APS manifestations, the safety and aPL data were analyzed for the entire cohort. Third, our findings cannot be used to elucidate the predictors of rituximab response; however, because the study was prospective and systematic, the results add to and improve the existing literature, which consists solely of case reports.

In conclusion, based on our pilot data, rituximab (or other B cell–directed therapies) may have a role in the treatment of persistently aPL-positive patients with non-criteria manifestations of APS.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Erkan 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 conception and design. Erkan, Kozora, Lockshin.

Acquisition of data. Erkan, Vega, Ramón, Lockshin.

Analysis and interpretation of data. Erkan, Vega, Ramón, Kozora, Lockshin.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Genentech had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Genentech.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

We thank the RITAPS Data and Safety Monitoring Board (Joseph Markenson, MD, Sergio Schwartzman, MD, and Margaret Peterson, PhD) for regularly reviewing the adverse events.

REFERENCES

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  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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ART_37759_sm_SupplInfo4.doc132KSupplementary Data 4

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