Alan Kivitz

Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: Results from two sequential placebo-controlled studies†

OBJECTIVE To assess the efficacy and safety of rilonacept (Interleukin-1 [IL-1] Trap), a long-acting and potent inhibitor of IL-1, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). METHODS Forty-seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score. RESULTS Forty-four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single-symptom disease flare days, single-symptom scores, physicians and patients global assessments of disease activity, limitations in daily activities, and C-reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions. CONCLUSION Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.

Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial

OBJECTIVE To assess the safety and efficacy of abatacept, a selective T cell costimulation modulator, in patients with psoriatic arthritis (PsA). METHODS In this 6-month, multicenter, randomized, double-blind, placebo-controlled, phase II study, 170 PsA patients with a psoriasis target lesion (TL) ≥2 cm who had previously taken disease-modifying antirheumatic drugs (DMARDs), including anti-tumor necrosis factor (anti-TNF) agents, were randomized (1:1:1:1) to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary end point was the American College of Rheumatology 20% criteria for improvement (ACR20 response) on day 169. Other key end points were magnetic resonance imaging (MRI) scores for joint erosion, osteitis, and synovitis, scores on the Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) health survey, the investigators global assessment of psoriasis, the TL score, and the Psoriasis Area and Severity Index (PASI) score. RESULTS Proportions of patients achieving an ACR20 response were 19%, 33%, 48%, and 42% in the placebo, the abatacept 3 mg/kg, the abatacept 10 mg/kg, and the abatacept 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10 mg/kg (P = 0.006) and 30/10 mg/kg (P = 0.022) groups, but not for 3 mg/kg group (P = 0.121). All abatacept regimens resulted in improved MRI, HAQ, and SF-36 scores, with 10 mg/kg showing the greatest improvements. Improvements in the TL and PASI scores were observed in all abatacept arms; a response according to the investigators global assessment was seen only with 3 mg/kg of abatacept. The safety profiles were similar among the treatment arms. CONCLUSION The results of this study suggest that 10 mg/kg of abatacept, the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis, may be an effective treatment option for PsA.

Long-Term Safety and Efficacy of Abatacept in Children With Juvenile Idiopathic Arthritis

OBJECTIVE We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks.

Objective: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. Methods: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. Results: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. Conclusion: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.

Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial†

OBJECTIVE To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. METHODS We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. RESULTS Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. CONCLUSION Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis: A Randomized Trial

Context In Chinese medicine, extracts of Tripterygium wilfordii Hook F (TwHF, known as lei gong teng or thunder god vine) are used to treat autoimmune and inflammatory conditions. Small clinical trials suggest that TwHF may benefit patients with rheumatoid arthritis. Contribution This trial compared TwHF extract with sulfasalazine in 121 patients with active rheumatoid arthritis who could continue oral prednisone and nonsteroidal anti-inflammatory drugs but not disease-modifying antirheumatic drugs. Among patients who continued treatment for 24 weeks, achievement of 20% improvement in American College of Rheumatology criteria was greater with TwHF than with sulfasalazine. Adverse event rates were similar. Caution Only 62% and 41% of patients continued TwHF and sulfasalazine treatment, respectively, and provided 24 weeks of data. The Editors Rheumatoid arthritis is characterized by chronic inflammation of the joint lining (synovial membrane) (1), which causes pain and swelling of diarthrodial joints. Over time, uncontrolled disease results in progressive joint damage, disability, and increased mortality (2). The evolving understanding of the immune mechanisms that perpetuate the inflammatory response has led to effective targeted therapies, including inhibitors of inflammatory cytokines (tumor necrosis factor, interleukin-1, and interleukin-6), modulators of activation of CD4+ T cells and dendritic cells, and agents that deplete B cells (3, 4). Despite the clinical efficacy of these therapies, many patients have no clinically meaningful response or discontinue treatment because of adverse events. Furthermore, the limited availability of effective biologics in developing countries, the need for parenteral administration of the biologics, and the relatively high cost all restrict access to these therapies in many patients with rheumatoid arthritis around the world (5). In traditional Chinese medicine, extracts of the roots of the medicinal vine Tripterygium wilfordii Hook F (TwHF) (known in China as lei gong teng or thunder god vine) have shown therapeutic promise in treating autoimmune and inflammatory conditions as well as cancer (68). More recently, different extracts of TwHF have been used in Chinese allopathic medicine for the treatment of autoimmune and inflammatory diseases, and small controlled trials reported good responses with TwHF extracts in patients with cadaveric kidney transplants (9, 10) and Crohn disease (11). Of the approximately 380 metabolites isolated from the plant, 95% are terpenoids (12, 13). Three diterpenoidstriptolide, tripdiolide, and triptonide (13)are the most abundant and account for the immunosuppressive and anti-inflammatory effects observed with the root extracts in both in vitro and in vivo studies (6). In 2 previous single-center trials of patients with rheumatoid arthritis, the extract was standardized by the content of triptolide and tripdiolide (14). This made it possible to use optimal doses identified in an open-label trial (15) for the design of a subsequent small placebo-controlled study (16). Although the number of patients was small, the apparent clinical impact and experimental results indicating potent inhibition of the expression of proinflammatory genes both in vitro and in vivo in animal models (1721) provided the rationale for our multicenter, double-blind, active comparator trial of a standardized TwHF extract in patients with active rheumatoid arthritis. Methods Design Overview This randomized, controlled, 24-week study was conducted between March 2004 and October 2005. All participants provided written informed consent to enter the trial, and the institutional review boards at the participating sites approved the protocol. All investigators and outcome assessors were blinded to group assignment of the patients. Our objective was to determine whether therapy with TwHF extract, 180 mg/d, was statistically significantly better than therapy with sulfasalazine, 2 g/d, over 24 weeks in patients with rheumatoid arthritis by using standard outcome measures. Setting and Participants Our study was conducted at 11 U.S. centers: 2 academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (1 each in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan). Eligible patients had to be at least 18 years of age and have established rheumatoid arthritis, defined by the American College of Rheumatology (ACR) classification criteria (22) as rheumatoid arthritis lasting longer than 6 months. Eligible patients had active disease, defined as 6 or more painful and swollen joints, a visual analogue scale score for pain of at least 3 (on a scale of 1 to 10, with 1 being mild), and a C-reactive protein (CRP) level of 57.14 nmol/L or greater (0.6 mg/dL) or an erythrocyte sedimentation rate (ESR) greater than 25 mm/h. Patients who were taking any disease-modifying antirheumatic drug at screening underwent a 28-day washout period. The use of oral prednisone, at stable doses up to 7.5 mg/d, and nonsteroidal anti-inflammatory drugs were allowed as long as the dose was not changed for 28 days before randomization and the patient agreed to continue to take the medication during the study. Table 1 lists baseline patient characteristics. Table 1. Patient Characteristics at Baseline Randomization and Interventions We used a computer-generated, pseudo-random code (with random, permuted blocks) to assign patients to treatment groups across all centers. We assigned eligible patients at a 1:1 ratio to receive either TwHF extract, 180 mg/d, or sulfasalazine, 2 g/d. In the event of gastrointestinal intolerance, the protocol allowed for temporary dose reduction of 50%. As described elsewhere (15, 16), the triptolide and tripdiolide content of the ethanol and ethylacetate extract (measured by high-performance liquid chromatography [22]) was used to standardize the drug preparation for this study. On the basis of data on in vitro activity and in vivo toxicity, 30 mg of TwHF extract were formulated per capsule. Our study was conducted under the U.S Food and Drug Administrationapproved Investigational New Drug application 39191. Outcomes and Measurements Patients were evaluated clinically and by laboratory measures at baseline, 2 weeks, and every 4 weeks for a total of 24 weeks. A rheumatologist or trained staff member masked to treatment allocation assessed the patients. Serum or plasma specimens were obtained from the patients at baseline, 4 weeks, and 24 weeks and stored at 80C until analysis. Radiographs of hands and feet were obtained at baseline and 24 weeks or at study discontinuation. The primary end point was a 20% improvement at 24 weeks, as defined by ACR criteria (ACR 20) (23). To meet criteria, a patient must have 20% or greater improvement in both tender and swollen joints (68 tender and 66 swollen joints were assessed) and 20% or greater improvement in 3 or more of the following: the physicians or patients assessment of global health status, the patients assessment of pain on a visual analogue scale, the patients assessment of function (using a modified version of the Health Assessment Questionnaire [HAQ]), and the serum CRP level. Secondary end points included the efficacy of TwHF in achieving ACR 50 and ACR 70 responses at 24 weeks, the improvement in the European League Against Rheumatism Disease Activity Score 28 (DAS 28) measure, and a change in the Sharpvan der Heijde score of the hand and foot radiographs (24). Radiographs were obtained at baseline and at the end of the study and were scored by 2 independent readers who were blinded to the randomization schedule and the radiograph sequence. Drug adherence was assessed by using a daily diary and by pill counts. Body weight, blood pressure, and serum glucose level were measured at each visit. Laboratory assessments included ESR (Westergren method); high-sensitivity CRP with normal levels up to 38.1 nmol/L (0.4 mg/dL), which was analyzed in a central laboratory; and interleukin-6 levels, which were measured at baseline, 4 weeks, and 24 weeks by using high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota). Rheumatoid factor was measured by immunonephelometry with a BNII analyzer (Siemens Medical Solutions Diagnostics, Newark, Delaware), cortisol and adrenocorticotropic hormone levels by immunochemiluminescence methods with an Immulite 2500 (Siemens Medical Solutions Diagnostics, Los Angeles, California), and plasma lipids by Synchron LX-20 automated analyzers (Beckman Coulter, Brea, California). Safety assessments consisted of all patients marking adverse events in their drug diaries, which were reviewed on each visit. Vital signs and safety laboratory measures, including a complete blood count and a chemistry profile (electrolyte and liver and kidney function tests), were recorded at each visit. Adverse events were graded by severity according to the National Cancer Institute Common Toxicity Criteria guidelines. An electrocardiogram (ECG) was obtained from all patients at baseline, 2 weeks, and the end of study. After 24 weeks, no follow-up was conducted. Statistical Analysis We designed our study to detect differences in the primary end point with greater than 90% power at a 2-sided level of significance of 0.05. To properly account for missing end point data due to dropouts, we used mixed-effects analyses to predict each patients ACR response at the end of study visit and to properly account for uncertainty in that prediction. The response was categorized according to the ACR 20, ACR 50, and ACR 70 criteria. In a similar manner, we compared changes in DAS 28 from baseline visit between treatment groups. We modeled the treatment group, visit number (2 random-effect terms for visit number and visit nu

Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial

Objective: To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo controlled, 24-week trial. Methods: Patients received adalimumab 40 mg every other week (eow) or placebo for 24 weeks in ATLAS. At week 24, patients were switched to open-label adalimumab 40 mg eow. Efficacy measures included 20% improvement in the Assessment in SpondyloArthritis International Society (ASAS) criteria (ASAS20), ASAS40 and ASAS partial remission responses and changes in individual components of the ASAS20 response evaluations, for example, Bath AS Functional Index (BASFI) and Bath AS Disease Activity Index (BASDAI). Two-year interim data were analysed based on the total duration of adalimumab exposure, irrespective of the treatment randomisation group. Results: At 2 years, 255 (82.0%) of the original 311 ATLAS patients continued receiving adalimumab treatment. Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment; 64.5% (200/310) were ASAS20 responders, 50.6% (157/310) were ASAS40 responders and 33.5% (104/310) had maintained ASAS-defined partial remission. Changes in individual ASAS response components were sustained or improved during long-term adalimumab treatment. From ATLAS baseline to 2 years of adalimumab exposure, respectively, BASDAI improved from 6.3 (SD 1.7) to 2.4 (SD 2.3) and BASFI improved from 5.2 (SD 2.4) to 2.9 (SD 2.5). Adalimumab was well tolerated. No cases of tuberculosis, congestive heart failure, lupus-like symptoms, or demyelinating disease were reported. Conclusions: Adalimumab reduced the signs and symptoms of AS and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile. Trial registration information: NCT00085644

Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial

Objective CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA). Methods Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance. Results Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose. Conclusions Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent.

A Randomized, Placebo-Controlled Study of the Effects of Denosumab for the Treatment of Men with Low Bone Mineral Density

CONTEXT Men with low bone mineral density (BMD) were treated with denosumab. OBJECTIVE Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. DESIGN, SUBJECTS, AND INTERVENTION This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. MAIN OUTCOME MEASURE The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. RESULTS Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. CONCLUSIONS One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.

Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial.

OBJECTIVE Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. METHODS One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. RESULTS The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. CONCLUSION Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.