Systemic lupus erythematosus
ALMS trial: Mycophenelate mofetil vs cyclophosphamide for lupus nephritis
| Article Name: Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis |
| URL: https://jasn.asnjournals.org/content/20/5/1103.long |
| Journal and year of publication: Journal of American Society of Nephrology, 2009 |
| Trial Design: Randomized clinical trial |
| Population: 370 patients Key inclusion criteria: – Aged 12 to 75 years, diagnosed with SLE – Patients with class III or V LN must have had proteinuria (at least 2 g/d) Key exclusion criteria: – Treatment MMF or IVC in the previous year – Continuous dialysis for >2 wk before randomization or anticipated duration longer than 8 wk |
| Intervention Studied: Mycophenolate Mofetil (MMF) |
| Control: Cyclophosphamide |
| Outcomes: – Response rates: MMF: 56.2% patients responded vs IVC: 53.0% patients responded – No significant differences in the rates of adverse events, serious adverse events, or infections between both groups The authors concluded that “Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis” |
| Citation: Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15. PMID: 19369404; PMCID: PMC2678035. |
ALMS-2 trial: Mycophenelate mofetil vs azathioprine for lupus nephritis
| Article Name: Mycophenolate versus Azathioprine as Maintenance Therapy for Lupus Nephritis |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1014460 |
| Journal and year of publication: NEJM, 2011 |
| Trial Design: Randomized clinical trial |
| Population: 370 patients Key inclusion criteria: – Kidney biopsy within the 6 months prior to first randomization with a histologic diagnosis of lupus nephritis – Active nephritis at screening Key exclusion criteria: – Previous kidney transplant or planned transplant – Autoimmune condition, or its treatment, that may affect the study assessments or outcomes |
| Intervention Studied: Mycophenolate Mofetil (MMF) |
| Control: Azathioprine |
| Outcomes: – Mycophenolate mofetil was superior to azathioprine with respect to the primary endpoint, time to treatment failure: Hazard ratio: 0.44 (95% CI: 0.25 to 0.77), P=0.003 – Time to renal flare and time to rescue therapy: Hazard ratio: <1.00; P<0.05 The authors concluded that “Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy.” |
| Citation: Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17;365(20):1886-95. doi: 10.1056/NEJMoa1014460. PMID: 22087680. |
Rheumatoid Arthritis
Infliximab and methotrexate for RA
| Article Name: Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis |
| URL: https://www.nejm.org/doi/full/10.1056/NEJM200011303432202 |
| Journal and year of publication: NEJM, 2000 |
| Trial Design: Randomized clinical trial |
| Population: 428 patients Key inclusion criteria: – Active RA despite treatment with at least 12.5 mg of methotrexate/week for 3 months at least with no break for more than 2 weeks Key exclusion criteria: – Using a DMARD other than methotrexate – Intraarticular, IM, or IV corticosteroids in the 4 weeks |
| Intervention Studied: Infliximab + Methotrexate |
| Control: Placebo + Methotrexate |
| Outcomes: – Clinical response: Infliximab + methotrexate: 51.8% vs Methotrexate alone: 17.0% (P<0.001) – Quality of life: Significantly better with infliximab + methotrexate, vs Methotrexate alone – Radiographic evidence of joint damage: Increased in those given methotrexate alone. Not increased in those given infliximab and methotrexate The authors concluded that “In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.” |
| Citation: Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000 Nov 30;343(22):1594-602. doi: 10.1056/NEJM200011303432202. PMID: 11096166. |
BeSt trial: Early combination therapy for RA
| Article Name: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial |
| URL: https://onlinelibrary.wiley.com/doi/full/10.1002/art.21405 |
| Journal and year of publication: Arthritis and Rheumatology, 2005 |
| Trial Design: Randomized clinical trial |
| Population: 508 patients Key inclusion criteria: – Age ≥18 years with early and active RA – Disease duration of ≤2 years Key exclusion criteria: – Using a DMARD other than methotrexate – Intraarticular, IM, or IV corticosteroids in the 4 weeks |
| Intervention Studied: Group 1: Sequential DMARD monotherapy Group 2: Step-up combination therapy Group 3: Initial combination therapy with tapered high-dose prednisone Group 4: Initial combination therapy with Infliximab |
| Control: See above |
| Outcomes: – Time to functional improvement: Achieved earlier in groups 3 and 4, in comparison to groups 1 and 2. – Mean scores of the Dutch version of the Health Assessment Questionnaire (D-HAQ) at 3 months: Groups 1 and 2: 1.0 vs Groups 3 and 4: 0.6 (P < 0.001) The authors concluded that “In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.” |
| Citation: Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005 Nov;52(11):3381-90. doi: 10.1002/art.21405. PMID: 16258899. |
Rituximab for RA
| Article Name: Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa032534 |
| Journal and year of publication: NEJM, 2004 |
| Trial Design: Randomized clinical trial |
| Population: 161 patients Key inclusion criteria: – At least 21 years of age, with active RA despite treatment with at least 10 mg of methotrexate per week. – Seropositive for rheumatoid factor Key exclusion criteria: – Other autoimmune disease (except concurrent Sjögren’s syndrome) – American Rheumatism Association functional class IV disease – Rheumatoid vasculitis |
| Intervention Studied: 1) Methotrexate (control) 2) Rituximab (1000 mg on days 1 and 15) 3) Rituximab plus cyclophosphamide (750 mg on days 3 and 17) 4) Rituximab plus methotrexate |
| Control: See above |
| Outcomes: – Achieving 50% improvement in disease symptoms (At week 24): – Methotrexate alone: 13% – Rituximab–methotrexate combination: 43% (P=0.005) – Rituximab–cyclophosphamide combination: 41% (P=0.005) – All ACR responses were maintained at week 48 in rituximab–methotrexate group The authors concluded that “In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.“ |
| Citation: Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81. doi: 10.1056/NEJMoa032534. PMID: 15201414. |
Vasculitis
Azathioprine vs cyclophosphamide for ANCA vasculitis
| Article Name: A Randomized Trial of Maintenance Therapy for Vasculitis Associated with Antineutrophil Cytoplasmic Autoantibodies |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa020286 |
| Journal and year of publication: NEJM, 2003 |
| Trial Design: Randomized clinical trial |
| Population: 144 patients Key inclusion criteria: – Diagnosis of Wegener’s granulomatosis, microscopic polyangiitis, or renal-limited vasculitis – Renal involvement, other threatened loss of function of a vital organ – ANCA positivity OR ANCA-negative + histologic confirmation of vasculitis Key exclusion criteria: – Another multisystem autoimmune disease – Hepatitis B e antigenemia, hepatitis C, or HIV |
| Intervention Studied: After remission, substitute regimen of azathioprine |
| Control: After remission, continued cyclophosphamide therapy |
| Outcomes: – Relapses: Azathioprine: 15.55 of patients vs Cyclophosphamide:13.7% (P=0.65) – Lower with microscopic polyangiitis patients than those with Wegener’s granulomatosis (P=0.03) The authors concluded that ” In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.“ |
| Citation: Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286. PMID: 12840090. |
RAVE trial: Rituximab for ANCA vasculitis
| Article Name: Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0909905 |
| Journal and year of publication: NEJM, 2010 |
| Trial Design: Randomized clinical trial |
| Population: 197 patients Key inclusion criteria: – Diagnosis of Wegener’s granulomatosis or Microscopic polyangiitis – Positive serum assay for PR3-ANCA or MPO-ANCA Key exclusion criteria: – Churg-Strauss syndrome or anti-glomerular basement membrane disease – Alveolar hemorrhage severe enough to require mechanical ventilation – Active systemic infection |
| Intervention Studied: Rituximab |
| Control: Cyclophosphamide |
| Outcomes: – Reaching the primary endpoint (remission of disease without the use of prednisone at 6 months): Rituximab: 64% of patients vs Cyclophosphamide: 53% of patients (Noninferiority P<0.001) – Inducing remission of relapsing disease: Rituximab: 67% of patients vs Cyclophosphamide: 42% of patients (P=0.01) The authors concluded that “Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.” |
| Citation: Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PMID: 20647199; PMCID: PMC3137658. |
Azathioprine vs Methotrexate for ANCA vasculitis
| Article Name: Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0802311 |
| Journal and year of publication: NEJM, 2008 |
| Trial Design: Randomized clinical trial |
| Population: 159 patients Key inclusion criteria: – Newly diagnosed Wegener’s granulomatosis or microscopic polyangiitis Key exclusion criteria: – Cancer not in remission for more than 3 years – HIV, HBV, HCV infection |
| Intervention Studied: 1) Azathioprine 2) Methotrexate |
| Control: See above |
| Outcomes: – Primary end point occurrence (adverse event requiring discontinuation of the study drug or causing death): Azathioprine: 7 patients vs Methotrexate: 12 patients (P=0.21) – No difference in relapses or adverse events The authors concluded that “These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegener’s granulomatosis and microscopic polyangiitis after initial remission.” |
| Citation: Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, Kyndt X, Lifermann F, Papo T, Lambert M, Le Noach J, Khellaf M, Merrien D, Puéchal X, Vinzio S, Cohen P, Mouthon L, Cordier JF, Guillevin L; French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.1056/NEJMoa0802311. PMID: 19109574. |
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