CD19 Targeted Low-Dose Rituximab Is Effective in the Management of Refractory Phospholipase A2 Receptor Antibody-Associated Membranous Nephropathy

To the Editor:

Varied dosing regimens of rituximab (RTX) have been successfully used in the management of primary membranous nephropathy (PMN).1, 2 An ideal RTX dose and the long-term adverse effect of a larger cumulative dose are not clear. CD19 levels are used to gauge the drug effect.¹ Economic viability is a major part of any new therapeutic regimen. Low-dose RTX (100 mg) has been successfully used in ABO incompatible renal transplant.³ In the present study, we report a similar approach of CD19 depletion using 100 mg of RTX in the management of M-type phospholipase A2 receptor antibody (aPLA₂R)-associated PMN refractory, dependent on or intolerant to conventional immunosuppressive regimens recommended by Kidney Disease: Improving Global Outcomes.⁴

All the study subjects had aPLA₂R-related PMN. The mean duration of nephrotic syndrome before RTX therapy was 33.67 ± 19.76 (median 13, range 10–62) months. Before receiving RTX, all the patients had an immunosuppression-free washout period of minimum 3 months. The mean proteinuria, serum albumin, and creatinine were 12.06 ± 10.78 (median 7.59, range 2.30–31.00) g/d, 2.09 ± 0.95 (median 1.64, range 1.30–3.50) g/dl, and 0.81 ± 0.21 (median 0.80, range 0.60–1.10) mg/dl, respectively. Five (83.3%) study subjects had nephrotic range proteinuria (>4 g/d) and 1 (16.7%) patient had subnephrotic proteinuria (2.3 g/d) and was treated as he had anasarca with severe hypoalbuminemia (1.3 g/dl) and hypercholesteremia. All the study subjects (4 resistant to cyclophosphamide and steroids, 1 intolerant to tacrolimus treatment, and 1 with relapsing disease) were treated with 100 mg of rituximab (CD19 monitored on day 2 and at every 4- to 6-week interval). In subjects with no response at 6 months, further infusion and monitoring was stopped (extended follow-up continued). All the subjects achieved CD19 depletion (<1%) with a single dose of 100 mg of RTX. All the patients received maximal tolerable doses of angiotensin receptor blockers (systolic blood pressure achieved was <130 mm Hg in all the subjects) and atorvastatin; doses of angiotensin receptor blockers were stable during the entire study period. During RTX therapy, the patients received no other immunosuppressive therapy. At the end of 6 months, 3 (50%) achieved remission in proteinuria with normalization of serum albumin, and had maintained it until the last follow-up (Table 1). All the subjects in clinical remission also had serological remission and nonresponders had persisting aPLA₂R (Table 1). The mean time for CD19 reconstitution was 2.17 ± 1.17 (median 2, range 1–4) months. A total of 16 additional doses of RTX were required (mean 2.67 ± 0.82, median 2.5, and range 2–4).

Table 1.

Clinical and biochemical parameters of all the 6 subjects

S No.	Primary IST	Indication	Baseline		Second month completion		Fourth month completion		Sixth month completion		F/U (mo)	Last follow-up		aPLA2R (RU/ml)		RTX
			UP (g/d)	Sr Alb (g/dl)	UP (g/d)	Sr Alb (g/dl)	UP (g/d)	Sr Alb (g/dl)	UP (g/d)	Sr Alb (g/dl)		UP (g/d)	Sr Alb (g/dl)	Pre-RTX	Post-RTX	Additional doses	Time (mo)
1	cCTX/GC	Relapse	8.98	3.10	3.88	3.10	3.60	3.20	1.03	3.60	14	0.701	3.70	73.11	4.528	02	03, 08
2	cCTX/GC	Resistant	6.20	1.40	1.20	5.50	1.25	5.20	3.00	2.10	12	3.20	3.10	121.59	93.99	03	01, 04, 05
3	TAC	Intolerant	2.30	1.30	2.90	3.13	2.86	3.42	1.92	4.32	15	0.29	4.32	28.87	2.00	04	04, 09, 12, 15
4	cCTX/GC	Resistant	5.50	3.50	2.90	3.90	3.10	3.20	3.20	4.40	13	1.13	4.34	111.87	2.00	02	02, 06
5	cCTX/GC	Resistant	31.00	1.68	16.220	1.59	3.80	1.98	19.60	1.83	10	8.80	3.50	27.13	79.76	02	01, 04
6	cCTX/GCa	Resistant	18.41	1.60	15.03	1.30	9.58	2.63	8.00	2.00	14	3.13	3.30	59.89	56.79	03	02, 05, 06

Mean time to CD19 repletion was 2.17 ± 1.17 (range 1–4) mo and all the subjects received further therapy (median doses 2.5, range 2–4).

aPLA₂R, m-type phospholipase A2 receptor antibody; cCTX/GC, cyclical cyclophosphamide and steroids; F/U, follow-up; IST, immunosuppressive therapy; RTX, rituximab; Sr Alb, serum albumin; TAC, tacrolimus; UP, urine protein.

^aPatient developed upper respiratory tract infection, which was successfully managed with oral antibiotics.

Low-dose RTX has been successfully used in ABO incompatible renal transplant. Nakao et al.³ reported successful use of 100 mg of RTX in 9 ABO incompatible renal transplant, with no difference in survival rates between low versus standard dose. Low dose of RTX has also been successfully evaluated in refractory rheumatoid arthritis.⁵ Shenoy et al.⁵ evaluated the therapeutic response of 100 mg of RTX in 14 patients with active rheumatoid arthritis; 58% and 42% of the patients achieved good and moderate response at 24 weeks, respectively. Seventy-nine percent of the patients achieved CD19 depletion (<0.01%) with single dose of RTX (100 mg). The CD19 depletion in the present study is better than that reported by Shenoy et al.; this may partly be explained by the difference in the definition of CD19 depletion (<1% and <5 cells in the present study vs. <0.01% in the study by Shenoy et al.).⁵

Ruggenenti et al.¹ studied RTX use in 100 subjects with PMN and reported a response rate of 56% (18 of 32 cases), when used as a second line agent. In the present study, the response rate of 50% was similar to that reported by Ruggenenti et al.¹ Ruggenenti et al. used a single dose of 375 mg/m² in all the patients compared with 100 mg with CD19 monitoring in the present study. Treatment protocol utilizing RTX in PMN widely varies among various centers; some prefer to use “extended protocol” of weekly (375 mg/m²) RTX for 4 weeks,⁶ whereas others choose to use CD19 targeted RTX infusion. Interestingly, most of the studies have demonstrated successful depletion of CD19 with a single dose, questioning the benefit of additional dosing, and many centers have evolved from “extended protocol” to “CD19 targeted dosing.”1, 6 Assuming that CD19 depletion primarily translates to clinical response, any dose that achieves it must be acceptable. aPLA₂R has very good association with clinical activity;⁷ in the present report, all the responders had reduction in aPLA₂R to <20 RU/ml, whereas none of the nonresponders achieved similar titer. Our results support the incorporation of aPLA₂R monitoring in the management of difficult to treat PMN.

To conclude, in cost-restrained setting, low-dose RTX targeting CD19 depletion can be used in the management of PMN refractory to standard immunosuppressive therapies with the acceptable side effect profile.

Disclosure

All the authors declared no competing interests.