Immunological changes and prevention of disease progression through elotuzumab therapy in refractory IgG4-related sclerosing mesenteritis

Comdühr, Sara; Dübbers, Alexander; Tharun, Lars; Graßhoff, Hanna; Stone, John; Pitann, Silke; Riemekasten, Gabriela; Lamprecht, Peter

doi:10.1093/rheumatology/keac302

Rheumatology key message

Elotuzumab therapy stopped disease progression and resulted in immunological changes in refractory IgG4-related sclerosing mesenteritis.

Dear Editor, IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory condition characterized by tumefactive lesions, dense lymphoplasmacytic infiltrates and abundant IgG4-bearing plasma cells. IgG4-RD comprises a multifaceted spectrum commonly affecting the pancreato-hepatobiliary tract, major salivary glands, lacrimal gland, retroperitoneum, kidneys, lungs and aorta. IgG4-related sclerosing mesenteritis (IgG4-RSM) is a rare manifestation typically occurring in the small bowel mesentery. Extra-mesenteric disease is unusual in patients with IgG4-RSM. The differential diagnosis of IgG4-RD includes myofibroblastic, inflammatory and neoplastic conditions [1].

Here we report on a 67-year-old Caucasian female suffering from abdominal pain due to biopsy-proven IgG4-RSM (supplementary Fig. S1, available at Rheumatology online) [1]. All laboratory findings including serum IgG4 concentration were within normal range. Her disease proved to be refractory to glucocorticoid therapy alone, and glucocorticoid in combination with thalidomide, rituximab and CYC, respectively. Abdominal CT imaging disclosed progression of soft-tissues masses encasing the superior mesenteric artery. Because cytotoxic CD4+SLAMF7+ innate-like T cells and plasmablasts are considered to be key drivers of IgG4-RD pathology, the patient was switched to a 3-month course of treatment with the monoclonal anti-SLAMF7 antibody elotuzumab. The patient provided informed consent for the compassionate use of elotuzumab. We applied an elotuzumab therapy protocol established for refractory multiple myeloma [2]. The patient received i.v. elotuzumab (10 mg per kilogram of body weight) every week for a total of 8 weeks, followed by biweekly elotuzumab infusions with the same dosage until week 12. The cumulative dose of elotuzumab during the treatment period was 6 g. The patient experienced no adverse events. A follow-up CT showed no progression of the mass-forming lesions in the abdomen. The patient’s disease has remained stable for 9 months.

We followed changes within the peripheral blood cellular compartment during the 12-week period of elotuzumab therapy by flow cytometric analysis. Staining of cellular surface markers with optimized concentrations of fluorochrome-conjugated antibodies (Biolegend, San Diego, California, USA) was performed using freshly collected whole blood as described earlier [3]. Stained samples were analysed on a CytoflexS cytometer using CytExpert software (Beckmann Coulter, Brea, California, USA) for data acquisition and FlowJo V.10 software (BD Biosciences, Franklin Lakes, New Jersey, USA) for analysis. A patient with granulomatosis with polyangiitis (GPA) and a healthy donor served as controls. Circulating B cells were not analysed due to low numbers. During the 12-week period, we observed a decrease of the frequency of SLAMF7+ cells within the neutrophil and monocyte population, and an increase within the lymphocyte population. We found a persistent expansion of T cells lacking CD28 expression within the CD4+ and CD8+ T cell populations. The vast majority of CD28– T cells displayed SLAMF7 expression, but lacked CD27. The percentage of CD4+CD8+ double-positive (DP) T cells was also increased. Nearly all DP cells were SLAMF7+. By contrast, the proportion of CD4–CD8– double-negative T cells was minimal (1%). Notably, we observed an increase in the frequency of CD3+CD56+ NKT and CD3–CD56+ NK cells during elotuzumab therapy. Virtually all NKT and NK cells expressed SLAMF7 (Table 1 and supplementary Fig. S2, available at Rheumatology online).

Table 1

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Cell counts and frequencies of cellular subsets in peripheral blood in the patient and controls

Cell counts (normal range) and frequencies (%)	IgG4-RSM			HD	GPA
Cell counts (normal range) and frequencies (%)	Baseline	Week 6	Week 12	HD	GPA
Neutrophil cell count (1500–7700/µl)	7990	8740	7810	5130	3930
% of SLAMF7+ neutrophils	61	16	10	10	54
SLAMF7+ neutrophil cell count/µl	4874	1404	781	513	2122
Monocyte cell count (100–1000/µl)	900	1230	860	780	980
% of SLAMF7+ monocytes	86	43	49	38	73
SLAMF7+ monocyte cell count/µl	774	529	421	296	715
Lymphocyte cell count (1100–4000/µl)	1280	1560	1230	2890	1900
% of SLAMF7+ lymphocytes	36	60	78	35	10
SLAMF7+ lymphocyte cell count/µl	461	936	959	1011	190
CD3+ T cell count (700–2100/µl)	1.097	995	1174	863	1177
% of SLAMF7+ cells within CD3+ T cell population	65	69	81	24	4
CD3+SLAMF7+ cell count/µl	713	687	950	207	47
CD4+ T cell count (300–1400/µl)	714	697	815	649	472
% of SLAMF7+ cells within CD4+ T cell population	47	30	63	4	22
CD4+SLAMF7+ cell count/µl	336	209	513	26	104
% of CD28+ cells within CD4+ T cell population	71	89	59	97	87
% of CD27– cells within CD4+CD28+ T cell population	23	23	36	4	9
% of SLAMF7+ cells within CD4+CD28+ T cell population	24	21	40	4	13
% of CD28– cells within CD4+ T cell population	29	11	41	3	13
% of CD27– cells within CD4+CD28– T cell population	99	99	99	5	96
% of SLAMF7+ cells within CD4+CD28– T cell population	99	91	96	13	91
CD8+ T cell cell count (200–900/µl)	391	329	399	216	683
% of SLAMF7+ cells within CD8+ T cell population	96	96	98	65	92
CD8+SLAMF7+ cell count/µl	375	315	391	140	638
% of CD28+ cells within CD8+ T cell population	27	33	21	86	15
% of CD27– cells within CD8+CD28+ T cell population	14	18	20	5	11
% of SLAMF7+ cells within CD8+CD28+ T cell population	82	89	94	60	47
% of CD28– cells within CD8+ T cell population	73	67	79	14	85
% of CD27– cells within CD8+CD28– T cell population	86	83	83	40	91
% of SLAMF7+ cells within CD8+CD28– T cell population	100	99	98	96	99
% of CD4+CD8+ DP cells within CD3+ T cell population	6	23	13	1	2
% of SLAMF7+ cells within CD4+CD8+ DP T cell population	98	99	99	22	70
% of CD56+ cells within CD3+ T cell population	19	26	30	5	18
% of SLAMF7+ cells within CD3+CD56+ NKT cell population	99	99	99	97	99
CD3+CD56+SLAMF7+ cell count/µl	206	256	350	40	209
CD19+ B cell cell count (100–500/µl)	7	8	10	128	1
CD3-CD56+ NK cells cell count (90–600/µl)	101	57	97	150	156
% of CD56+ cells within CD3– cell population	8	31	59	52	50
% of SLAMF7+ cells within CD3–CD56+ NK cell population	98	99	98	98	99
CD3–CD56+SLAMF7+ cell count/µl	7	16	56	77	76

Cell counts (normal range) and frequencies (%)	IgG4-RSM			HD	GPA
Cell counts (normal range) and frequencies (%)	Baseline	Week 6	Week 12	HD	GPA
Neutrophil cell count (1500–7700/µl)	7990	8740	7810	5130	3930
% of SLAMF7+ neutrophils	61	16	10	10	54
SLAMF7+ neutrophil cell count/µl	4874	1404	781	513	2122
Monocyte cell count (100–1000/µl)	900	1230	860	780	980
% of SLAMF7+ monocytes	86	43	49	38	73
SLAMF7+ monocyte cell count/µl	774	529	421	296	715
Lymphocyte cell count (1100–4000/µl)	1280	1560	1230	2890	1900
% of SLAMF7+ lymphocytes	36	60	78	35	10
SLAMF7+ lymphocyte cell count/µl	461	936	959	1011	190
CD3+ T cell count (700–2100/µl)	1.097	995	1174	863	1177
% of SLAMF7+ cells within CD3+ T cell population	65	69	81	24	4
CD3+SLAMF7+ cell count/µl	713	687	950	207	47
CD4+ T cell count (300–1400/µl)	714	697	815	649	472
% of SLAMF7+ cells within CD4+ T cell population	47	30	63	4	22
CD4+SLAMF7+ cell count/µl	336	209	513	26	104
% of CD28+ cells within CD4+ T cell population	71	89	59	97	87
% of CD27– cells within CD4+CD28+ T cell population	23	23	36	4	9
% of SLAMF7+ cells within CD4+CD28+ T cell population	24	21	40	4	13
% of CD28– cells within CD4+ T cell population	29	11	41	3	13
% of CD27– cells within CD4+CD28– T cell population	99	99	99	5	96
% of SLAMF7+ cells within CD4+CD28– T cell population	99	91	96	13	91
CD8+ T cell cell count (200–900/µl)	391	329	399	216	683
% of SLAMF7+ cells within CD8+ T cell population	96	96	98	65	92
CD8+SLAMF7+ cell count/µl	375	315	391	140	638
% of CD28+ cells within CD8+ T cell population	27	33	21	86	15
% of CD27– cells within CD8+CD28+ T cell population	14	18	20	5	11
% of SLAMF7+ cells within CD8+CD28+ T cell population	82	89	94	60	47
% of CD28– cells within CD8+ T cell population	73	67	79	14	85
% of CD27– cells within CD8+CD28– T cell population	86	83	83	40	91
% of SLAMF7+ cells within CD8+CD28– T cell population	100	99	98	96	99
% of CD4+CD8+ DP cells within CD3+ T cell population	6	23	13	1	2
% of SLAMF7+ cells within CD4+CD8+ DP T cell population	98	99	99	22	70
% of CD56+ cells within CD3+ T cell population	19	26	30	5	18
% of SLAMF7+ cells within CD3+CD56+ NKT cell population	99	99	99	97	99
CD3+CD56+SLAMF7+ cell count/µl	206	256	350	40	209
CD19+ B cell cell count (100–500/µl)	7	8	10	128	1
CD3-CD56+ NK cells cell count (90–600/µl)	101	57	97	150	156
% of CD56+ cells within CD3– cell population	8	31	59	52	50
% of SLAMF7+ cells within CD3–CD56+ NK cell population	98	99	98	98	99
CD3–CD56+SLAMF7+ cell count/µl	7	16	56	77	76

IgG4-RSM: IgG4-related sclerosing mesenteritis; GPA: granulomatosis with polyangiitis; HD: healthy donor.

Table 1

Open in new tab

Cell counts and frequencies of cellular subsets in peripheral blood in the patient and controls

Cell counts (normal range) and frequencies (%)	IgG4-RSM			HD	GPA
Cell counts (normal range) and frequencies (%)	Baseline	Week 6	Week 12	HD	GPA
Neutrophil cell count (1500–7700/µl)	7990	8740	7810	5130	3930
% of SLAMF7+ neutrophils	61	16	10	10	54
SLAMF7+ neutrophil cell count/µl	4874	1404	781	513	2122
Monocyte cell count (100–1000/µl)	900	1230	860	780	980
% of SLAMF7+ monocytes	86	43	49	38	73
SLAMF7+ monocyte cell count/µl	774	529	421	296	715
Lymphocyte cell count (1100–4000/µl)	1280	1560	1230	2890	1900
% of SLAMF7+ lymphocytes	36	60	78	35	10
SLAMF7+ lymphocyte cell count/µl	461	936	959	1011	190
CD3+ T cell count (700–2100/µl)	1.097	995	1174	863	1177
% of SLAMF7+ cells within CD3+ T cell population	65	69	81	24	4
CD3+SLAMF7+ cell count/µl	713	687	950	207	47
CD4+ T cell count (300–1400/µl)	714	697	815	649	472
% of SLAMF7+ cells within CD4+ T cell population	47	30	63	4	22
CD4+SLAMF7+ cell count/µl	336	209	513	26	104
% of CD28+ cells within CD4+ T cell population	71	89	59	97	87
% of CD27– cells within CD4+CD28+ T cell population	23	23	36	4	9
% of SLAMF7+ cells within CD4+CD28+ T cell population	24	21	40	4	13
% of CD28– cells within CD4+ T cell population	29	11	41	3	13
% of CD27– cells within CD4+CD28– T cell population	99	99	99	5	96
% of SLAMF7+ cells within CD4+CD28– T cell population	99	91	96	13	91
CD8+ T cell cell count (200–900/µl)	391	329	399	216	683
% of SLAMF7+ cells within CD8+ T cell population	96	96	98	65	92
CD8+SLAMF7+ cell count/µl	375	315	391	140	638
% of CD28+ cells within CD8+ T cell population	27	33	21	86	15
% of CD27– cells within CD8+CD28+ T cell population	14	18	20	5	11
% of SLAMF7+ cells within CD8+CD28+ T cell population	82	89	94	60	47
% of CD28– cells within CD8+ T cell population	73	67	79	14	85
% of CD27– cells within CD8+CD28– T cell population	86	83	83	40	91
% of SLAMF7+ cells within CD8+CD28– T cell population	100	99	98	96	99
% of CD4+CD8+ DP cells within CD3+ T cell population	6	23	13	1	2
% of SLAMF7+ cells within CD4+CD8+ DP T cell population	98	99	99	22	70
% of CD56+ cells within CD3+ T cell population	19	26	30	5	18
% of SLAMF7+ cells within CD3+CD56+ NKT cell population	99	99	99	97	99
CD3+CD56+SLAMF7+ cell count/µl	206	256	350	40	209
CD19+ B cell cell count (100–500/µl)	7	8	10	128	1
CD3-CD56+ NK cells cell count (90–600/µl)	101	57	97	150	156
% of CD56+ cells within CD3– cell population	8	31	59	52	50
% of SLAMF7+ cells within CD3–CD56+ NK cell population	98	99	98	98	99
CD3–CD56+SLAMF7+ cell count/µl	7	16	56	77	76

Cell counts (normal range) and frequencies (%)	IgG4-RSM			HD	GPA
Cell counts (normal range) and frequencies (%)	Baseline	Week 6	Week 12	HD	GPA
Neutrophil cell count (1500–7700/µl)	7990	8740	7810	5130	3930
% of SLAMF7+ neutrophils	61	16	10	10	54
SLAMF7+ neutrophil cell count/µl	4874	1404	781	513	2122
Monocyte cell count (100–1000/µl)	900	1230	860	780	980
% of SLAMF7+ monocytes	86	43	49	38	73
SLAMF7+ monocyte cell count/µl	774	529	421	296	715
Lymphocyte cell count (1100–4000/µl)	1280	1560	1230	2890	1900
% of SLAMF7+ lymphocytes	36	60	78	35	10
SLAMF7+ lymphocyte cell count/µl	461	936	959	1011	190
CD3+ T cell count (700–2100/µl)	1.097	995	1174	863	1177
% of SLAMF7+ cells within CD3+ T cell population	65	69	81	24	4
CD3+SLAMF7+ cell count/µl	713	687	950	207	47
CD4+ T cell count (300–1400/µl)	714	697	815	649	472
% of SLAMF7+ cells within CD4+ T cell population	47	30	63	4	22
CD4+SLAMF7+ cell count/µl	336	209	513	26	104
% of CD28+ cells within CD4+ T cell population	71	89	59	97	87
% of CD27– cells within CD4+CD28+ T cell population	23	23	36	4	9
% of SLAMF7+ cells within CD4+CD28+ T cell population	24	21	40	4	13
% of CD28– cells within CD4+ T cell population	29	11	41	3	13
% of CD27– cells within CD4+CD28– T cell population	99	99	99	5	96
% of SLAMF7+ cells within CD4+CD28– T cell population	99	91	96	13	91
CD8+ T cell cell count (200–900/µl)	391	329	399	216	683
% of SLAMF7+ cells within CD8+ T cell population	96	96	98	65	92
CD8+SLAMF7+ cell count/µl	375	315	391	140	638
% of CD28+ cells within CD8+ T cell population	27	33	21	86	15
% of CD27– cells within CD8+CD28+ T cell population	14	18	20	5	11
% of SLAMF7+ cells within CD8+CD28+ T cell population	82	89	94	60	47
% of CD28– cells within CD8+ T cell population	73	67	79	14	85
% of CD27– cells within CD8+CD28– T cell population	86	83	83	40	91
% of SLAMF7+ cells within CD8+CD28– T cell population	100	99	98	96	99
% of CD4+CD8+ DP cells within CD3+ T cell population	6	23	13	1	2
% of SLAMF7+ cells within CD4+CD8+ DP T cell population	98	99	99	22	70
% of CD56+ cells within CD3+ T cell population	19	26	30	5	18
% of SLAMF7+ cells within CD3+CD56+ NKT cell population	99	99	99	97	99
CD3+CD56+SLAMF7+ cell count/µl	206	256	350	40	209
CD19+ B cell cell count (100–500/µl)	7	8	10	128	1
CD3-CD56+ NK cells cell count (90–600/µl)	101	57	97	150	156
% of CD56+ cells within CD3– cell population	8	31	59	52	50
% of SLAMF7+ cells within CD3–CD56+ NK cell population	98	99	98	98	99
CD3–CD56+SLAMF7+ cell count/µl	7	16	56	77	76

IgG4-RSM: IgG4-related sclerosing mesenteritis; GPA: granulomatosis with polyangiitis; HD: healthy donor.

In this report, we followed the clinical course and changes within the peripheral blood cellular compartment in a patient with refractory IgG4-RSM treated with elotuzumab. Disease progression was stopped. Persistence of peripheral B cell depletion suggested possible additional lasting effects of previous immunosuppressive therapies. Elotuzumab does not bind to the same epitope recognized by the anti-SLAMF7 antibody clone 162.1 (Biolegend), allowing unaffected cellular staining and flow cytometric analysis [4]. The cellular compartments were affected differentially by elotuzumab therapy, with a decrease of SLAMF7+ cell fractions within the circulating neutrophil and monocyte populations and an increase within the lymphocyte population. We found a persistent expansion of CD28–CD27–SLAMF7+ cells within CD4+ and CD8+ T cell populations, similar to that previously observed in IgG4-RD with multi-organ involvement [5, 6]. SLAMF7 expressing CD4+CD28–CD27– and CD8+CD28–CD27– T cells are a subset of innate-like T cells displaying cytotoxicity and cytokine production [6]. In addition, we observed an increase in the percentage of CD4+CD8+ DP T cells expressing SLAMF7, which remained unaffected by elotuzumab therapy. Expansion of circulating CD4+CD28–CD27– and CD8+CD28–CD27– innate-like T cells and CD4+CD8+ DP T cells is a hallmark of various infections and autoimmune diseases including GPA and has been linked to inflammation and autoimmunity [3, 7]. Finally, we disclosed an increase in the frequency of SLAMF7 expressing CD3+CD56+ NKT and CD3–CD56+ NK cells during elotuzumab therapy in our patient. Elotuzumab promotes NK cell activation, resulting in enhanced plasma cell killing [8]. Thus, changes in NKT and NK cell frequencies suggest an immunological response induced by elotuzumab.

In conclusion, refractory IgG4-RSM is a therapeutic challenge. The findings reported herein are descriptive and require further evaluation. Anecdotal reports fall short of demonstrating generalizable cause–effect relationships. However, the presented findings are suggestive of a therapeutic elotuzumab-induced effect with prevention of disease progression and an immunological response. Elotuzumab could be a therapeutic option in IgG4-RD and is currently being tested in a two-part multicentre clinical trial in the USA (NCT04918147).

Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: J.S. received support for NCT04918147 ‘Elotuzumab in Immunoglobulin G4-related disease (IgG4-RD)’. S.C., A.D., L.T., H.G., S.P., G.R. and P.L. have declared no conflicts of interest.

Consent: Informed consent was received from the patient.

Data availability statement

All data are incorporated into the article and its online supplementary material.

Supplementary data

Supplementary data are available at Rheumatology online.

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Immunological changes and prevention of disease progression through elotuzumab therapy in refractory IgG4-related sclerosing mesenteritis

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Immunological changes and prevention of disease progression through elotuzumab therapy in refractory IgG4-related sclerosing mesenteritis

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