Lupus (2002) 11, 287± 292 www.lupus-journal.com
PAPER
Clinical and immunogenetic characterization of Mexican patients with ‘Rhupus’ 1
JA Simo´n1*, J Granados1, J Cabiedes1, J Ruõ´z Morales1 and J Alcocer Varela1
Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Me´xico DF, Me´xico
The coexistence of systemic lupus erythematosus and rheumatoid arthritis (rhupus), is a rare clinical condition. To date, 50 cases of rhupus have been described worldwide; however, the lack of clinical criteria for this rheumatic condition has created confusion in the characterization of this disorder. Nevertheless, in this paper we describe a comprehensive clinical and serological characterization of a cohort of 22 Mexican patients with rhupus, supported by generic HLA-DR phenotyping. We found that rhupus patients have a special clinical behavior. In this setting, the signs and symptoms of rheumatoid arthritis prevail, little organic damage associated with systemic lupus erythematosus (SLE) exists and none of the cases present thrombosis or morbidity during pregnancy in spite of presenting a high frequency of anticardiolipin antibodies. We also found an increased frequency of HLA-DR1 and HLA-DR2 alleles compared to healthy ethnically matched controls, systemic lupus erythematosus and rheumatoid arthritis patients. Lupus (2002) 11, 287–292. Key words: rhupus; systemic lupus erythematosus; rheumatoid arthritis; coexistence
Introduction The coexistence of two or more connective tissue diseases in the same patient is a rare phenomenon,1 particularly the coexistence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), which has been estimated at between 0.01 and 2%.2,3 This peculiar clinical condition is termed as ‘rhupus’, and was described in 1971 by Schur.4 Toone made the rst clinical observations that helped to identify this entity in 1960.5 In the original paper he described the presence of the LE cell phenomenon in patients with RA; until then, this phenomenon was considered exclusive of SLE. Since then, 50 cases of rhupus have been described, the majority of them isolated cases.6–14 Nevertheless, there are three published series3,15,16 that include approximately 28 cases; unfortunately they lack homogeneous clinical de nitions, resulting in the inclusion of SLE patients with arthropathy, RA patients with extra-articular manifes*Correspondence: JA Simo´n, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, Vasco de Quiroga no. 15, colonia seccio´n XVI, Tlalpan, CP 14000, Me´xico DF, Me´xico. E-mail:
[email protected] Received 3 September 2001; accepted 28 January 2002 # Arnold 2002
tations or patients with mixed connective tissue disease (MCTD). These disadvantages make the characterization of rhupus a dif cult task. Previous reports of rhupus patients show that RA is presented as the initial disease and probably some hormonal factors participate in the expression of the SLE,17 but the precise clinical behavior of both rheumatic conditions when they coexist in the same patient is not known with certainty.18,19 In this report we aimed to select a group of patients which might help to characterize rhupus. We de ned rhupus as a clinical condition in which the same patient presents clinical signs and symptoms of both SLE and RA.
Materials and methods In the rst phase of the study, all clinical charts of patients who attended between January 1985 to January 2000 with both diagnoses (RA and SLE) were reviewed. Patients were evaluated by a rheumatologist, and were classi ed either as SLE or RA following American College of Rheumatology (ACR) for each criteria.20,21 RA patients must have had at least erosive arthropathy whereas SLE patients had anti-Sm or anti-double-stranded DNA (dsDNA) antibodies as 10.1191=0961203302lu189oa
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the main requirements for the diagnosis. We excluded all patients with MCTD criteria, 22 and also all those who had taken any drug known to be related to ‘druginduced lupus’ at least 1 year before the SLE symptoms began (ie azul dine, D-penicillamine or gold salts). In a second phase, all patients with criteria for both diseases were included, and in addition to the clinical examination, the articular painful, swollen joints count, and the HAQ-D1, SLE disease activity index (SLEDAI) and systemic lupus erythematosus collaborating clinics ACR damage index (SLICCACR) were recorded; hand radiography and immunological tests (anti-dsDNA antibodies, anti-Ro, anti-La, anti-U1RNP, anti-Sm, anti-cardiolipin (aCL), rheumatoid factor (RF), anti-nuclear antibodies (ANA), antib2GP-I and C3, C4 proteins) were also recorded. Finally generic HLA-DR typing was performed in rhupus patients and was compared with healthy individuals (n ˆ 99) and RA (n ˆ 48) and SLE (n ˆ 75) patients from the same ethnic group (Mexican Mestizos) that were randomly selected. HLA-DRB1 typing Genomic DNA was extracted from 10 ml of peripheral blood by standard salting out methods. Generic HLADRB1 typing was performed by PCR-SSO reverse dot Table 1
blot using the Amplicor Kit (Hoffman La Roche, Basel, Switzerland). Immunological tests were performed using standard methodology as previously described.23–27 Statistical analysis The signi cance of the differences between groups was performed using chi-squared analysis with combined the 2£2 tables using the EPISTAT statistical program. If the number in any cell was < 5, Fisher’s exact test was used. P-values were corrected according to Yates. Odds ratios (OR) with 95% con dence intervals (95% CI) were calculated using the Mantel – Haenszel method
Results From a cohort of 1500 SLE patients and 2000 RA patients, we found 116 with both clinical conditions. Ninety-four patients were excluded for several reasons: 32% were SLE patients with arthropathy; 16% were lost during the follow-up; 15% had RA with extra-articular manifestations; 9% had MCTD; and the remainder showed various clinical conditions such as Still’s disease, or SLE plus arthrosis. The nally
Clinical and laboratory features of patients with rhupus
Characteristics
Cohen4
Panush5
Brand6
Current
Total
11 60 9=2 41 52 11
6 35 5=1 — — —
11 52 11=0 — — —
22 45 22=0 30 34 4.3
50 48 47=3 35.5 43 7.6
Patients number Mean age (years) Sex, female =male Age of onset RA (years) Age of onset SLE (years) Interval RA-SLE (years) RA criteria, n (%) Criteria 1 — 4 Nodules Rheumatoid factor On X-ray erosions Total RA criteria (mean)
11 5 10 9
(100) (45) (90) (81) 6.2
6 2 4 4
(100) (33) (66) (66) 5.3
11 2 11 6
(100) (18) (100) (54) 5.7
22 9 22 22
(100) (40) (100) (100) 6.4
50 18 37 41
SLE criteria, n (%) Malar rash Discoid lupus Photosensitivity Oral ulcers Serositis Renal Neurological Hematological DNA antibodies Antinuclear antibodies Total SLE criteria
6 1 3 2 4 7 0 11 11 11
(54) (9) (27) (18) (36) (63) (0) (100) (100) (100) 5.3
3 2 1 0 0 1 0 4 2 6
(50) (33) (16) (0) (0) (16) (0) (66) (33) (100) 4.5
2 1 6 4 5 7 0 5 11 11
(18) (9) (54) (36) (45) (63) (0) (45) (100) (100) 5.1
16 1 18 13 12 5 0 19 22 22
(72) (4) (82) (59) (54) (22) (0) (86) (100) (100) 6.5
27 (54) 5 (10) 28 (56) 19 (38) 21 (42) 20 (40) 0 (0) 39 (78) 46 (92) 50 (100) 5.35
1 1 1 0
(16) (16) (16) (0)
Other, n (%) ENA antibodies Raynaud’s phenomenon Myositis Drugs related with SLE
5 (45) — 1 (9) 2 (18)
— — — 3 (27)
RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; ENA, extractable nuclear antigens. Lupus
1 2 0 0
(4) (9) (0) (0)
7 2 2 5
(100) (36) (74) (82) 5.9
(14) (4) (4) (10)
Rhupus JASimoÂn et al
diagnosis of rhupus was established in 22 of them (18.9%). All rhupus patients were females (Table 1); the mean age was 45.5§ 10.17 years (range 23 – 65), and the mean follow-up time was 11.2§ 6.1 years (range 1 – 22). In 15 patients (68%) RA was the initial illness and in seven (32%) both diseases started simultaneously. No patient presented SLE as the initial clinical diagnosis. The interval between the appearance of RA and SLE was of 4.3§ 4.76 years (range 0 – 14). In 60% of the patients we recorded family history of either RA or SLE (11 RA and 2 SLE). RA clinical characteristics Mean age at onset of RA symptoms was 30 § 8.2 years (range 16 – 46). Mean ACR criteria for RA was 6.4 (range 6 – 7). Table 1 summarizes the clinical characteristics of the patients, comparing them with previous reports. It shows that all patients had large and small joint erosive arthritis with positive RF. Morning stiffness time duration was 152§ 92 min (range 60 – 360) and 41% had rheumatoid nodules. Table 2 shows the characteristics at the time of clinical evaluation, here we found that the mean painful articular count was 11 (range 11 – 30) and swollen articular count was 12 (range 0 – 30). The HAQ-D1 mean value was of 0.60 and disease severity mean in a visual analog scale (VAS) was 5 cm by the physician and 6 cm by the patient. Six patients also had Sjo¨gren’s syndrome. In all patients but one, the predominant clinical manifestations were related to RA. The mean number of immunosuppressive drugs use was three and the persistent arthritis was the reason for using them. The most common immunosuppressive drug was methotrexate, which was prescribed in 86% of the patients.
Table 2
Evaluation for RA and SLE
Evaluation Rheumatoid arthritis HAQ-D1 score§ s.d. Tender joint count, number§ s.d. Swollen joint count§ s.d. Disease severity (physician) VAS cm § s.d. Disease severity (patient) VAS cm § s.d. Cytotoxic drugs, number§ s.d. Systemic lupus erythematosus SLEDAI, score § s.d. SLICC-ACR score § s.d. Mean steroids dose, mg=day § s.d. Predominant symptoms, RA=SLE Mortality, number (%) RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; s.d., standard deviation; VAS, visual analog scale.
Score 0.60§ 0.33 11§ 10 11.8§ 11.1 5§ 3 6§ 4 3 § 1.5 4.23§ 4.81 2.1§ 1.77 6.5§ 4 21=1 1 (4)
SLE clinical characteristics
289
Mean starting age for SLE was 34§ 10 years (range 15 – 53; Table 1). The mean number of ACR criteria for SLE was 6.5 (range 5 – 9). The most common clinical manifestations were cutaneous (photosensitivity 82%, malar erythema 72.7% and discoid lupus 4%) and hematological manifestations included lymphopenia in 86.4%, leucopenia in 45% and thrombocytopenia in 18%. Fifty-four percent of the patients had serositis, with pleural damage (six patients) followed by pericarditis (four patients). Only ve patients had renal damage; their kidney biopsy showed mesangial damage in two of them, diffuse proliferative in two and membranous in the remaining one. None of these patients have end-stage renal disease so far (8.6 years of follow-up). Three patients presented transverse myelitis and two multiplex mononeuritis; all were associated with aCL antibodies. Other frequent manifestations were alopecia (16 patients), fever (four patients) and cutaneous vasculitis (six patients). The mean SLICC index at the evaluation time was 2.1 (Table 2) and the SLEDAI index was less than 5 in all cases (except one) including two points from arthritis. The only fatal outcome in this study was a 29-year-old female in whom the SLE symptoms predominated but who had had a previous diagnosis of RA 10 years before developing SLE criteria characterized by fever, generalized lymphadenopathy, malar erythema, pleural and pericardial effusion as well as ascitis; her laboratory tests showed lymphopenia, neutropenia, thrombocytopenia, hemolytic anemia (with positive Coombs test), low complement levels (C3 and C4) and positive ANA with a homogeneous pattern (1 : 160 titer). She was treated with 50 mg of prednisone, with improvement, however 1 year later she developed massive pulmonary hemorrhage and died. The postmortem evaluation showed positive IgG, IgM, IgA and C1q deposits in both lungs and kidneys tissues. Mesenteric and cervical ganglia showed Fujimoto Kikuchi disease. With the exception of this patient, we found no evidence of serious organic damage in rhupus patients. Immunological tests The mean RF titer was of 1478 UI (range 40 – 132 000). All were ANA positive. Sixty-eight percent had a homogeneous pattern and 45% a speckled pattern (some patients sera were IIF-positive with more than one pattern). All cases had positive anti-dsDNA antibodies and 66% of them also had aCL (IgG nine patients and IgM 14 patients), interestingly without thrombosis or recurrent abortions. All sera were negative for anti-b2GP-I antibodies. The anti-Sm antibody was also negative in all cases. Six patients had Lupus
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anti-La antibodies and in three there were anti-Ro antibodies. Only 36% had low levels of C3 and C4 proteins. Only one patient had low titers of antiU1RNP antibodies without clinical manifestations of MCTD. Other autoimmune diseases We found that seven rhupus patients (31%) had more than two autoimmune diseases, and two of them had four, including myasthenia gravis, thyroid autoimmune disease and Sjo¨gren’s syndrome. HLA-DRB1 genes typing Table 3 summarizes the results of HLA-DR typing in rhupus patients as compared with other relevant groups (namely, SLE n ˆ 75, RA n ˆ 48 and healthy controls n ˆ 99). HLA-DR1 frequency is increased in rhupus compared to RA (gene frequency (gf): 0.125 vs 0.041; P ˆ 0.084; OR 3.0), as well as to healthy controls (gf 0.125 vs 0.050; P ˆ 0.085; OR 2.47). Interestingly, rhupus patients differ from SLE patients in that HLA-DR3 is decreased in rhupus (gf 0.025 vs 0.117; P ˆ 0.062; OR 0.21) having found only one rhupus patient positive for this allele. Another interesting nding is the relatively high frequency of HLA-DR2 in rhupus patients as compared to healthy controls, (gf 0.150 vs 0.090; P ˆ 0.076; OR 2.28). We also found a decreased frequency of HLA-DR7 in rhupus patients as compared to healthy controls (gf 0.025 vs 0.111; P ˆ 0.071; OR 0.22). Other minor differences among the groups were the increased frequency of HLA-DR10 in rhupus as compared to healthy controls (gf 0.050 vs 0.005; P ˆ 0.074) and also to SLE (gf 0.050 vs 0.0; P ˆ 0.043). However the Table 3 DR typing DR4 DR6 DR2 DR1 DR8 DR10 DR3 DR7 DR5 DR9
small size of the sample in the rhupus group makes it dif cult to describe these differences further. Also worth noting was the decreased frequency of HLADR5 in rhupus patients. Table 4 describes HLA-DR phenotypes in the rhupus group with a summary of the clinical characteristic in each one of the patients.
Discussion Rhupus is a rare clinical condition in which patients show signs and symptoms characteristic of both RA and SLE, which makes it dif cult to support the diagnosis of any of these diseases as an isolated entity. Thus, we considered it mandatory to establish a potential and clear de nition for rhupus.18,19 In the present study we de ned rhupus as erosive and symmetrical polyarthritis, accompanied by clinical signs and symptoms of SLE and the presence of autoantibodies with high speci city (ie native antiDNA antibody or anti-Sm). We found that Mexican patients with rhupus showed a disease onset characteristic for RA, but on average 4 years later they presented signs and symptoms that allowed the diagnosis of SLE, including laboratory abnormalities that suggested the coexistence of both diseases in the same individual. Predominant RA manifestations in all rhupus patients were erosive arthropathy with almost half of them having rheumatoid nodules. At the time of appearance of SLE manifestations, these were characterized by cutaneous and hematological alterations with mild renal damage. On the other hand more than 50% of the patients also presented serosal involvement.
Gene frequencies of HLA-DR alleles in rhupus patients compared to RA, SLE and healthy individuals Rhupus (n ˆ 40)
gf
Healthy (n ˆ 198)
gf
RA (n ˆ 96)
gf
SLE (n ˆ 150)
gf
13 7 6 5 5 2 1 1 0 0
0.325 0.175 0.150 0.125 0.125 0.050 0.025 0.025 0.000 0.000
47 31 18 10 33 1 11 22 22 3
0.237 0.155 0.090* 0.050** 0.165 0.005 0.055 0.111*** 0.111{ 0.015
34 18 12 4 13 3 4 5 3 0
0.354 0.187 0.125 0.041{ 0.135 0.031 0.041 0.052 0.015 0.000
40 27 23 15 15 0 19 11 0 0
0.246 0.180 0.153 0.092 0.092 0.000{{ 0.117§ 0.067 0.000 0.000
Healthy individuals, RA and SLE patients belong to cohorts from the same ethnic groups (Mexican Mestizo). gf, gene frequency; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus. *Rhupus vs healthy, P ˆ 0.076, OR 2.28, CI 95% (0.92 – 5.65). **Rhupus vs healthy, P ˆ 0.085, OR 2.47, CI 95% (0.89– 6.85). ***Rhupus vs healthy, P ˆ 0.071, OR 0.22, CI 95% (0.01 – 1.50). { Rhupus vs healthy, P ˆ 0.014, OR 0.00, CI 95% (0.00 – 1.04). { Rhupus vs RA, P ˆ 0.084, OR 3.00, CI 95% (0.85 – 10.6). {{ Rhupus vs SLE, P ˆ 0.043, OR 4.90, CI 95% (3.70 – 6.50). § Rhupus vs SLE, P ˆ 0.062, OR 0.21, CI 95% (0.03 – 1.55). Lupus
Rhupus JASimoÂn et al
Table 4
291
Comprehensive description of clinical and immunogenetic features of Mexican rhupus patients
Patients HLA-DR typing SLICC SLEDAI HAQ-D1 SJC Principal target organ 1
DR4-DR8
6
4
0.33
3
2 3 4 5 6 7 8 9
DR13-DR8 DR1-DR8 DR1-DR4 DR4-DR10 DR15-DR13 DR2-DR14 DR7-DR10 —
3 1 3 1 2 1 0 2
4 4 4 4 0 4 0 24
1.1 1.1 0.33 1 0.33 0.44 0 0.5
22 5 18 18 0 4 0 10
10 11 12 13 14 15 16 17 18 19 20 21 22
DR4-DR14 DR2-DR4 DR2-DR4 DR4-DR4 DR2-DR4 DR1-DR4 DR1-DR8 DR4-DR14 — DR2-DR8 DR13-DR14 DR4-DR4 DR1-DR3
2 6 6 2 1 2 1 1 2 3 1 1 1
4 0 4 0 4 4 4 5 4 4 4 0 4
1.1 0.66 1 0.55 0.55 0.44 0.22 0.33 0.33 1 0.77 0.66 0.55
28 0 4 0 22 24 12 0 6 28 30 0 26
Skin, serosa, kidney, heart and joints Skin, serosa and joints Skin and joints Skin, serosa, CNS and joints Skin, blood and joints Skin, kidney and joints Skin and joints Skin and joints Skin, kidney, lung, serosa, digestive tract and joints Skin and joints Skin, serosa and joints Skin, nervous system and joints Skin and joints Skin and joints Skin, serosa and joints Skin, kidney and joints Blood and joints Skin and joints Skin, kidney and joints Blood and joints Skin, serosa and joints Skin, serosa and joints
Predominant symptoms Antibodies RA
DNA, ANA, RF, La
RA RA RA RA Remission RA Remission SLE
DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA,
ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA,
RF, RF, RF, RF, RF, RF, RF, RF
aCL aCL La aCL, RNP aCL, La aCL, Ro, La Ro, aCL
RA Remission RA Remission RA RA RA Remission RA RA RA Remission RA
DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA, DNA,
ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA, ANA,
RF, RF RF, RF, RF, RF, RF RF, RF RF, RF RF, RF,
aCL aCL aCL aCL, La aCL aCL aCL, Ro aCL aCL, Ro
SJC, swollen joint count; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; ANA, antinuclear antibodies; RF, rheumatoid factor; aCL, anticardiolipin antibodies; RNP, ribonucleoproteins.
Regarding disease activity and organ damage, evaluation indexes showed that RA was more severe, while SLE damage and activity were considerably lower compared with a historic cohort of SLE patient of our Institute.28 Interestingly, although this cohort of patients showed a signi cantly high frequency of aCL antibodies, and more than 50% of them also showed high titers of aCL antibodies, none of the patients developed thrombosis or any other clinical condition suggestive of antiphospholipid syndrome. However, three patients had myelitis transverse, a manifestation that has been related in some cases to a thrombotic background.29 Rhupus patients are distinguished by the presence of HLA-DR4, DR2, DR6 and DR1 alleles, as shown in Table 3. This differs from RA and SLE patients in whom there is an increased frequency of HLA-DR1 in rhupus as compared to RA as well as a low frequency of HLA-DR3 allele when compared to SLE. The above-mentioned clinical ndings are similar to those described by Cohen,15 Panush2 and Brand,16 particularly the high prevalence of cutaneous, hematological and serosal manifestations, and the predominance of RA symptoms. However, Mexican rhupus patients differ from the Australian patients described by Cohen15 and Brand16 in that they showed low prevalence of renal damage, but were similar to North American patients studied by Panush.2 The HLA ndings are dif cult to compare because the only previous work16 that included HLA typing
described only ve Australian patients in whom HLADR2, DR3 and DR4 predominate. The fact that Mexican patients with rhupus have more RA- and less SLE-associated damage supports the theory of Mawson,30 who postulates that it is possible that RA and SLE are diseases with an inverse pathophysiological relationship (ie different HLA polymorphism, TH1 effect in RA and TH2 effect in SLE, different response to hormonal stimuli) as well as other unidenti ed factors such as changes in hormonal levels that occur during lifespan.17 On the other hand, the majority of Mexican rhupus patients showed high titers for RF, which is interesting because it has been proposed that RF could function as a protective element for organ damage, thereby explaining, at least partially, the low prevalence of renal damage observed in this cohort. This could be due to a blockade in the deposition of immune complexes as a result of the xation of RF to the antigen – antibody complexes.31–34 Finally the absence of clinical manifestations associated with antiphospholipid syndrome could be caused for cross-reaction of the RF to phospholipids instead of pathogenic phospholipid antibodies.35 The presence of high titer of aCL antibodies and the absence of reactivity against b2GP-I correlate with the absence of clinical manifestations associated with pathogenic antiphospholipid antibodies. Similar results haven been found in RA patients in which the prevalence of aCL antibodies has been estimated Lupus
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at about 30%; nevertheless, thrombotic manifestation in these patients is a rare clinical condition.36 Although some researchers have postulated that RF could be a protecting factor against thrombotic phenomena, there is no strong evidence to support the hypothesis.37 However, it is important to know the mechanism by which the aCL antibodies are generated in those patients and further investigations are needed. In conclusion, our study provides evidence that the coexistence of SLE and RA in a patient has a special clinical behavior, in which the signs and symptoms of RA prevail, with activity and existence of organic damage associated with SLE. In addition, rhupus patients have an absence of thrombotic events or morbidity during pregnancy in spite of the presence of aCL antibodies. Finally the rhupus could be sustained by the presence of certain HLA phenotypes, but the role of HLA molecules on the pathophysiology of this particular disease entity requires further investigation.
Acknowledgements Effy Solõ´s-Bolio, Martõ´n Zapata-Zun˜iga and Luis Felipe Flores-Sua´rez are thanked for suggestions and for reviewing the manuscript.
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