Joint Bone Spine 78 (2011) 241–245 Review Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology Maxime Samson a,b , Sylvain Audia a,b , Daniela Lakomy b,c , Bernard Bonnotte a,b , Christian Tavernier d , Paul Ornetti d,∗,e a Department of Internal Medicine and Clinical Immunology, Dijon University Hospital, 21079 Dijon, France CR Inserm U866, Lipids Nutrition Cancer, 21000 Dijon, France c Laboratory of Immunology, Dijon University Hospital, 21079 Dijon, France d Department of Rheumatology, hôpital général, Dijon University Hospital, 3, rue du Faubourg-Raines, 21000 Dijon, France e Inserm U887, 21078 Dijon, France b a r t i c l e i n f o Article history: Accepted 4 August 2010 Available online 30 October 2010 Keywords: Hypogammaglobulinemia Chronic inﬂammatory rheumatism Primary immunodeﬁciency Diagnosis Etiologies a b s t r a c t The discovery of hypogammaglobulinemia, which is deﬁned as a plasmatic level of immunoglobulin (Ig) under 5 g/L is rare in clinical practice. However, the management of immunodepressed patients in rheumatology, sometimes due to the use of immunosuppressive treatments such as anti-CD20 in chronic inﬂammatory rheumatisms, increases the risk of being confronted to this situation. The discovery of hypogammaglobulinemia in clinical practice, sometimes by chance, must never be neglected and requires a rigorous diagnosis approach. First of all, in adults, secondary causes, in particular lymphoid hemopathies or drug-related causes (immunosuppressors, antiepileptics) must be eliminated. A renal (nephrotic syndrome) or digestive (protein-losing enteropathy) leakage of Ig is also possible. More rarely, it is due to an authentic primary immunodeﬁciency (PID) discovered in adulthood: common variable immunodeﬁciency (CVID) which is the most frequent form of PID, affects young adults between 20 and 30 years and can sometimes trigger joint symptoms similar to those in rheumatoid arthritis; or Good syndrome, which associates hypogammaglobulinemia, thymoma and recurrent infections around the age of 40 years. In most cases, after conﬁrming hypogammaglobulinemia on a second test, biological examinations and thoracic-abdominal-pelvic CT scan will guide the diagnosis, after which the opinion of a specialist can be sought depending on the ﬁndings of the above examinations. At the end of this review, we provide a decision tree to guide the clinician confronted to an adult-onset hypogammaglobulinemia. © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. The discovery of hypogammaglobulinemia (< 5 g/L) during a check-up or the follow-up of a patient with chronic inﬂammatory rheumatism is a rare but not exceptional situation in everyday clinical practice. This biological abnormality is a real diagnostic challenge for practitioners. Indeed, a deﬁcit in immunoglobulins (Ig) brings into question the management of the rheumatism (iatrogenic effect of immunosuppressors, hematological complication of the chronic arthritis, or possibly polyarthritis directly related to Ig deﬁciency). All of these etiologies must be considered when complementary examinations are conducted to guide the diagnosis in cases of hypogammaglobulinemia. The ﬁrst question that needs to be answered is the possible iatrogenic cause of the hypogammaglobulinemia, in particular when a patient with inﬂammatory rheumatism is treated by immunosuppressors. The growing use of anti-CD20 antibodies in rheumatology, such as rituximab and soon ocrelizumab, has increased the risk of hypogammaglobulinemia occurring during ∗ Corresponding author. Tel.: +33 3 80 29 37 45; fax: +33 3 80 29 36 78. E-mail address: [email protected] (P. Ornetti). the follow-up, with the subsequent risk of infectious complications . The second question concerns the possible neoplastic complication of the chronic inﬂammatory rheumatism (rheumatoid arthritis (RA), Gougerot-Sjögren syndrome, systemic lupus erythematosus), notably lymphoma. The third question concerns a possible link between polyarthralgia presented by the patient and primary immunodeﬁciency (PID), even though the occurrence of PID in the form of inﬂammatory rheumatism in adulthood is rather exceptional. All things considered, the discovery of hypogammaglobulinemia requires a coherent diagnostic approach to determine the origin, so that an appropriate etiological treatment and if necessary polyvalent Ig replacement therapy can be implemented. After a short reminder about the physiopathology, this review will describe in the ﬁrst part the different etiologies that should be considered in cases of hypogammaglobulinemia, focusing on the most frequently causes seen in the ﬁeld of rheumatology. In the second part, a diagnostic decision tree is proposed to help practitioners confronted to this unusual clinicobiological situation in order to guide the choice of complementary examinations, before seeking the opinion of a specialist. 1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.09.016 242 M. Samson et al. / Joint Bone Spine 78 (2011) 241–245 Table 1 Function, molecular weight, serum levels, roles and half-life of the different immunoglobulins in adults. Heavy chain Molecular weight (kDa) Serum level (g/L) in adults Half-life in serum (days) Activation of classical complement pathway Activation of alternative complement pathway Placental transfer Binding to Fc receptors High afﬁnity binding to mastocytes and basophils a IgG1 IgG2 IgG3 IgG4 IgM IgA1 IgA2 IgD IgE ␥1 146 9 21 ++ − +++ + − ␥2 146 3 20 + − + − − ␥3 165 1 7 +++ − ++ + − ␥4 146 0.5 21 − − +/− +/− − 970a 1.5 10 ++++ − − − − ␣1 160 3.0 6 − + − + − ␣2 160 0.5 6 − − − + − ␦ 184 0.03 3 − − − − − 188 5 × 10−5 2 − − − + +++ Molecular weight of the pentamer. 1. Physiopathogenic aspects Igs are glycoproteins encountered either as membranous receptor (BCR) on B cells or produced by plasma cells as soluble molecules, called “antibodies” (Ab) and present in the serum and extracellular ﬂuids. There are different classes of Ig: IgG1 to IgG4, IgA1 and IgA2 , IgM, IgD and IgE, the function and half-life of which are very different, from several hours to several weeks (Table 1) . Only IgG, IgA and IgM play a role in anti-infectious immunity , through different mechanisms: neutralization of the antigen, bactericidal effect by activation of the classical pathways of complement (complement dependent cytotoxicity [CDC]), bactericidal effect via mechanisms of Ab-dependent cytotoxicity (antibodydependent-cell-mediated cytotoxicity [ADCC]), opsonization of rapidly developing extracellular bacteria such as Gram positive cocci and enterobacteria, thus facilitating phagocytosis. Concerning other classes of Ig, IgM are the predominant antibodies during the primary immune response and are essentially conﬁned to the intravascular compartment. IgM are powerful activators of classical complement pathway. IgG are the most abundant Ig and are equally distributed in the vascular and extravascular compartments. IgG interact with various receptors of the Fc fragment (Fc␥R) expressed by various subsets of immune cells, especially from the myeloid lineage such as monocytes or macrophages. IgG1 and IgG3 are also able to activate complement. The main role of IgA is to inhibit the adherence of bacteria on the mucosa of the respiratory, gastrointestinal and genital tracts. On serum protein electrophoresis (SPE), Ig migrate mainly in the zone of gammaglobulins. Normal levels vary with age. They range from 8 to 12 g/L in healthy adults. Hypogammaglobulinemia is deﬁned by a level less than 5 g/L. The term agammaglobulinemia describes situations that associate a level of gammaglobulins below 1 g/L and the absence of circulating B lymphocytes. As well as the fall in the level of gammaglobulins, other elements must be searched for on the SPE to begin the etiological investigation: a monoclonal peak or hypoalbuminemia. The latter could suggest a renal or digestive leakage of Ig. 2. Principal causes of hypogammaglobulinemia 2.1. Context of discovery The most frequent context of discovery in everyday practice is chance. A variety of clinical manifestations frequent in rheumatology (described as follows) may also lead to a prescription of SPE to screen for hypogammaglobulinemia. 2.1.1. Infection The main risk of a deﬁcit in Ig, whether primary or secondary, is an increased susceptibility to infections by encapsulated germs, such as Streptococcus pneumoniae and Haemophilus inﬂuenzae but also other Streptococci, Staphylococci or enterobacteria [4–6]. The infections are mainly recurrent and/or severe and concern the ENT or airways. In clinical practice, the onset of more than two episodes of sinusitis or pneumopathy in a year, or more than eight episodes of acute middle-ear otitis should bring to mind immune deﬁciency. 2.1.2. Autoimmune manifestations Autoimmune cytopenia , polyarthritis  or any other manifestation of immune dysfunction must lead to an SPE. However, no studies have validated the interest of the systematic prospective SPE in the onset of inﬂammatory rheumatism of unknown origin. 2.1.3. Peripheral lymphadenopathy, hepatomegaly and splenomegaly This clinical picture should lead to systematic SPE, since there is a question of hemopathy. In the majority of cases, the rheumatologist is faced with hypogammaglobulinemia with no clinical signs to help guide the diagnosis. It is this embarrassing clinical situation for the clinician that led us to propose the diagnostic decision tree in the next section. Simple biological surveillance is not recommended because the etiology needs to be found quickly. Indeed, the therapeutic approach may be totally different depending on the cause: interruption of an immunosuppressive treatment in case of iatrogenic hypogammaglobulinemia or implementation of a cytotoxic treatment in case of lymphoid hemopathy. 2.2. Etiologies It is possible to distinguish between primary causes (PID) and secondary causes of hypogammaglobulinemia with a wide variety of etiologies, which must be immediately searched for in adults. 2.2.1. Medication Many medicines can induce hypogammaglobulinemia, among which some are widely prescribed by rheumatologists (Table 2). Among the medicines on this list, all of which require a pharmacovigilance investigation, we can focus on the following: • antiepileptics and in particular carbamazepine (Tegretol® ), phenytoin (Dihydan® , Dilantin® ) and clonazepam (Rivotril® ). The deﬁciency affects all classes of Ig and is usually reversible and disappears with cessation of the treatment [9–11]. Complications due to infections are generally rare [12–16]; • disease modifying treatments for chronic inﬂammatory rheumatism, in particular d-penicillamine (Trolovol® ), gold salts and sulfasalazine (Salazopyrine® ). They principally cause IgA deﬁciency, but hypogammaglobulinemia has also been described, often with no clinically important consequences [17–22]. Some observations have suggested that methotrexate may also cause such deﬁciencies, but the risk seems to be lower in comparison with the treatments above ; • targeted biotherapies, employed in oncohematology and more recently in the treatment of immune dysfunction, in particular anti-CD20, such as rituximab (Mabthera® ). The onset of M. Samson et al. / Joint Bone Spine 78 (2011) 241–245 243 Table 2 Principal medicines that cause hypogammaglobulinemia. Frequent Quite frequent ® Cyclophosphamide (Endoxan ) Corticosteroids Rituximab (Mabthera® ) Imatinib (Glivec® ) Rare ® Carbamazepine (Tegretol ) Phenytoin (Di-hydan® , Dilantin® ) Sulfasalazine (Salazopyrine® ) Gold salts d-penicillamine (Trolovol® ) hypogammaglobulinemia under rituximab was ﬁrst described in oncohematology, in which it is often prescribed with other cytotoxic drugs. The princeps study reported hypogammaglobulinemia without infectious complications and with a deﬁciency that concerned almost exclusively IgM . Doubts were cast on the ﬁndings of this study by later studies that reported authentic hypogammaglobulinemia complicated by sometimes severe recurrent bacterial and viral infections, notably cytomegalovirus and varicella-zoster [4,25,26]. A retrospective study involving 97 patients treated by rituximab and cytotoxic drugs for malignant hemopathy, with a follow-up of 3 years, reported an incidence of 43% of infections (bronchitis, sinusitis and pneumoniae) that were not associated with episodes of neutropenia. In every case, hypogammaglobulinemia was associated with these infections . Hypogammaglobulinemia under anti-CD20 has also been reported in non-oncological indications, but generally the condition is moderately severe with no infectious complications . However, the risk of new-onset hypogammaglobulinemia increases with iterative treatments by rituximab, rising from less than 10% with the ﬁrst course to 30% with the fourth course . A recent study, with a follow-up of more than 6 years, showed that repeated treatment with rituximab in RA was not associated with a signiﬁcant increase in the number of severe episodes of infection. There was, however, a non-signiﬁcant trend towards an increase in severe infectious episodes in patients with a decrease in levels of IgM and IgG after several courses of rituximab ; • classically, corticosteroids cause lymphopenia mainly involving T CD4+ lymphocytes, but they may also induce hypogammaglobulinemia [30–34]. Generally speaking, the episodes are moderately severe (between 4 and 5 g/L) and essentially concern IgG (IgG1 in particular), and IgA and IgM to a lesser degree. These deﬁciencies have been reported in all types of corticosteroid therapy: low-dose long-term therapy (> 5 mg/d for more than 2 years) , or high-dose short-term therapy . The prevalence of hypogammaglobulinemia in these populations was around 12 to 17% [32,34]. The mechanism is still unclear: corticosteroids may increase catabolism  and reduce the synthesis of Ig via their action on intracellular pathways . It seems that the infectious consequences of this deﬁciency are slight, even though there is sometimes an impaired response to vaccines, notably anti-pneumococcal vaccine [32,34]; • there have also been reports associated with the use of aspirin and other immunosuppressors (azathioprine, ciclosporine), but such reports are rather exceptional. 2.3. Lymphoid hemopathy Once the medication-related etiology has been ruled out or put to one side, the clinician must focus the investigations on the search for malignant hemopathy in the case of new-onset hypogammaglobulinemia in adults, even in the absence of associated clinical Sodium valproate (Dépakine® ) Levetiracetam (Keppra® ) Clonazepam (Rivotril® ) Phenobarbital (Gardenal® ) Acetylsalicylic acid (Aspirin® ) Azathioprine (Imurel® ) Ciclosporine (Neoral® , Sandimmun® ) Captopril (Lopril® ) Thyroxine (Levothyrox® , l-thyroxine® ) Chlopromazine (Largactil® ) signs. This mainly concerns lymphoid hemopathy: chronic lymphocytic leukemia (CLL), multiple myeloma (MM), Waldenström’s disease or non-Hodgkin’s lymphoma (NHL). In MM, hypogammaglobulinemia may be linked to MM itself (light chain MM or non-secretory MM), or may be secondary to AL amyloidosis via nephrotic syndrome. Myelogram, serum immunoﬁxation and serum free light chain assay (FLC) will guide the diagnosis. A recent study showed that a rise in FLC or a hypogammaglobulinemia may precede the diagnosis of CLL by several years . This highlights how important it is to vigorously search for malignant hemopathy when hypogammaglobulinemia is discovered in adults. 2.3.1. Hypogammaglobulinemia due to renal, digestive or capillary leakage These causes are less frequent and are generally accompanied by clinical symptoms that guide the diagnosis, such as diarrhea or diffuse edema. Hypogammaglobulinemia due to renal or digestive leakage is generally associated with severe hypoalbuminemia (< 30 g/L). The discovery of signiﬁcant proteinuria will guide the diagnosis towards renal leakage. In cases of nephrotic syndrome, there will be a leakage of IgG rather than IgM or IgA. In the absence of signiﬁcant proteinuria, it is necessary to screen for protein-losing enteropathy. There may be rheumatological symptoms associated with the underlying disease (Crohn’s disease, systemic sclerosis, systemic lupus erythematosus. . .). The diagnosis is conﬁrmed by the discovery of an increase in fecal ␣1-antitrypsin clearance. This is the most sensitive screening test, though stool samples need to be collected on three consecutive days. The association of hypogammaglobulinemia and transient hypoalbuminemia may also be encountered in systemic capillary leak syndrome (Clarkson’s syndrome), though this is rather rare . The diagnosis is based on episodes of severe acute shock associated with hemoconcentration and hypoprotidemia (with hypoalbuminemia), which resolves during the acute episode. 2.3.2. Hypogammaglobulinemia due to impaired secondary production Etiologies of hypoalbuminemia associated with hypogammaglobulinemia is not restricted to extraplasma or extracorporeal protein leakage. Transient hypogammaglobulinemia may be found during an acute episode of infection or in contrast may indicate a chronic inﬂammatory process or severe malnutrition. 2.3.3. Primary hypogammaglobulinemia in adults PID is a rare cause of hypogammaglobulinemia and generally affects younger patients with regard to hypogammaglobulinemia due to a secondary cause. A family history of PID, a personal or family history of severe recurrent infections or severe hypogammaglobulinemia (< 2 g/L) with a total deﬁciency of IgA (< 0.07 g/L) suggest PID . Most PID do not lead to hypogammaglobuline- 244 M. Samson et al. / Joint Bone Spine 78 (2011) 241–245 mia . In adults, the two main PID to consider in the context of hypogammaglobulinemia are common variable immunodeﬁciency (CVID) and Good’s syndrome. 220.127.116.11. CVID. This is the most frequent PID (20.7% in a European cohort ) after selective IgA deﬁciency, with an incidence estimated at 1/75000 and a sex ratio of 1 . Most of these cases are sporadic and only 10 to 15% are familial . The condition is generally diagnosed between the age of 20 and 30 years. The diagnostic criteria for CVID are hypogammaglobulinemia affecting at least two isotypes of Ig, and recurrent sinopulmonary infections associated with an impaired response to vaccines [5,43]. Antibioticresistant infections are the most frequent clinical manifestations of CVID (85% of cases). These infections mainly concern the airways or the digestive system (50% of patients with CVID have chronic diarrhea). Approximately 25% of patients suffer from autoimmune manifestations, principally autoimmune cytopenia [5,7,44] but also: Biermer’s disease, autoimmune thyroiditis, vitiligo and less often with chronic mono, oligo or polyarthritis often mimicking RA . Generally speaking, these types of arthritis respond to Ig replacement treatment . Then, 10 to 22% of patients with CVID present a clinical picture of systemic granulomatosis similar to sarcoidosis. From an immunopathological point of view, CVID is an extremely heterogeneous disease [43,45]. In certain cases, there is an abnormal regulation of Ig gene expression. Certain CVID are linked to genomic abnormalities of B cell activating factor belonging to the TNF family (BAFF), a cytokine binding to different receptors (BAFF-R, TACI and BCMA) and playing an important role in the differentiation and survival of B cells. Recently, CVID and IgA deﬁciency have been associated with other mutations, most often heterozygous, of the TACI gene. This autosomal dominant form could account for 10 to 20% of CVID [46,47]. 18.104.22.168. Good’s syndrome. This is a particular form of adult-onset hypogammaglobulinemia, ﬁrst described in 1956 . The clinical presentation is similar to that in CVID but occurs at an older age, between 40 and 50 years. The clinical picture associates severe hypogammaglobulinemia, recurrent infections and thymoma. The prognosis and life expectancy are not as good as those in CVID. Certain biological abnormalities may guide the diagnosis: lymphopenia with an almost permanent absence of B cells, an increase in T CD8+ lymphocytes and a decrease in T CD4+ lymphocytes leading to an inbalance within the CD4/CD8 ratio; a deﬁciency in NK cells and neutrophils; and auto-immune erythroblastopenia. Diagnosis is conﬁrmed by the discovery of thymoma on thoracic imaging. Thymectomy does not modify the course of the disease. The presence of this syndrome justiﬁes a systematic thoracic CT scan in any case of adult-onset hypogammaglobulinemia with no obvious causes . Other PID leading to hypogammaglobulinemia are much more rare and generally diagnosed in childhood: Purtilo syndrome, hyper IgM syndromes [43,50], X-related agammaglobulinemia (Bruton) in boys and autosomal recessive or dominant agammaglobulinemia (which may manifest itself as rheumatism). Fig. 1. Diagnostic strategy in the face of adult-onset hypogammaglobulinemia (< 5 g/L). The grey boxes are diagnostics classically associated with hypoalbuminemia (< 30 g/L). HMG: hepatomegaly; SMG: splenomegaly; ADP: adenopathy; ENT: ear nose and throat; SPE: serum protein electrophoresis; FBC: fool blood count; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CVID: common variable immunodeﬁciency. *A thoracic-abdominal-pelvic CT scan is recommended if there is no obvious cause of the hypogammaglobulinemia. 3.1. The ﬁrst step The ﬁrst step is to conﬁrm hypogammaglobulinemia. It is essential to conﬁrm the condition with a second assay to avoid unnecessary explorations. Moreover, cryoglobulinemia may lead to “false” hypogammaglobulinemia, and thus needs to be screened for early on. This diagnosis may be revealed by the discovery of hypogammaglobulinemia in the presence of clinical signs compatible with cryoglobulinemia: polyarthritis, vascular purpura, neuropathy. . . In such cases, SPE at 37 ◦ C gives the precise levels of different gammaglobulins. However, in certain affections, cryoglobulinemia and authentic hypogammaglobulinemia may exist together: MM, NHL or lupus in particular. 3.2. The second step involves searching for a secondary cause 3. Diagnostic strategy in cases of adult-onset hypogammaglobulinemia Once hypogammaglobulinemia has been conﬁrmed in a second sample, a biological examination is necessary to narrow down the investigation. Then, depending on the clinical orientation, complementary examinations and specialist opinion reveal in most cases the origin of hypogammaglobulinemia (Fig. 1). In practice, a pharmacovigilance investigation needs to be carried out as well as further biological tests. In the absence of an obvious cause, a thoracic-abdominal-pelvic CT scan is required. Even after the pharmacovigilance investigation, the implication of a particular drug is sometimes difﬁcult to prove. From a therapeutic point of view, if possible, the interruption of a medical treatment must be considered. This may also serve as a diagnostic test. The time needed for the resolution of hypogammaglobulinemia varies M. Samson et al. / Joint Bone Spine 78 (2011) 241–245 considerably: several months for carbamazepine , up to 2 years for corticosteroids, and sometimes several years for anti-CD20 [36–37]. When the link is weak and the hypogammaglobulinemia severe (< 4 g/l) or when the resolution of hypogammaglobulinemia after cessation of the suspected drug is incomplete, it is essential to search for another cause of hypogammaglobulinemia. In the initial biological examination, a full blood count (FBC), inﬂammatory tests (ESR and C-reactive protein), albuminemia, proteinuria over 24 h, quantiﬁed Ig assay and serum immunoﬁxation will be performed systematically. Albuminemia < 30 g/L would guide the diagnosis towards a renal or digestive origin, whereas albuminemia > 30 g/L would suggest a hematological, drug-related or immunological cause. 3.3. The third step is the opinion of a specialist This is to complete the complementary investigations depending on the ﬁndings. At this stage, immunologists, internists, hematologists, nephrologists or gastroenterologists are most frequently consulted. After this consultation, treatment of hypogammaglobulinemia will be discussed. 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