Biological therapies are used in a large number of rheumatic and autoimmune diseases, predominantly under specific license but also off-label . Although these agents have demonstrated acceptable safety and tolerability profiles, autoimmune processes appearing after their use have increasingly been reported (Table 1). During the last 5 years we have investigated the characteristics of both systemic and organ-specific autoimmune processes triggered by biological agents . The purpose of this review is to update current knowledge on this topic.
SYSTEMIC AUTOIMMUNE DISEASES
We reviewed in 2008 the main characteristics of nearly 200 cases of systemic autoimmune diseases triggered by biological agents, overwhelmingly anti-Tumor Necrosis Factor (TNF) . The most frequent induced diseases were lupus, vasculitis and sarcoidosis, and less frequently antiphospholipid syndrome and inflammatory myopathies.
Lupus induced by biologics
More than 140 cases of lupus induced by biological agents (LIBAs) have been reported . Lupus-like mucocutaneous features are frequent and include malar rash, oral ulcers, discoid lupus or photosensitivity; a recent study  described five cases of chilblain lupus induced after anti-TNF therapy, a specific cutaneous form of lupus consisting of acral, ischemic-like lesions. Involvement of vital organs (kidneys or central nervous system, CNS) is infrequent (less than 10% of reported cases).
The majority of reported patients with LIBA have rheumatoid arthritis (RA) (72%) . Two recent studies focused on patients with inflammatory bowel disease (IBD) and ankylosing spondiloarthropathy (SpA) treated with anti-TNF agents. Beigel et al. found a prevalence of 44 and 16% of antinuclear antibodies (ANA) and anti-dsDNA, respectively, in 180 patients with IBD, whereas Puertas-Abreu et al. found much lower frequencies in 57 patients with SpA (7 and 3%, respectively). The figures were similar for the prevalence of induced systemic lupus erythematosus (SLE) (1% in IBD and 1.75% in SpA). Multivariate logistic regression analysis found that SLE was more frequent in older patients, and those with baseline-raised anti-dsDNA, but not in those with ANA . Less than 40% of reported cases of LIBA fulfilled the classification criteria for SLE. Some patients treated with anti-TNF may develop a systemic drug-induced syndrome (asthenia, general malaise, fever, cutaneous rashes, arthralgia and/or myalgia); this clinical presentation, together with the frequent induction of ANA/anti-dsDNA by anti-TNF agents, may result in a lupus-like presentation of a systemic reaction against the drug rather than a true drug-induced SLE.
Rituximab, which has been used extensively in the off-label treatment of patients with SLE (and less frequently, patients with antiphospholipid syndrome -APS-) , has recently been associated with the paradoxical development of SLE and APS [7,8].
Vasculitis induced by biologics
More than 140 cases of vasculitis induced by biological agents have been reported , although less than 10% fulfilled the American College of Rheumatology classification criteria for systemic vasculitis. Although the clinical spectrum of vasculitic features was wide, nearly 90% of patients presented cutaneous vasculitic involvement, followed by peripheral neuropathy and glomerulonephritis . Sokumbi et al. have recently reported eight patients with vasculitis induced by anti-TNF agents diagnosed at the Mayo Clinic during a 14-year period, and also found a predominance of cutaneous vasculitis.
A novel aspect is the possible association between TNF blockade and an enhanced susceptibility to the development of Henoch–Schönlein vasculitis, of which six cases have been reported [11–16]. A recent study linked the development of vasculitic features after TNF blockade with increased rheumatoid factor (RF) levels , and because etanercept has been associated with increased IgA RF levels , this might increase the risk of Henoch–Schönlein vasculitis in some patients treated with anti-TNF agents.
Although cases of vasculitis have been overwhelmingly related to the administration of the most-frequently used anti-TNF agents (infliximab, etanercept, adalimumab), Parekh et al. reported the first case of granulomatosis with polyangiitis associated with the administration of golimumab in a patient with RA.
Sarcoidosis induced by biologics
The clinical picture of sarcoidosis induced by biologics is of predominantly pulmonary and cutaneous involvement, with ocular involvement being infrequent . Fonollosa et al. describe seven patients presenting with sarcoid uveitis induced by anti-TNF therapy, and Seve et al. have reported an additional case. In all these cases, management included discontinuation of the biological agent, with the addition of immunosuppressive agents in five cases.
A recent review has analysed the main nonmalignant haematological complications associated with anti-TNF therapies [22▪▪].
Cytopenia induced by biologics
Bessissow et al.[22▪▪] analysed the main characteristics of 19 cases of thrombocytopenia related to TNF blockade (53% related to infliximab) with no reported serious complications. Data collected by drug manufacturers during clinical trials suggest an incidence of 0.1% for adalimumab and 0.5–1.9% for infliximab [22▪▪].
The same authors [22▪▪] reviewed 111 patients with neutropenia associated with anti-TNF. Neutropenia was mainly reported in RA patients (83% of cases) and associated with etanercept (73%), with most cases being transient neutropenia. Severe infections occurred in only four (4%) patients with no death related to infection. Patients with a previous history of drug-related neutropenia or with baseline neutropenia had a higher risk of developing neutropenia after receiving anti-TNF therapy. Neutropenia has also been reported in patients with lupus or vasculitis treated with tocilizumab [23,24].
Thrombotic events induced by biologics
Bessissow et al.[22▪▪] identified 91 cases of thrombosis related to anti-TNF therapy (69 venous and 20 arterial). However, the potential prothrombotic effect of biological agents is not clear . Some reported cases have associated prothrombotic conditions (severenephrotic syndrome, antiphospholipid antibodies), and baseline atherosclerotic processes might play a role in other patients, whereas some of the diseases for which patients received biological agents are prothrombotic per se (IBD, Behçet's disease or Wegener granulomatosis). Therefore, it may be difficult to differentiate whether thrombosis was induced by the biological agent or was associated with comorbidities or with the disease itself.
Hypereosinophilic processes induced by biologics
Isolated cases of eosinophilia associated with pulmonary involvement, eosinophilic cellulitis, eosinophilic fasciitis and atopic dermatitis have been reported in patients treated with anti-TNF agents [22▪▪,25].
Hemophagocytic syndrome induced by biologics
Hemophagocytic syndrome is an immune-mediated life-threatening disease characterized by fever, hepatosplenomegaly, cytopenia and the finding of macrophages in hematopoietic organs. Although hemophagocytic syndrome is overwhelmingly related to infectious triggers, it has also been associated with some drugs. There are 10 reported cases of hemophagocytic syndrome related to biological agents, including infliximab (n = 6) [26–31], etanercept (n = 3) [32–34] and adalimumab (n = 1) .
Anti-TNF therapy-associated disorders have emerged as a new class of drug-related demyelinating neurological disease (either of the peripheral or the CNS) . Demyelinating disorders are reported in postmarketing surveillance and isolated case reports of the first three anti-TNF agents to be licensed. Nozaki et al. recently reported seven additional cases seen in the Medical University of South Carolina between 2002 and 2010, including five cases of peripheral neuropathies (three demyelinating, one axonal and one small fibre polyneuropathies) and two cases of multiple sclerosis (MS)-like demyelinating lesions.
Central nervous system disease induced by biologics
We recently analysed 151 reported cases of demyelinating CNS processes after initiation of anti-TNF therapies, including mainly optic neuritis (80% of cases) but also MS/MS-like disease and myelitis . Encephalitis has recently been added to the spectrum of CNS diseases induced by biologics. Brigo et al. reported a patient who developed seizures after infliximab treatment for Crohn's disease, with MRI disclosing encephalopathy involving mainly cortical regions; the patient completely recovered a few days after infliximab withdrawal.
Peripheral neuropathies induced by biologics
Anti-TNF-related neuropathies were reviewed and classified by Stübgen . Of the 41 reported cases, 16 consisted of Guillain–Barre syndrome (including the Miller–Fisher variant in two), 10 were multifocal motor neuropathy with conduction block, five chronic inflammatory demyelinating polyradiculoneuropathy, seven peripheral neuropathies and two Lewis–Summer syndrome, a multifocal acquired demyelinating sensory and motor neuropathy .
Interstitial lung disease (ILD) is a known side effect of various drugs , including biological agents. There are 122 reported cases of ILD associated with biological agents in patients with underlying rheumatic diseases , which were related to anti-TNF agents in all cases but three, which were associated with rituximab.
A recent review by Hadjinicolaou et al.[42▪] analysed 121 cases of rituximab-related ILD, nearly all in patients with haematological malignancies, with only seven cases reported in patients with autoimmune diseases (focal-segmental glomerulosclerosis in one case, RA in three and SLE in three cases). Arulkumaran et al. reported an additional case in a patient with granulomatosis and polyangiitis.
Other pulmonary diseases reported after anti-TNF therapies are pulmonary hemorrhage and bronchiolitisobliterans organizing pneumonia .
Another recent review  studied ILD linked to the use of new biological agents and identified four patients included in five controlled trials of golimumab (one case of ILD, two cases of pneumonitis and one case of fibrosing alveolitis), three cases related to tocilizumab (one case each of new-onset ILD, idiopathic pulmonary fibrosis and allergic pneumonitis) and no cases associated with certolizumab or abatacept. An additional case of a fatal exacerbation of RA-associated ILD following tocilizumab therapy was recently reported .
Inflammatory ocular disease (IOD) may also occur after initiation of biological therapies: we have identified 69 cases of uveitis, 16 of scleritis and two cases of endogenous endophthalmitis . Wendling et al.[46▪▪] recently reviewed 152 cases (31 from the French ‘Club Rhumatismes et Inflamation’ registry and 121 cases from the literature), of which 84% were related to etanercept and 72% occurred in patients diagnosed with ankylosing spondylitis. The authors reported the resolution of uveitis in most cases even those in which the anti-TNF agent was continued, suggesting a weak role for anti-TNF agents in the induction of IOD. Some patients with SpA may develop uveitis after a successful articular response to anti-TNF therapy, suggesting differing etiopathogenic pathways in ocular and articular inflammation in response to TNF blockade.
Tocilizumab has recently also been associated with the development of IOD, including acute anterior uveitis and ulcerative keratitis associated with hypereosinophilia .
A novel paradoxical example of diseases induced by biologics is the development of new IBD or exacerbation of previously confirmed IBD. Two recent multicenter studies have identified 29 cases of IBD induced by anti-TNF agents. van Dijken et al. identified 13 cases of IBD (10 Crohn's disease) in patients with juvenile inflammatory arthritis treated with etanercept. In adults, Toussirot et al. reported 16 cases and reviewed 23 additional cases, observed mainly in patients with ankylosing spondylitis and overwhelmingly related to etanercept. The type of induced IBD was mainly Crohn's disease or Crohn's disease-like disease, with an estimated frequency of 0.15%.
Less often, IBD has been associated with other biologics, including rituximab in six cases [50–54]) and golimumab in three .
Autoimmune hepatitis has also recently been linked to biological therapies [56▪▪]. We characterized 19 cases of autoimmune hepatitis after initiation of anti-TNF therapy . Recent reports have focused on the management of induced autoimmune hepatitis, reporting the use of budenoside–mycophenolate  or a successful change of agent (adalimumab instead of infliximab, abatacept instead of adalimumab) [58,59].
Psoriasis is another example of the paradoxical relationship between biological agents and diseases for which their use is licensed. Collamer and Battafarano  reviewed 104 cases of psoriasis induced by anti-TNF therapy until September 2007 and, more recently, Shmidt et al. reported 56 additional cases from the Mayo Clinic, mainly presenting with plaques (48% of cases) and palmoplantar pustulosis (45%); psoriasis was resolved in more than 70% of cases in whom anti-TNF agents were discontinued in comparison with only 40% in whom biological therapy was continued.
Two recent studies [62▪,63] evaluated the induction of psoriasis by anti-TNF agents in IBD patients. Harrison et al. identified 25 (0.25%) new cases of psoriasis in 9826 patients treated with anti-TNF (with a higher rate in those receiving adalimumab) in comparison with none of 2880 patients treated with disease-modifying antirheumatic drugs. Werner de Castro et al. recently hypothesized that vitamin D may have a potential role in the treatment of psoriasis induced by anti-TNF agents.
Psoriasis induced by rituximab has been less frequently reported. Thomas et al. found only seven cases in 1927 patients with RA (two cases of new-onset psoriasis and five of a flare of pre-existing psoriasis). The first cases of psoriasis associated with abatacept [67–69] and anakinra  have been reported.
The list of cutaneous diseases other than psoriasis induced by biological agents is wide and includes pyoderma gangrenosum, pustular folliculitis, erythema multiforme, lichenoid reactions, interface dermatitis, granuloma annulare, neutrophilic eccrine hidradenitis and Sweet's syndrome [7,71].
OUTCOMES OF INDUCED AUTOIMMUNE DISEASES
Autoimmune diseases associated with biological agents may appear during the first day of treatment or after years of use, with a mean time of nearly 40 weeks . Fortunately, more than 85% of reported cases have a favorable outcome , but some induced autoimmune diseases have poorest outcomes, especially ILD and CNS demyelinating disease (resolution in 63–70% of cases). The mortality rate of induced autoimmune diseases is less than 1%, and death occurs mainly during the first 6 weeks of therapy. The majority of reported deaths are related to the development of ILD, especially in patients already diagnosed with interstitial pulmonary disease.
Management of induced autoimmune disease includes cessation of biological therapy in more than 90% of reported cases . Corticosteroid therapy has been used in nearly 50% of cases and immunosuppressive agents/intravenous immunoglobulins in 15%. The use of a different biological agent to treat the induced autoimmune disease has been reported by Diaz et al., who successfully treated three patients with lupus induced by anti-TNF agents with rituximab, and by Sansó Sureda et al., who used ustekinumab for treating both adalimumab-induced psoriasis and the underlying Crohn's disease.
We reviewed 54 reported cases in which anti-TNF therapy was reinitiated to control the active underlying disease once the induced autoimmune disease was resolved; a rechallenge phenomenon (reappearance or worsening of symptoms on re-exposure to the same agent) was observed in 65% of cases in comparison with only 29% of cases who relapsed after using a different biological agent . Recent data suggest the successful use of certolizumab in patients with lupus induced by established anti-TNF agents. Verma et al.[74▪] successfully initiated certolizumab in six cases of lupus induced by established anti-TNF agents, whereas Subramanian et al. reported 13 cases of lupus-like disease induced by anti-TNF agents in patients with IBD, of whom six were retreated with certolizumab with only one relapse (17%) and two with adalimumab (one relapse, 50%).
More than 1500 cases of nearly 50 different systemic and organ-specific autoimmune diseases have been reported in patients with underlying autoimmune diseases treated with biological therapies. Although almost all reports come from small case series or isolated case reports due to the low prevalence of these induced processes (<1%), there are increasing reports from controlled trials and large postmarketing studies. Logically, nearly all these processes occur in diseases for which biological agents are licensed and extensively used (patients with RA, SpA, psoriasis and IBD exposed to anti-TNF therapy). Paradoxically, for many of these drug-related autoimmune processes, current treatment indications include the very biological agent producing the adverse event. As the use of biologics other than anti-TNF agents expands, the number and diversity of induced autoimmune disorders should be expected to increase.
However, the level of association between a new agent and the induced autoimmune disease should always be evaluated according to the estimated total population exposed to this agent. The appearance of new biologics targeting other molecules may be providential, as it could increase the number of agents that we could use to control the underlying disease in place of the agent causing the induced autoimmune process.
In spite of the limited quality of the available data, some recommendations for the management of patients with autoimmune diseases triggered by biological agents may be suggested as follows:
- Careful pretherapeutic clinical evaluation (pay special attention to pre-existing features suggestive of lupus, vasculitis, CNS or pulmonary involvement).
- Baseline laboratory work-up (hemogram, liver tests, hepatitis B virus, hepatitis C virus and HIV tests) and chest radiograph.
- Pretherapeutic immunological study (ANA, anti-dsDNA, RF, aPL and ANCA) available at least 6 months before initiation of therapy.
- In patients with suspected previous pulmonary/CNS involvement, a pretherapeutic specific imaging evaluation (computed tomography pulmonary scan, cerebral MRI) is recommended.
- Carefully evaluate nonspecific symptoms like asthenia, general malaise, fever, cutaneous rashes, arthralgia and/or myalgia suggestive of a systemic drug-induced reaction before diagnosing a true induced autoimmune disease.
- Discontinuation of biological therapy is mandatory in patients with involvement of internal organs and recommended in patients with mild features (cutaneous, articular and/or general involvement).
- Continuation of biological therapy may be considered, with a closer follow-up, only in patients with mild features when biological therapy is considered essential to control the underlying disease.
- Corticosteroids and/or immunosuppressive agents may be required in severe cases to control the induced autoimmune disease in spite of the withdrawal of the biological agent.
- Once the induced autoimmune disease is resolved, reinitiate biological therapy with a different class of agent in order to control the active underlying disease.
The BIOGEAS Study group was supported financially by educational grants from Roche and Abbott.
The authors wish to thank David Buss for his editorial assistance.
The members of the Spanish Study Group of Biological Agents in Autoimmune Diseases (BIOGEAS) of the Spanish Society of Internal Medicine (SEMI) are as follows:
M. Ramos-Casals (Coordinator, Hospital Clinic, Barcelona)
M.M. Ayala (Hospital Carlos Haya, Málaga)
M.J. Barragán-González (Hospital Valle del Nalón, Asturias).
X. Bosch (Hospital Clinic, Barcelona)
A. Bové (Hospital Clinic, Barcelona)
P. Brito-Zerón (Hospital Clinic, Barcelona)
G. Calvo (Hospital Clinic, Barcelona)
J.L. Callejas (Hospital San Cecilio, Granada)
L. Caminal-Montero (Hospital Central Asturias)
M.T. Camps (Hospital Carlos Haya, Málaga)
J. Canora-Lebrato (Hospital Universitario de Fuenlabrada, Madrid)
M. J. Castillo-Palma (Hospital Virgen del Rocío, Sevilla)
A. Colodro (Complejo Hospitalario de Jaen)
M.J. Cuadrado (St Thomas Hospital, London)
E. de Ramón (Hospital Carlos Haya, Málaga)
C. Díaz-Lagares (Hospital Clínic, Barcelona)
M.V. Egurbide (Hospital Cruces, Barakaldo)
D. Galiana (Hospital de Cabueñes, Gijón)
F.J. García Hernández (Hospital Virgen del Rocío, Sevilla)
A. Gil (Hospital La Paz, Madrid)
R. Gómez de la Torre (Hospital San Agustín, Avilés)
R. González-León (Hospital Virgen del Rocío, Sevilla)
C. Hidalgo (Hospital Virgen de las Nieves, Granada)
J. Jiménez-Alonso (Hospital Virgen de las Nieves, Granada)
M.A. Khamashta (St Thomas Hospital, London)
A. Martínez-Berriotxoa (Hospital Cruces, Barakaldo)
F. Medrano (Hospital Universitario de Albacete)
M.L. Micó (Hospital La Fe, Valencia)
S. Muñoz (Hospital Clinic, Barcelona)
C. Ocaña (Hospital Virgen del Rocío, Sevilla)
J. Oristrell (Hospital ParcTaulí, Sabadell)
N. Ortego-Centeno (Hospital San Cecilio, Granada)
L. Pallarés (Hospital Son Dureta, Mallorca)
I. Perales-Fraile (Hospital Universitario de Fuenlabrada, Madrid)
M. Pérez de Lis (Hospital Meixoeiro, Vigo)
R. Perez-Alvarez (Hospital Meixoeiro, Vigo)
J. Rascón (Hospital Son Dureta, Mallorca)
S. Retamozo (Hospital Clinic, Barcelona)
J.J. Ríos-Blanco (Hospital La Paz, Madrid)
A. Robles (Hospital La Paz, Madrid)
G. Ruiz-Irastorza (Hospital Cruces, Barakaldo)
L. Saez (Hospital Universitario Miguel Servet, Zaragoza)
G. Salvador (Hospital de Sagunt, Valencia)
J. Sánchez-Roman (Hospital Virgen del Rocío, Sevilla)
A. Selva-O’Callaghan (Hospital Valld’Hebron, Barcelona)
C.P. Simeón (Hospital Valld’Hebron, Barcelona)
A. Sisó (CAPSE/GESCLINIC, Barcelona)
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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